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About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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December 8, 2014

That Same Sort of Job

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Posted by Derek

I was reading this interesting commentary on the bizarre meltdown of The New Republic, when something struck me. Megan McArdle is talking here about how hard it can be to manage journalists:

Both journalists and non-journalists usually fail to understand just how weirdly different media companies are from other sorts of firms, which means they don't understand that experience with one side gives you virtually zero insight into how the other kind works. . .

. . .Prominent among the unique challenges of the media manager: the frequent tension between the actions that build your reputation and audience, and those that monetize it; the difficulty of getting creative types to produce great stuff on demand; the astonishing amount of autonomy that journalists need, because it's impossible to write hard guidelines, and too expensive to supervise long hours of reporting and typing; the fact that great writers are frequently terrible managers and editors, which screws up the normal management pyramid; the simultaneous need for speed and accuracy; the fact that media employment selects for a cluster of personality traits that resists closer management;. . .

All you have to do is substitute "scientist" or "researcher" for every mention of "journalist" or "writer" in there. Sounds pretty familiar, doesn't it?

Comments (18) + TrackBacks (0) | Category: Business and Markets | Life in the Drug Labs | Life in the Drug Labs

That Same Sort of Job

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Posted by Derek

I was reading this interesting commentary on the bizarre meltdown of The New Republic, when something struck me. Megan McArdle is talking here about how hard it can be to manage journalists:

Both journalists and non-journalists usually fail to understand just how weirdly different media companies are from other sorts of firms, which means they don't understand that experience with one side gives you virtually zero insight into how the other kind works. . .

. . .Prominent among the unique challenges of the media manager: the frequent tension between the actions that build your reputation and audience, and those that monetize it; the difficulty of getting creative types to produce great stuff on demand; the astonishing amount of autonomy that journalists need, because it's impossible to write hard guidelines, and too expensive to supervise long hours of reporting and typing; the fact that great writers are frequently terrible managers and editors, which screws up the normal management pyramid; the simultaneous need for speed and accuracy; the fact that media employment selects for a cluster of personality traits that resists closer management;. . .

All you have to do is substitute "scientist" or "researcher" for every mention of "journalist" or "writer" in there. Sounds pretty familiar, doesn't it?

Comments (18) + TrackBacks (0) | Category: Business and Markets | Life in the Drug Labs | Life in the Drug Labs

October 23, 2014

Atmospheric Conditions

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Posted by Derek

Well, I've been busy sciencing away all morning, and we're having the kind of weather outside that makes a person want to stay indoors and do chemistry: rainy, chilly, and windy. You wonder why more big chemical discoveries don't come out of the places that have these sorts of conditions all the time!

Air handling and climate control notwithstanding, this sort of weather naturally raises the humidity, and if I were having to worry about tiny moisture-sensitive reactions, these are not the conditions I would pick. But neither were the conditions back in the Southern US in the summertime - some afternoons down there, the humidity is like sticking your head into a dishwasher. How anyone managed to get chemistry done under those conditions in the days before air conditioning is a mystery to me.

My German lab, on my post-doc, was not air-conditioned (in keeping with much of the rest of the country) and had windows that opened, as very few other labs I've worked in ever have. But a German summer is not like an Arkansas one - in fact, every so often, a German summer can resemble an Arkansas winter. Even so, we did have to watch the air-sensitive reagents, because conditions certainly varied. My summer research in Arkansas, though, back when I was an undergrad, was conducted on the fourth floor of a building with no windows, so when the air conditioning went out there, we basically had to flee after a while. The plastic caps used on the old ether cans would come popping off in the heat, and that was a pretty good sign that it was time to pack it in for the day.

And my grad-school lab was also a windowless cave, thanks to the design of the building, but I really didn't get to experience un-air-conditioned chemistry in there. If the AC was down, it meant that the whole air handling system was messed up, which meant that the lab itself rapidly became uninhabitable. Decades of grad student-led contamination led to a pestilential funk that you could breast-stroke through; there was no way that I was going to hang around and experience it for any longer than I had to.

But all this is first-world complaining - I've had Indian colleagues, among others, describe really severe climate-influenced lab work. So feel free to add your worst examples in the comments, but expect the folks with experience in the tropics to win the competition!

Comments (59) + TrackBacks (0) | Category: Life in the Drug Labs

September 10, 2014

Grinding Up Your Reactions

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Posted by Derek

I'd seen various solventless reactions between solid-phase components over the years, but never tried one until now. And I have to say, I'm surprised and impressed. I can't quite say which literature reference I'm following, unfortunately, because it might conceivably give someone a lead on what I'm making at the moment, but it's a reference that I found as a new technique for an old reaction. Doing it in solution gives you a mess, but just grinding up the two solid reactants and the reagent, in a mortar and pestle, gives you a very clean conversion. The stuff turns into a sort of ugly clay inside the mortar, but it looks are deceiving. I feel like an alchemist. Consider me a convert to the solventless lifestyle - I'll try this again on some other reaction classes when I get the chance. Anyone else ever ground up some solids and made a new product?

Comments (41) + TrackBacks (0) | Category: Life in the Drug Labs

August 18, 2014

One of Those Days

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Posted by Derek

I spent the morning in the lab pretty much destroying whatever I touched: wrong solvents for chromatography, dropping things in the sink, bumping solutions all over the inside of my rota-vap. This is, though, a Monday, so at least I have that to blame. But if everyone started out the week the way I did, then scientific progress came to a juddering halt around 11 AM EST. My hope is that I can be less of a wrecking ball during the rest of the day and start working my way back into positive territory.

Comments (17) + TrackBacks (0) | Category: Life in the Drug Labs

July 16, 2014

What Structures Have Turned on You?

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Posted by Derek

When you ask a bunch of medicinal chemists to look over a list of structures - screening hits, potential additions to the compound collection, that sort of thing - you'll find that everyone will cross some of them off. But the agreement between the chemists on which ones need to go, that's the tough part. It's been shown that we don't overlap very much in our preferences, at least when it comes to the structures we'd prefer not to try to advance. That's because we don't overlap as well as we think we do when it comes to the rules we're using.

So here's a question, which might illustrate the point: what compound classes or scaffolds have you been burned by? I think that's one big factor that we all use when we're evaluating one of those compound lists - which ones are in that "Fooled me once" category? For me, a recent experience with NH pyrroles has me reluctant to go there again. And I'm not interested in things with napthalenes hanging off of them, naproxen notwithstanding. I'd also rather not see Mannich products, since I've personally seen a number of those misbehave.

So what's on your list? I think that everyone can agree on things like rhodanines, although even those have their partisans. But what semi-decent looking compounds will you go ahead and blackball, based on your own nasty experiences with them?

Comments (17) + TrackBacks (0) | Category: Life in the Drug Labs

July 14, 2014

How to Run a Drug Project: Are There Any Rules at All?

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Posted by Derek

Here's an article from David Shayvitz at Forbes whose title says it all: "Should a Drug Discovery Team Ever Throw in the Towel?" The easy answer to that is "Sure". The hard part, naturally, is figuring out when.

You don’t have to be an expensive management consultant to realize that it would be helpful for the industry to kill doomed projects sooner (though all have said it).

There’s just the prickly little problem of figuring out how to do this. While it’s easy to point to expensive failures and criticize organizations for not pulling the plug sooner, it’s also true that just about every successful drug faced some legitimate existential crisis along the way — at some point during its development , there was a plausible reason to kill the program, and someone had to fight like hell to keep it going.

The question at the heart of the industry’s productivity struggles is the extent to which it’s even possible to pick the winners (or the losers), and figuring out better ways of managing this risk.

He goes on to contrast two approaches to this: one where you have a small company, focused on one thing, with the idea being that the experienced people involved will (A) be very motivated to find ways to get things to work, and (B) motivated to do something else if the writing ever does show up on the wall. The people doing the work should make the call. The other approach is to divide that up: you set things up with a project team whose mandate is to keep going, one way or another, dealing with all obstacles as best they can. Above them is a management team whose job it is to stay a bit distant from the trenches, and be ready to make the call of whether the project is still viable or not.

As Shayvitz goes on to say, quite correctly, both of these approaches can work, and both of them can run off the rails. In my view, the context of each drug discovery effort is so variable that it's probably impossible to say if one of these is truly better than the other. The people involved are a big part of that variability, too, and that makes generalizing very risky.

The big risk (in my experience) with having execution and decision-making in the same hands is that projects will run on for too long. You can always come up with more analogs to try, more experiments to run, more last-ditch efforts to take a crack it. Coming up with those things is, I think, better than not coming up with them, because (as Shayvitz mentions) it's hard to think of a successful drug that hasn't come close to dying at least once during its development. Give up too easily, and nothing will ever work at all.

But it's a painful fact that not every project can work, no matter how gritty and determined the team. We're heading out into the unknown with these drug candidates, and we find out things that we didn't know were there to be found out. Sometimes there really is no way to get the selectivity you need with the compound series you've chosen - heck, sometimes there's no way to get it with any compound series you could possibly choose, although that takes a long time to become obvious. Sometimes the whole idea behind the project is flawed from the start: blocking Kinase X will not, in fact, alter the course of Disease Y. It just won't. The hypothesis was wrong. An execute-at-all-costs team will shrug off these fatal problems, or attempt to shrug them off, for as long as you give them money.

But there's another danger waiting when you split off the executive decision-makers. If those folks get too removed from the project (or projects) then their ability to make good decisions is impaired. Just as you can have a warped perspective when you're right on top of the problems, you can have one when you're far away from them, too. It's tempting to thing that Distance = Clarity, but that's not a linear function, by any means. A little distance can certainly give you a lot of perspective, but if you keep moving out, things can start fuzzing back up again without anyone realizing what's going on.

That's true even if the managers are getting reasonably accurate reports, and we all know that that's not always the case in the real world. In many large organizations, there's a Big Monthly Meeting of some sort (or at some other regular time point) where projects are supposed to be reviewed by just those decision makers. These meetings are subject to terrible infections of Dog-And-Pony-itis. People get up to the front of the room and they tell everyone how great things are going. They minimize the flaws and paper over the mistakes. It's human nature. Anyone inclined to give a more accurate picture has a chance to see how that's going to look, when all the other projects are going Just Fine and everyone's Meeting Their Goals like it says on the form. Over time (and it may not take much time at all), the meeting floats away into its own bubble of altered reality. Managers who realize this can try to counteract it by going directly to the person running the project team in the labs, closing the office door, and asking for a verbal update on how things are really going, but sometimes people are so out of it that they mistake how things are going at the Big Monthly Meeting for what's really happening.

So yes indeed, you can (as is so often the case) screw things up in both directions. That's what makes it so hard to law down the law about how to run a drug discovery project: there are several ways to succeed, and the ways to mess them up are beyond counting. My own bias? I prefer the small-company back-to-the-wall approach, of being ready to swerve hard and try anything to make a project work. But I'd only recommend applying that to projects with a big potential payoff - it seems silly to do that sort of thing for anything less. And I'd recommend having a few people watching the process, but from as close as they can get without being quite of the project team themselves. Just enough to have some objectivity. Simple, eh? Getting this all balanced out is the hard part. Well, actually, the science is the hard part, but this is the hard part that we can actually do something about.

Comments (14) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Life in the Drug Labs

June 26, 2014

Absence Makes the Ideas Flow?

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Posted by Derek

Something I've noticed for many years now is that I tend to get the most number of chemical ideas - bench chemistry relating to my current work - when I'm in a big conference room far removed from my actual lab. Take me off site, send me to a distant meeting, and I get all sorts of brainstorms about what I should be doing in front of my hood. Does anyone else have this problem (if it is a problem?) I write down all the things I'm thinking of, naturally, so I can actually get around to doing them. But it's funny how the ideas seem to come out of hiding once I'm not actually doing the work.

Comments (53) + TrackBacks (0) | Category: Life in the Drug Labs

June 25, 2014

That's Just Too Colorful

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Posted by Derek

orange%20compound.jpgI have just made the most eyewateringly fluorescent orange compound of my entire chemical career. It's not in a structural class that normally I would be exploring, but it's been a while since I was on a normal project, so that's fine. But this thing - yikes. I keep telling myself "It's a probe, it's a tool, don't worry", as all my med-chem instincts tell me that a compound like this, whose color would blend in only with a pile of nasturtiums, cannot be clean. But it is. And those same instincts keep telling me that a compound this wildly colorful can never, ever be of any use in a biological setting. It's an irrational prejudice, but it dies hard.

Comments (57) + TrackBacks (0) | Category: Life in the Drug Labs

May 21, 2014

This All Too Open Office

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Posted by Derek

Many of you will have seen this article in C&E News on open-plan offices. Its author, Alex Scott, got in touch with me while writing it, and there are a lot of interesting things in it. But as Chemjobber says here, some of the claims that Scott's interviewees make are a bit hard to believe. I refer specifically to one Bill Odell. I had exactly the same reaction Chemjobber did when I read this part:

Bill Odell is the director of the science and technology group for design and architecture firm HOK and has been creating open-plan science buildings for three decades. He sees evidence that open-space research is better at meeting the needs of scientists as science becomes ever more complex and multidisciplinary.

HOK recently designed an open-plan research building in the U.S. that Odell says has enabled a leading pharma company’s scientists to reduce lab size and increase office space by moving temporary walls just as a drug candidate goes from the lab development phase into administration-heavy clinical trials.

Now, this truly sounds like a load of crap. How, exactly, does lab space get turned into administrative office space, and vice versa? Useful lab space is a very specialized thing to build - benches and hoods, air handling, water, gas, and electricity lines, shelving. None of that translates into office space, does it? And if this is a "leading pharma company", why are they so tight for space that they would contemplate such a thing? And how do they only have this one drug candidate whose passage through development changes the entire layout of the building as it progresses into the clinic? Isn't there, like, some other compound coming through at some point? None of that statement makes any sense. If anyone from HOK would like to take another crack at explaining it, my inbox is waiting.

One problem with any discussion of open-plan labs is that no one is quite sure what the term means. (A cynic would say that it means whatever the architects think you'll buy). Does it mean that no one has a permanent desk? Does it mean that no one has a door? Do people share a lot of lab equipment, or is the number of people per lab more than usual? Or are the labs pretty much like usual, but surrounded by lots of glassy spaces and coffee areas designed to make people run into each other? These are all different things, but they get lumped together when the phrase "open plan" comes up.

Chemjobber also highlights another Odell statement that seems to have been pulled right out of thin air (or from some other handy storage compartment):

Any dislike of open-plan science buildings is something that Odell predicts will fade over time because it is the older generation of scientists accustomed to closed environments who oppose open-plan buildings. “That is because people in their 30s and 20s work in a completely different way than anyone older. Putting them in a cell is just anathema,” he says, citing examples of how the younger generation prefer to use headphones and work on mobile electronic devices in open spaces.

Here's a useful rule: whenever someone tries to tell you that you don't understand about this new generation, because they're so totally different, which makes them act so totally differently than anyone older - you're being sold something. Marketers absolutely love to pretend that this is how the world works, as do many varieties of consultant, because it gives them a chance to sell their hot, happening expertise that you don't have, you see, because you're behind the times. Kids these days! You just have no idea.

But one small compensation of experience is that you note the same sales pitches coming around again and again. This one, which I call Dig the New Breed, is a perennial. There are indeed such things are generational differences, although you'll have a fun time trying to define "generation". (For instance, I was born in 1962, and despite what article after article will tell you, I have little in common with the classic "Baby Boom" generation. I was seven years old when Woodstock was going on; it didn't have much effect on me). But generalizing about these differences is usually a sign of lazy thinking (or, as noted, a sign of a sales pitch). I see that Odell is sort of hand-waving in everyone from 20 to 40, but you know, that that's a pretty heterogeneous group, like any other 20-year span in the population. They're not all chatty wanderers wearing headphones, happy to mill around all day in a great big cavern of randomly placed desks, especially ones that used to be lab benches.

Personally, I'm sticking with another line from Scott's article as the real take-home about open office plans. That's the one where he says that "open-space labs are cheaper to construct and operate.". Those are the magic words; all the stuff about collaboration and productivity comes afterwards, and whether there's anything to it or not is for me still an open question. It's certainly possible to design research buildings that reduce productivity, but increasing it is elusive (and elusive to measure). But no matter what, there's one area that never does seem to turn into a big, open, collaborative share-space: wherever the higher-level executives work. Funny how that happens.

Comments (39) + TrackBacks (0) | Category: Life in the Drug Labs

May 13, 2014

How Many Elements Have You Used, As Elements?

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Posted by Derek

I've written before about how many different elements I've used over the course of my chemical career, but here's a more demanding variant of that question: how many elements have you used in their elemental form? Here's my list - I'm including things that have been transformed, and some that haven't, but I'm not counting structural metals:

Hydrogen (hydrogenations, naturally)
Helium (carrier gas in GC)
Lithium (Barbier reactions, Birch reduction, etc.)
Carbon (decolorizing)
Nitrogen (inert gas)
Oxygen (oxidized a couple of anions over the years, etc.)
Sodium (making alkoxides, Birch reduction)
Magnesium (Grignard formation)
Phosphorus (red phosphorus in a halogenation)
Sulfur (cleaning up mercury!)
Argon (inert gas)
Potassium (drying solvents)
Iron (reduction of nitro groups)
Nickel (as Raney nickel)
Copper (making carbenes, among other things)
Zinc (reductions, zinc-copper couple)
Selenium (as a catalyst in a Kjeldahl, years ago as an undergraduate)
Bromine (many nasty brominations)
Ruthenium (hydrogenation catalyst)
Rhodium (high-pressure hydrogenation, once)
Palladium (hydrogenation)
Silver (well, produced some in a Tollens)
Tin (reduction)
Iodine (Grignard initiation, TLC)
Platinum (hydrogenation)
Mercury (vacuum lines, etc.)

So that takes me to 24 26 elements used in their pure forms, 21 of them as part of actual chemical transformations, more or less. Notable omissions are sulfur, which I don't think I've actually used as elemental sulfur, and chlorine (not quite). There are a few other opportunities (silver, samarium, and indium I've seen used as the metals, for example), but not that many, at least for an organic chemist.

Updates are due to people reminding me of things in the comments! And no, I don't think I've ever used samarium metal itself, although that's certainly another easy one to rack up. As for Raney nickel, it starts out being an aluminum/nickel alloy, but my impression was that the aluminum got pretty well eaten out of it by all that sodium hydroxide. I've made the stuff (once), and a more tedious experience I do not wish for. I've also realized that I used elemental sulfur one time as an undergrad, along with elemental copper, to make cupric sulfide, which is perhaps a more elevated activity than cleaning up mercury spills.

Comments (51) + TrackBacks (0) | Category: Life in the Drug Labs

April 17, 2014

Gitcher SF5 Groups Right Here

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Posted by Derek

I think that several of us in medicinal chemistry have been keeping our eyes out for a chance to work in a pentafluorosulfanyl (SF5) group. I know I have - I actually have a good-sized folder on the things, and some of the intermediates as well, but I've never found the right opportunity. Yeah, I know, they're big and greasy, but since when that that ever stop anyone in this business?

Well, here are are some new routes to (pentafluorosulfanyl)difluoroacetic acid, a compound that had previously only existed in a few scattered literature reports (and those from nasty chemistry). So we all have even less of an excuse to start polluting enhancing our screening collections with these things. Who's first?

Comments (24) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs

February 12, 2014

The Bread Rolls of Synthesis

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Posted by Derek

Over at Colorblind Chemistry, I came across a quote from Fritz Haber, writing about his thesis work:

The thesis is miserable. One and a half years of new substances prepared like baker’s bread rolls… and in addition, lots of negative results just where I was looking for significant results, and further, results that I cannot even publish because I fear that a competent chemist will find them and prove to me that the camel is missing its humps. One learns to be modest.

Now, Haber was definitely someone to take seriously. He's showing up in "The Chemistry Book", for sure, both for his historic ammonia process and his work in chemical warfare. He was a good enough chemist to know that his doctoral work was not all that great, although he seems to have followed my own recommended path to get that degree as soon as is consistent with honor and not making enemies.

The post's author, MB, wonders what this says about organic synthesis in general. How much of it is just baking bread rolls, and how bad is that? My own take is that the sort of think that Haber was regretting is the lowest form of synthesis. We've all seen the sorts of papers - here is a heterocyclic core, of no particular interest that anyone has ever been able to show. Here it has an amine. Here are twenty-five amides of that amine. Here is our paper telling you about them. Part fourteen in a series. In six months, the sulfonamides. This sort of things gets published, when it does, in the lowest tiers of the journals, and rightly so. There's nothing wrong with it (well, not usually, although this stuff isn't always the most careful work in the world). But there's nothing right with it either. It's reference data. Someone, someday, might stumble into this area of chemical space again, and when they do, they'll find a name scratched onto the wall and below it, a yellowing pile of old spectral data.

I've wondered before about what to do with those sorts of papers. There are so many compounds in the world of organic chemistry that the marginal utility of describing new random ones, while clearly not zero, is very, very close to it, especially if they're not directed towards any known use other than to make a manuscript. So if this is what's meant by baking rolls, then it's not too useful.

But I'm a medicinal chemist. When I start working on a new hit structure, I will most likely turn around and put the biggest pan of bread rolls into the biggest oven I can find. This, though, is chemistry with a purpose - there's some activity that I'm seeking, and if cranking out compounds is the best and/or fastest way to move in on it, then crank away. I'm not going to turn that blast of analogs into a paper; most (maybe all) of them will be tested, found wanting, and make their way into our compound archives. Their marginal utility is pretty low, too, given the numbers of compounds already in there, but it's still by far the best thing to do with them. Any that show activity, though, will get more attention.

I really don't mind that aspect of the synthesis I do. Setting up a row of easy reactions is actually kind of pleasant, because I know that (1) they're likely to work, and (2) they're going to tell me something I really want to know after I send them off for testing. Maybe they aren't bread rolls after all - they're bricks, and I can just possibly build something from them.

Comments (15) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs

January 31, 2014

"The Time Had Now Come to Attempt the First Large-Scale Reaction. . ."

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Posted by Derek

Here's a look at the life of a process/scale-up chemist while trying to get a key reaction to fly right. This is just the sort of problem these people deal with all the time - time pressure, troublesome reagent sourcing, purity and workup problems. And there's no place to hide, because you're always working on compounds that everyone cares about. (This story has a happy ending, but those are not guaranteed!)

Comments (16) + TrackBacks (0) | Category: Life in the Drug Labs

Beelzebub Pharma, Inc.

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Posted by Derek

I wanted to note my latest column for the RSC's Chemistry World, because I thought many readers here would be able to relate to it. I have a series of proposals for running the worst drug discovery organization I can think of - a set of simple rules that I think would bring things to a frantic, juddering halt while seeming to aim at enhancing everyone's productivity. A sample:

Appearances matter. And if it comes to a contest between surface and substance, then the glossiest surface wins. Woe to anyone whose presentations are not smooth and slick, with as many colorful charts as possible. Woe, similarly, to those who fail to tell anyone who asks (and many who don’t) how cleanly and tightly their current project is running. The first step to making problems disappear is to get them out of everyone’s sight. Right?

There will be many, many meetings to show off those beautiful slides. Multiple overlapping layers of meetings: it’s the only way to keep things running smoothly. Your worth as a manager, and as a human being, is tied to how many people you can cause to assemble in a room on a regular basis and how frequently you can get them to stand up in front of you.

I'm coming up (this fall) on twenty-five years of industrial research, and I found this column alarmingly easy to write. I was reminded of C. S. Lewis' experience in composing The Screwtape Letters, and his reluctance to write any more in that style. It really does just come out like opening up a water line once you get started, which says something about human nature.

Comments (43) + TrackBacks (0) | Category: Life in the Drug Labs | The Dark Side

January 21, 2014

Throwing Out the Files

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Posted by Derek

Since I'm in the process of moving my office, I've been taking time to do something that's needed to be done for quite a while: cleaning out my files. Somewhere around 2007 or so, I made the switchover to keeping PDFs as my primary filing system, with paper copies when needed. There was a transitional period, which I ended up splicing together by checking through my recent printed copies and backfilling those into my digital archive, but after that, it was all digital. (For the record, I'm still using Zotero for that purpose, although there are several equally valid alternatives, both commercial and freeware).

But I still had a pretty massive filing cabinet full of stuff, and I let that remain undisturbed, even though I knew some of it was surely junk. Only when I started digging into it did I realize just how much of it was little more than that. I'd estimate that I've thrown at least 80% of my files into the recycling bin, an act that would have made me uneasy only a few years ago, and horrified me in, say, 2004. It was easier than I thought, though.

That's because the folders easily fell into several broad categories. In the medical/biological sections of the cabinet, there were "Topics I'm Unlikely to Revisit - And When I Do, It Won't Be With These References". Those went right into the recycling bin. And there were "Topics I May Well Revisit, But When I Do, It Won't Be With These References". Those, after a glance through their contents, went into the bin as well. These were folders on (for example) disease areas that I've worked on in the past, and might conceivably work on again, but a folder full of ten-year-old biomedical articles is not that useful compared to the space it takes up and the trouble it takes to move it. And if that sounds borderline to you, how about the ones that hadn't been updated since the late 1990s? Junk. Nothing in the literature goes out of date faster than a state-of-current-disease-research article.

Moving to the chemistry folders, I was quickly surprised at how many of those I was throwing away as well. The great majority of the printed papers I kept were chemistry ones, but the great majority of what I started out with went into the recycling bin anyway. Digging through them was, in many cases, a reminder of what keeping up with the literature used to be like, back in the day. It was a time when if you found a useful-looking paper, you copied it out and put it in your files, because there was no telling when or if you'd be able to find it again. If you were one of the supremely organized ones, you drew a key reaction or two on an index card and filed that according to some system of your own devising - that's before my time, but I saw people doing that back when I was a grad student. The same sort of pack-ratting persisted well into the 1990s, though, but eroded in the face of better access to Chemical Abstracts (and the rise of competing databases). Finding that reaction, or others like it, or even better references than the ones you knew about, became less and less of a big deal.

So in my files, over in the section for "Synthesis of Amines", there was a folder on the opening of epoxides by amines. And in it were several papers I'd copied in the late 1980s. And some printed-out hits from SciFinder searches in about 1993. And a couple of reactions that I'd seen at conferences, and a paper from 1997 showing how you could change the site of ring opening, sometimes, with some systems. Into the bin it went, despite the feeling (not an inaccurate one) that I was throwing away work that I'd put into assembling all that. But if I find myself wanting to run such a reaction, I can probably set something up that'll work fairly well, and if it doesn't, I can probably find a review article (or two) where someone else has assembled the previous literature.

One of the biggest problems with my chemistry files, I realized, was the difficulty of searching them. I'd gotten used to the world of SciFinder and Reaxsys and Google and PubMed, where information can be called up any way you like. File folders, though, do not speak of their contents. Unless you have the main points of that content committed to memory, you have to open them up and flip through them, hoping for something relevant to pop up. I can well remember doing that in the early 1990s with some of these very folders ("Hmm, let's see what methods I have for such-and-such"), but that style of searching disappeared many years ago. You can now see what methods everyone has, and quickly find out what's been added to the pile since the last time you looked. Younger researchers who've grown up in that world may find it odd that I'm pointing out that water is wet, but my earliest file-cabinet folders were started in another time. File folders are based on tagging (and in its purest form, a physical label), and I agree with people who say that the ability to search is more important and useful than the ability to tag.

So, what did I keep? Folders on specialized topics that I recalled were very difficult to assemble, in a few cases. Papers that I know that I've referred to several times over the years. Papers that refer directly to things that I'm currently working on. Some stuff that's so old that it falls under the category of memorabilia. And finally, papers on more current topics that I want to make sure that I also have in digital form, but didn't have time to check just now. But that three-inch-thick collection of nuclear receptor papers from 2000-2002? The papers on iron dienyl reagents that I copied off during a look at that chemistry in 1991, and never had a need to refer to after about ten days? A folder of reductive amination conditions from the late 1980s? Into the big blue bin with all of it.

Comments (23) + TrackBacks (0) | Category: Life in the Drug Labs | The Scientific Literature

January 8, 2014

Evidence Against Open Offices

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Posted by Derek

It's clear that many readers here are not fans of open-office designs - and whether that percentage is higher or lower among chemists (or scientists in general) is an interesting question that hasn't been settled yet. But if you're one of those dissenters, take heart: this New Yorker piece is the herald of the backlash.

In 2011, the organizational psychologist Matthew Davis reviewed more than a hundred studies about office environments. He found that, though open offices often fostered a symbolic sense of organizational mission, making employees feel like part of a more laid-back, innovative enterprise, they were damaging to the workers’ attention spans, productivity, creative thinking, and satisfaction. Compared with standard offices, employees experienced more uncontrolled interactions, higher levels of stress, and lower levels of concentration and motivation. . .

There are plenty more links of the same type in the post, so if you're looking for ammunition against open-office plans, that's your one-stop superstore. Designers of new spaces in this industry sure do seem to love 'em, though. But personally, I'm not enthusiastic. I like talking to people about ideas, and I like hearing what other people are up to. But when I'm thinking, I shut the door. When I'm interrupted, my thoughts take off like the pigeons do when someone rides their VestaVespa into the market square in an old Italian movie. Update: my brain was apparently thinking about the asteroid instead of the scooter). It's almost physically painful to feel the structure I was building collapse, knowing that I'm going to have to assemble it all again.

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January 6, 2014

Positive Rules and Negative Ones

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Posted by Derek

I enjoyed this take on med-chem, and I think he's right:

There are a large set of "don't do this". When they predict failure, you usually shouldn't go there as these rules are moderately reliable.

There is an equally large set of "when you encounter this situation, try this" rules. Their positive predictive power is very very low.

Even the negative rule, the what-to-avoid category, aren't as hard as fast as one would like. There are some pretty unlikely-looking drugs out there (fosfomycin, nitroglycerine, suramin, and see that link above for more). These structures aren't telling you to go out and immediately start imitating them, but what they are telling you is that things that you'd throw away can work.

But those rules are still right more often than the "Here's what to do when . . ." ones, as John Alan Tucker is saying. Every experienced medicinal chemist has a head full of these things - reduce basicity to get out of hERG problems, change the logP for blood-brain-barrier penetration, substitute next to a phenol to slow glucuronidation, switch tetrazole/COOH, make a prodrug, change the salt, and on and on. These work, sometimes, but you have to try them every time before moving on to anything more exotic.

And it's the not-always-right nature of the negative rules, coupled with the not-completely-useless nature of the positive ones, that gives everyone room to argue. Someone has always tried XYZ that worked, while someone else has always tried XYZ when it didn't do a thing. Pretty much any time you try to lay down the law about structures that should or shouldn't be made, you can find arguments on the other side. The rule-of-five type guidelines look rather weak when you think about all the exceptions to them, but they look pretty strong when you compare them to all the other rules that people have tried, and so on.

In the end, all we can do is narrow our options down from an impossible number to a highly improbable number. When (or if) we can do better, medicinal chemistry will change a great deal, but until then. . .

Comments (8) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs

December 9, 2013

What Reagents Will You Never Forget?

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Posted by Derek

I've had the chance to use good old elemental bromine this morning, for the first time in several years. I can never see the stuff without thinking of this incident, a memorable part of the first synthetic scheme I ever tried that involved bromine. In the same way, every time I come across thiophenol - which isn't often, fortunately - I'm immediately taken back to this chemistry, which is a reaction I'll never forget either, despite numerous attempts to expunge it from my memory.

So here's a good question for a Monday: what reagents immediately recall something from your chemical past, and why? I'd assume that most working organic chemists have a few of these in their past. The common reagents all tend to blur together, but there will always be a few that have shown up only in one or two memorable instances. So what are yours?

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October 31, 2013

Merck's Aftermath

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Posted by Derek

So the picture that's emerging of Merck's drug discovery business after this round of cuts is confused, but some general trends seem to be present. West Point appears to have been very severely affected, with a large number of chemists shown the door, and reports tend to agree that bench chemists were disproportionately hit. The remaining department would seem to be top-heavy with managers.

Top-heavy, that is, unless the idea is that they're all going to be telling cheaper folks overseas what to make, that is. So is Merck going over to the Pfizer-style model? I regard this as unproven on this scale. In fact, I have an even lower opinion of it than that, but I'm sure that my distaste for the idea is affecting my perceptions, so I have to adjust accordingly. (Not everything you dislike is incorrect, just as not every person that's annoying is wrong).

But it's worth realizing that this is a very old idea. It's Taylorism, after Frederick Taylor, whose thinking was very influential in business circles about 100 years ago. (That Wikipedia article is written in a rather opinionated style, which the site has flagged, but it's a very interesting read and I recommend it). One of Taylor's themes was division of labor between the people thinking about the job and the people doing it, and a clearer statement of what Pfizer (and now Merck) are trying to do is hard to come by.

The problem is, we are not engaged in the kind of work that Taylorism and its descendants have been most successfully applied to. That, of course, is assembly line work, or any work flow that consists of defined, optimizable processes. R&D has proven. . .resistant to such thinking, to put it mildly. It's easy to convince yourself that drug discovery consists of and should be broken up into discrete assembly-line units, but somehow the cranks don't turn very smoothly when such systems are built. Bits and pieces of the process can be smoothed out and improved, but the whole thing still seems tangled, somehow.

In fact, if I can use an analogy from the post I put up earlier this morning, it reminds me of the onset of turbulence from a regime of laminar flow. If you model the kinds of work being done in some sort of hand-waving complexity space, up to a point, things run smoothly and go where they're supposed to. But as you start to add in key steps where the driving forces, the real engines of progress, are things that have to be invented afresh each time and are not well understood to start with, then you enter turbulence. The workflow become messy and unpredictable. If your Reynolds numbers are too high, no amount of polish and smoothing will stop you from seeing turbulent flow. If your industrial output depends too much on serendipity, on empiricism, and on mechanisms that are poorly understood, then no amount of managerial smoothing will make things predictable.

This, I think, is my biggest problem with the "Outsource the grunt work and leave the planning to the higher-ups" idea. It assumes that things work more smoothly than they really do in this business. I'm also reminded a bit of the Chilean "Project Cybersyn", which was to be a sort of control room where wise planners could direct the entire country's economy. One of the smaller reasons to regret the 1973 coup against Allende is that the chance was missed to watch this system bang up against reality. And I wonder what will happen as this latest drug discovery scheme runs into it, too.

Update: a Merck employee says in the comments that there hasn't been talk of more outsourcing, If that proves to be the case, then just apply the above comments to Pfizer.

Comments (98) + TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History | Life in the Drug Labs

October 3, 2013

A Decent Smell, For Once

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Posted by Derek

This is not one of the most pressing topics in the world, but it's certainly on my mind right now. I'm in the process of weighing out a number of acetophenones (literally - the balance is waiting for me over to my right). And I have to tell you, 2-acetylpyridine really smells like corn chips. I think several others in this group also have some of that character, but they're overwhelmed by the sheer tortillachipivity of the 2-acetylpyridine. Now I want a bowl of salsa, and it's only ten o'clock in the morning.

So, fellow organic chemists: what reagents remind you of food? We've talked about things that smell awful around here. How about things that actually smell appealing, for once? Nominations in the comments. . .

Update: by gosh, my nose is not leading me astray. 2-acetylpyridine is indeed found in tortilla chips.

Second update: in further news, I can now report that 3,4-dimethoxyacetophenone smells rather like a freshly opened package of bacon. Science sure is marching along this morning.

Third update: to judge from the color of the subsequent reaction, which might now be described as "spicy Szechuan motor oil", were there such a thing, I'd be willing to bet that it doesn't smell very much like tortilla chips any more. I will not, I think, be reporting back on what it does smell like.

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September 10, 2013

Bring Me More Cute Ring Systems

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Posted by Derek

Here's a paper from the Carreira group at the ETH, in collaboration with Roche, that falls into a category I've always enjoyed. I put these under the heading of "Synthetic routes into cute functionalized ring systems", and you can see my drug-discovery bias showing clearly.

Med-chem people like these kinds of molecules. (I have a few of them drawn here, but all the obvious variations are in the paper, too). They aren't in all the catalogs (yet), they're in no one's screening collection, and they have a particular kind of shape that might not be covered by anything else we already have in our files. There's no reason why something like this might not be the core of a bunch of useful compounds - small saturated nitrogen heterocycles fused to other rings sure do show up all over the place.
azaspiros.png
And the purpose of this sort of paper matches a drug discovery person's worldview exactly: here's a reasonable way into a large number of good-looking compounds that no one's ever screened, so go to it. (Here's an earlier paper from Carreira in the same area). The chemistry involved in making this things is good, solid stuff: it's not cutting-edge, but it doesn't have to be. It's done on a reasonable scale, and it certainly looks like it would work just fine. I can understand why readers from other branches of organic chemistry would skip over a paper like this. No theoretical concerns are addressed in the syntheses, no natural products are produced, no new catalysts are developed, and no new reactions are discovered. But new scaffolds are being made, and for a medicinal chemist, that's more than enough right there. This is chemistry that does just what it needs to do, quickly, and gets out of the way, and I wouldn't mind seeing a paper or two like this every time I open up my RSS feeds.

Comments (18) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs

September 4, 2013

Stack Ranking in Pharma: Bad Idea

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Posted by Derek

Steve Ballmer's departure from Microsoft, snidely remarked on here, has prompted any number of "What went wrong?" pieces to appear. One of the key documents, though, is from last year: Kurt Eichenwald's writeup in Vanity Fair. The editorial staff has helpfully illustrated it with a photo of Ballmer himself that's so characteristic of his style that it's liable to give ex-Microsofters the shivering flashbacks.

One of the common themes to all these articles is the company's use of "stack ranking", where you evaluate your direct reports and rank them top to bottom. The bottom performers get hammered, no matter how they might have done on some hypothetical absolute scale. If you happen to have a great group of high-performing people working for you - too bad. Some of them are going to be ranked at the imaginary bottom, and get punished for it. Here's Eichenwald:

At the center of the cultural problems was a management system called “stack ranking.” Every current and former Microsoft employee I interviewed—every one—cited stack ranking as the most destructive process inside of Microsoft, something that drove out untold numbers of employees. The system—also referred to as “the performance model,” “the bell curve,” or just “the employee review”—has, with certain variations over the years, worked like this: every unit was forced to declare a certain percentage of employees as top performers, then good performers, then average, then below average, then poor.

“If you were on a team of 10 people, you walked in the first day knowing that, no matter how good everyone was, two people were going to get a great review, seven were going to get mediocre reviews, and one was going to get a terrible review,” said a former software developer. “It leads to employees focusing on competing with each other rather than competing with other companies.”

. . .For that reason, executives said, a lot of Microsoft superstars did everything they could to avoid working alongside other top-notch developers, out of fear that they would be hurt in the rankings. And the reviews had real-world consequences: those at the top received bonuses and promotions; those at the bottom usually received no cash or were shown the door.

You can well imagine the sorts of behaviors this system promotes. A Microsoft engineer said in the article that "One of the most valuable things I learned was to give the appearance of being courteous while withholding just enough information from colleagues to ensure they didn’t get ahead of me on the rankings". What's even more dysfunctional about this system is that it was not officially acknowledged by the managers. Here's a former Microsoft employee writing in Slate:

Then I had to explain things to my reports. This illustrated another problem with the system: It destroyed trust between individual contributors and management, because the stack rank required that all lower-level managers systematically lie to their reports. Why? Because for years Microsoft did not admit the existence of the stack rank to nonmanagers. Knowledge of the process gradually leaked out, becoming a recurrent complaint on the much-loathed (by Microsoft) Mini-Microsoft blog, where a high-up Microsoft manager bitterly complained about organizational dysfunction and was joined in by a chorus of hundreds of employees. The stack rank finally made it into a Vanity Fair article in 2012, but for many years it was not common knowledge, inside or outside Microsoft. It was presented to the individual contributors as a system of objective assessment of “core competencies,” with each person being judged in isolation.

Why do I bring this up? Because many large drug companies persist in ranking-and-rating behaviors that are very nearly as stupid, and very nearly as destructive. And we've been doing it for years. At any rate, I've been complaining about it for years, and I'm certainly not alone. Rating people in research is notoriously difficult already, but rating them by jamming them into an artificial (and mathematically illiterate) template is even worse. If you want people to focus on stepping over each other, pit them against each other with a good, hard stack ranking system. If you'd like them to do something else with their time, you might want to rethink.

Comments (55) + TrackBacks (0) | Category: Business and Markets | Life in the Drug Labs

July 26, 2013

Instrument Nostalgia

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Posted by Derek

Andre the Chemist is talking Lab Instrument Nostalgia at his blog. I know what he means, but mostly, when I think of old equipment, I'm just glad that I'm not using it any more. I remember, for example, the JEOL NMR machines with the blue screen and light pen, and a water-cooled 80MHZ NMR made by IBM, of all people. But if I saw either of them today, I would react with a sort of interested horror.

Update: a little searching around brought me this picture of the IBM machine. Check out the cool 1980 tech!

Comments (60) + TrackBacks (0) | Category: Life in the Drug Labs

July 25, 2013

Biogen Idec Goes Open-Office

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Posted by Derek

Here's a new development in the office/lab architecture topic, which has been the subject of lively discussion around here over the years. Biogen Idec has been putting up a new building (I've been following its progress as I go past it), and they're getting ready to move in. According to the Boston Globe, the entire thing is a completely office-less and cubicle-less space.

Building 9 has no private offices, just individually designed workstations called “I spaces” and common “huddle rooms” for private phone calls or spontaneous meetings. Each floor has two “walk stations” where employees can work while walking on treadmills. The company has scrapped telephone landlines for Building 9 employees, who are issued laptops and headsets.

“This whole idea of no offices is a little controversial,” admitted chief executive George Scangos. “It’s a new way of working. The idea is to foster more collaboration. People can talk to each other now. A lot of ideas can come out of these informal discussions.”

. . .But will some Biogen Idec recruits be pining for their own private offices?

“There may be some people who say, ‘I don’t want this, I want an office,’ ” Scangos acknowledged. After pausing, he said quietly, “Then they don’t come here.”

Problem is, like all other big-culture-change ideas, it takes years before you find out if it's working or not. But Biogen seems to be very big on the idea, and it'll be quite interesting to hear reports about how it's working (or not).

Thanks to Lisa Jarvis at C&E News for the tip, via Twitter.

Comments (49) + TrackBacks (0) | Category: Life in the Drug Labs

June 27, 2013

Sealed Up And Ready to Go

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Posted by Derek

I was running some good old brute force reactions in the lab the other day, the kind with rock-solid reactants and products. The way to get such reactions to go, if they're a bit slow on you, is of course to heat them up. One of my Laws of the Lab, formulated back in grad school, was "A slow reaction at room temperature is Nature's way of telling you to reflux that sucker".

That's not always true - there are reactants that won't put it with that sort of treatment and find something else to do, just as there are products that are unstable to the heat that might have been used to make them. (That last situation is a natural for flow chemistry, by the way, where you might be able to get the products out of the hot zone before they have a chance to do something else). But for the things I was doing, and for many other kinds of reactions, a good blast of heat can be just the thing.

The microwave reactor is a good way to put this into practice. Seal up your reaction in a vial and tell the thing to heat up the contents to, say, 120C for half an hour. Reaction done, or not? If not, then maybe another half hour - or maybe you should set one up where you hit it at 140C for a shorter time? Or 160? Why not? You might have a bunch of five- or ten-minute reactions ready to go, and you won't know until you crank on them a bit. You might also have a shortcut to a tube of blackened gorp, but how else do you find out that you've gone too far? The nice thing about the sealed microwave vials is that they can take a good amount of pressure. You can use "normal" solvents at higher temperature than you would ordinarily. My limit is acetonitrile at about 190C in a small vial, which is about triple its standard boiling point, and gives (in my case) a pressure of about 17 or 18 atmospheres in the tube.

Now, this can take some getting used to, for less experienced chemists. One of the things that is drummed into students in the lab is the Never Heat a Closed System, and there are clearly a lot of good reasons for caution. But sometimes heating a closed system is just the thing. There are several lab-scale gizmos to allow sealed-tube reactions to be run more safely, for just these Need For Heat reasons. Another nice thing about a sealed tube is that your reactants (and products) can't get away. Running stuff in decalin or sulfolane (classic high-boiling solvents) can put you in a situation where the reaction is merrily boiling away in the flask, but some of your own materials are fleeing up the condenser in terror, likely to whoof off and vanish out the fume hood exhaust if you keep it up.

I would be a lot more circumspect about such conditions if it weren't for the robustness of the commercial microwave platform. People run stuff like this all the time, so you can blast away with more confidence. Not that you can't blow one out, especially if there's an exothermic reaction waiting to take off on you. You'll want to sneak up on a new reaction to make sure that it's not waiting for you with one of those thermodynamic jack-in-the-boxes. And keep in mind that I'm a discovery chemist. A fifty-milligram reaction is fine by me. Proposing to the scale-up group, though, that they run a bunch of sealed acetonitrile reactions at 190C will get you a different reception. You can do that stuff on larger scale, though, if you're truly motivated. That's what those big solid metal reactors with the screwed-down tops are for, but that's also what pressure monitors, blast shields, and differential scanning calorimeters are for, too. Scale matters - it matters a lot, and a liter of hot acetonitrile (much less fifty liters) under high pressure is a very different thing than a couple of mLs in a thick-walled vial. The latter could easily be one of a dozen routine reactions queued up in a microwave rack, but the former could easily be your last sight on this earth, and you'd better plan accordingly.

Comments (42) + TrackBacks (0) | Category: Life in the Drug Labs

June 12, 2013

Product Inhibition, Or Grinding To A Halt

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Posted by Derek

Here's a neat bit of reaction optimization from the Aubé lab at Kansas. Update: left the link out before - sorry!) They're trying to make one of their workhorse reactions, the intramolecular Schmidt, a bit less nasty by cutting down on the amount of acid catalyst. The problem with that is product inhibition: the amide that's formed in the reaction tends to vacuum up any Lewis acid around, so you've typically had to use that reagent in excess, which is not a lot of fun on scale.

By varying a number of conditions, they've found a new catalyst/solvent system that's quite a bit friendlier. I keep meaning to try some of these reactions out (they make some interesting molecular frameworks), and maybe this is my entry into them. But the general problem here is one that every working organic chemist has faced: reactions that, for whatever reason, stop partway through. In this situation, there's at least a reasonably hypothesis why things grind out, and there's always been a less-than-elegant way around it (dump in more Lewis acid).

I'm sure, though, that everyone out there at the bench has had reactions that just. . .stop, for reasons unknown, and can't be pushed forward by addition of more anything. I've always wondered what's going on in those situations (probably a lot of things, from case to case), and they're always a reminder of just how little we sometimes really understand about what's going on inside our reaction flasks. Aggregates or other supramolecular complexes? Solubility problems? Adsorption onto heterogeneous reactants? Getting a handle on these things isn't easy, and most people don't bother doing it, unless they're full-out process chemists in industry.

Comments (12) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs

May 30, 2013

Making the Non-Flat, Non-Aromatic Compounds

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Posted by Derek

Here's a question for the organic chemists in the crowd, and not just those in the drug industry, either. Over the last few years, though, there's been a lot of discussion about how drug company compound libraries have too many compounds with too many aromatic rings in them. Here are some examples of just the sort of thing I have in mind. As mentioned here recently, when you look at real day-to-day reactions from the drug labs, you sure do see an awful lot of metal-catalyzed couplings of aryl rings (and the rest of the time seems to be occupied with making amides to link more of them together).

Now, it's worth remembering that some of the studies on this sort of thing have been criticized for stacking the deck. But at the same time, it's undeniable that the proportion of "flat stuff" has been increasing over the years, to the point that several companies seem to be openly worried about the state of their screening collections.

So here's the question: if you're trying to break out of this, and go to more three-dimensional structures with more saturated rings, what are the best ways to do that? The Diels-Alder reaction has come up here as an example of the kind of transformation that doesn't get run so often in drug research, and it has to be noted that it provides you with instant 3-D character in the products. What we could really use are reactions that somehow annulate pyrrolidines or tetrahydropyrans onto other systems in one swoop, or reliably graft on spiro systems where there was a carbonyl, say.

I know that there are some reactions like these out there, but it would be worthwhile, I think, to hear what people think of when they think of making saturated heterocyclic ring systems. Forget the indoles, the quinolines, the pyrazines and the biphenyls: how do you break into the tetrahydropyrans, the homopiperazines, and the saturated 5,5 systems? Embrace the stereochemistry! (This impinges on the topic of natural-product-like scaffolds, too).

My own nomination, for what it's worth, is to use D-glucal as a starting material. If you hydrogenate that double bond, you now have a chiral tetrahydropyran triol, with differential reactivity, ready to be functionalized. Alternatively, you can go after that double bond to make new fused rings, without falling back into making sugars. My carbohydrate-based synthesis PhD work is showing here, but I'm not talking about embarking on a 27-step route to a natural product here (one of those per lifetime is enough, thanks). But I think the potential for library synthesis in this area is underappreciated.

Comments (32) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs

May 22, 2013

Underappreciated Analytical Techniques

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Posted by Derek

A conversation the other day about 2-D NMR brought this thought to mind. What do you think are the most underused analytical methods in organic chemistry? Maybe I should qualify that, to the most underused (but potentially useful) ones.

I know, for example, that hardly anyone takes IR spectra any more. I've taken maybe one or two in the last ten years, and that was to confirm the presence of things like alkynes or azides, which show up immediately and oddly in the infrared. Otherwise, IR has just been overtaken by other methods for many of its application in organic chemistry, and it's no surprise that it's fallen off so much since its glory days. But I think that carbon-13 NMR is probably underused, as are a lot of 2D NMR techniques. Any other nominations?

Comments (62) + TrackBacks (0) | Category: Analytical Chemistry | Life in the Drug Labs

April 22, 2013

Real Reactions, From Real Lab Notebooks

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Posted by Derek

Over at NextMove software, they have an analysis of what kinds of reactions are being run most often inside a large drug company. Using the company's electronic notebook database and their own software, they can get a real-world picture of what people spend their time on at the bench.

The number one reaction is Buchwald-Hartwig amination. And that seems reasonable to me; I sure see a lot of those being run myself. The number two reaction is reduction of nitro groups to amines, which surprises me a bit. There certainly are quite a few of those - the fellow just down the bench from me was cursing at one just the other day - but I wouldn't have pegged it as number two overall. Number three was the good old Williamson ether synthesis, and only then do we get to the reaction that I would have thought would beat out either of these, N-acylation. After that comes sulfonamide formation, and that one is also a bit of a surprise. Not that there aren't a lot of sulfonamides around, far from it, but I was under the impression that a lot of organizations gave the the semi-official fish-eye, due to higher-than-average rates of trouble (PK and so on) down the line.

My first thought was that there might have been some big and/or recent projects that skewed the numbers around a bit. These sorts of data sets are always going to be lumpy, in the same way that compound collections tend to be (and for the same reasons). The majority of compounds (and reactions) pile up when a great big series of active compounds comes along with Structure X made via Reaction Scheme Y. But that, in a way, is the point: different organizations might have a slightly different rank-ordering, but it seems a safe bet that the same eight or ten reactions would always make up most of the list. (My candidate for number 6, the next one down on the above list: Suzuki coupling).

There's also a pie chart of the general reaction types that are run most often. The biggest category is heteroatom alkylation and arylation, followed by acylation in general. By the time you've covered those two, you've got half the reactions in the database. Next up is C-C bond formations (there are those Suzukis, I'll bet) and reductions. (Interestingly. oxidations are much further down the list). That same trend was noted in an earlier analysis of this sort, and nitro-to-amine reactions were thought to be the main reason for it, as seems to be the case here. There's at least one more study of this sort that I'm aware of, and it came to similar conclusions.

One of the things that might occur to an academic chemist looking over these data is that none of these are exactly the most exciting reactions in the world. That's true, and that's the point. We don't want exciting chemistry, because "exciting" means that it has a significant chance of not working. Our reactions are dull as the proverbial ditchwater (and often about the same color), because the excitement of not knowing whether something is going to pan out or not is deferred a bit down the line. Just getting the primary assay data back on the compounds you just made is often an exercise in finger-crossing. Then waiting to see if your lead compound made it through two-week tox, now that's exciting. Or the first bit of Phase I PK data, when the drug candidate goes into a person's mouth for the first time. Or, even more, the initial Phase II numbers, when you find out if it might actually do something for somebody's who's sick. Now those have all the excitement that you could want, and often quite a bit more. With that sort of unavoidable background, the chemistry needs to be as steady and reliable as it can get.

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April 10, 2013

Old Friends, And Those Other Guys

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Posted by Derek

I have affection for some reagents, and have taken a dislike to others. That might be seen as odd, because if there's anything that can't return your feelings, it's a chemical reagent. But after some years in the lab, you associate some compounds (and some reactions) with good events, and others with spectacularly bad ones, so it's a natural response.

Today, for example, I'm breaking out some potassium hexamethyldisilazide, known in the trade (for obvious reasons) as K-HMDS. I'm in need of a strong base, and this one has worked for me in a couple of tight spots over the years, which makes me very friendly towards it. The first of those was back in grad school. It was, in retrospect, one of the first times I ever figured out what was going wrong with a reaction from first principles. Knowledge being power and all that, I was then able to come up with a fix, switching my base away from the lithium reagents I'd been using to KHMDS. I can still remember looking at the TLC plate in disbelief, having suddenly seen the yield go from flat zero to over 90%. I'll always be loyal after an experience like that.

There are others. As I've mentioned, I'll always love copper sulfate, just because of its color and because it was one of the first chemical reagents I ever owned as a boy. There are a couple of carbohydrate derivatives (such as good ol' "diacetone glucose") that, unlike some of their cousins, always treated me well during my PhD work, and I'm happy to see them on the rare occasions I have use for them. And as usual with the human brain, there are certain chemical smells that I immediately associate, nostalgically, with old labs. I'm not even sure what some of these are, but they're immediately recognizable, and my first thought is "Now that's chemistry".

But there's a flip side. There are reagents that have done nothing but waste my time and chew up my starting materials, and it's hard for me to warm up to them after that. I'm not sure if anyone likes trimethyl phosphite - it has a smell that seems as if would work its way through a concrete block - but I spent too much time trying to use it (unsuccessfully) for a tricky way out of a problem back in grad school, and I now associate its odor with frustration. I can tell that it's not just that it has a bad odor in general - ethyl vinyl ether is nobody's cologne, either, but that one makes me think of the summer of 1984 and bunch of Claisen rearrangements I was running, and I don't mind that at all. Mercuric oxide is colorful, so you'd think I might like it, but aside from it being toxic, I had some painful experiences with it in some old desulfurization reactions, and it'll never recover with me. And the so-called "higher-order" cuprates, made with copper cyanide - I'm not sure if anyone uses those any more, but I swore years ago to never touch one of those evil things again, and I've stuck to that.

My lists aren't always that absolute. As mentioned here, I went through a period where I absolutely could not take tosyl chloride, but not having to work with kilos of the stuff has gradually allowed it to move back into what's at least neutral territory. For me, that reagent is like running into someone from your old school that you didn't always care for at the time, but with whom you now seem to have at least some common ground in which to share memories.

So my shelves are full of friends and enemies. And now I'm off to see if my old pal, KHMDS, can come through for me again!

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March 7, 2013

I'll Just Take a Tour of Your Lab Drawers Here

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Posted by Derek

I enjoyed this from postdoc JesstheChemist on Twitter: "Busted. Just caught someone (who doesn't work in my lab) going through my lab drawers." Now that's a real-life lab comment if I ever saw one. It's a constant feature in academic labs, where there's usually limited equipment of one sort of another. There's less of it in industry, where we're relatively equipment-rich, but it certainly doesn't go away.

Glassware gets rummaged through, whether for that one tiny Dean-Stark trap, a funny-sized ground-glass stopper, or something as petty as a clean 25 mL round bottom. Run out of that fancy multicolor pH paper? The guy next to you keeps it in the second drawer. One-mL syringes ran out, and you need to dispense something right now? Third drawer.

I've seen people borrow things while they're in use. In grad school, I once had a short-path vacuum distillation going, with the receiving flasks cooled in a bath supported by a lab jack. I left for a few minutes while things were warming up, only to find my lab jack pilfered and replaced by a ragged stack of cork rings, which was not what I had in mind. Peeved, I hunted through the labs until I found the jack in the hood of a post-doc who was running something of his own. "I didn't think you were using it", was his response, which prompted me to ask what it looked like when I was actually using it.

Then you have reagent burgling, which is epidemic at all levels of bench chemistry. No one has everything to hand, and you always run out of things. The stockroom may be some distance away, or take too much time, or there may be only one bottle of 2-methyl bromowhatsicene in the lab (and you don't have it). This can be innocent, as in taking 500mg of some common reagent out of a large bottle that someone has handy. Or it can be more serious (but still well-intentioned), in the "I'm going to bring it right back" way. Further down the scale, you have plain nastiness, of the "I need this and screw the rest of you" kind. I told the story here of having had most of a fresh bottle of borane/THF jacked from me, and you know, that happened in 1986 and I'm still a little cheesed off about it. Many readers will have experienced similar sensations.

Once, during my grad school days, I went off on a rare vacation and left notes in the various drawers of my bench. "It's not here!" read one of them, and another advised people "Take this from (fellow student X). He has a lot more of them than I do". When I came back, people told me that they enjoyed my notes. There you have it.

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March 1, 2013

The Finest Green in the Lab?

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Posted by Derek

nickelchloride.jpgFor Friday afternoon, I thought I'd put up another color post. That's nickel (II) chloride hydrate, and the only time I've used it was in a modified borohydride reduction. But that was a glorious prep, at least until the borohydride went in and everything turned black. Nickel chloride in methanol is as green as it gets - that's another one that I'm going to have just take a photo of sometime.

It's fake-looking, like some sort of dye, especially when you see it in an organic chemistry lab. Green is one of the harder colors for "normal" organic compounds to take on, so a vivid lime-gelatin-mix reaction really stands out. Does anyone have any other candidates?

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February 15, 2013

The Finest Blue in the Lab

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Posted by Derek

CuSO4.jpg
For Friday afternoon, a bit of chem-geekery. I recently had occasion to use some copper sulfate, and the bottle I had was marked "large crystals" of the pentahydrate. I have loved the color of that stuff since I was a kid, and still do. Powdered, you lose a lot of the effect, but the chunks of crystalline stuff are the very definition of blue. (Photo from egeorge96 on Flickr).

Does anyone know a better one? That's my candidate for the solid phase. In solution, the complex of copper II and pyridine is a good one, a bit more towards royal blue/purple. You can definitely see the change when the pyridine hits it. I can't find a photo of that one on the web; if anyone has one, I'll be glad to post it. More colors to come on other slow Friday afternoons.

Update: a rare gas-phase blue (!) from the comments. Never seen that before!

And another one from the comments: here's someone who really, really, really likes copper sulfate. Here's how it was done.

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January 28, 2013

Asking the Hard Questions

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Posted by Derek

Well, it is a hard question, and I don't know the answer, either. On Twitter, See Arr Oh wonders:

Know that tangy smell that LAH / NaH give off? Is that oil volatiles, or trace H2 being formed from room moisture?

I'm not sure, but I'd be willing to bet that hydrogen has no smell at all - it would seem too small and too bereft of interactions to see off the nasal receptors. So my guess is mineral oil constituents in the case of sodium hydride, which I usually handle as the dispersion. Now, the lithium aluminum hydride is a dry powder, so in that case, I'd say that I'm smelling the real stuff, which can't be improving my nose very much. That lines up with Chemjobber's explanation: "It's the smell of your nose hairs being deprotonated." Any other guesses?

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January 25, 2013

Down With the Ullmann

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Posted by Derek

Have I mentioned recently what a pain the rear the Ullmann reaction is? Copper, in general? Consider it done, then. I'm trying to make biaryl ethers, not something I'd usually do, and these reactions are the traditional answer. One of my laws of the lab, though, is that when there are fifty ways of doing some reaction in the literature, it means that there's no good way to do it, and the Ullmann is the big, hairy, sweaty example of just that phenomenon. Even when it works, there are worries. But you have to get it to work first. . .

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January 4, 2013

An Article That Shows What Med-Chem Is Like?

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Posted by Derek

Here's a query that I received the other day that I thought I'd pass on to the readership: "What's the one journal article or book chapter that you'd assign to a class to show them what medicinal chemistry and drug discovery are really like?"

That's a tricky one, because (as in many fields) the "what it's really like" aspect doesn't always translate to the printed page. But I'd be interested in seeing some suggestions.

Comments (15) + TrackBacks (0) | Category: Life in the Drug Labs | The Scientific Literature

November 27, 2012

How Do Chemist (Think That They) Judge Compounds?

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Posted by Derek

There's an interesting paper out in PLoS One, called "Inside the Mind of a Medicinal Chemist". Now, that's not necessarily a place that everyone wants to go - mine is not exactly a tourist trap, I can tell you - but the authors are a group from Novartis, so they knew what they were getting into. The questions they were trying to answer on this spelunking expedition were:

1) How and to what extent do chemists simplify the problem of identifying promising chemical fragments to move forward in the discovery process? 2) Do different chemists use the same criteria for such decisions? 3) Can chemists accurately report the criteria they use for such decisions?

They took 19 lucky chemists from the Novartis labs and asked them to go through 8 batches of 500 fragments each and select the desirable compounds. For those of you outside the field, that is, unfortunately, a realistic test. We often have to work through lists of this type, for several reasons: "We have X dollars to spend on the screening collection - which compounds should we buy?" "Which of these compounds we already own should still be in the collection, and which should we get rid of?" "Here's the list of screening hits for Enzyme Y: which of these look like useful starting points?" I found myself just yesterday going through about 350 compounds for just this sort of purpose.

They also asked the chemists which of a set of factors they used to make their decisions. These included polarity, size, lipophilicity, rings versus chains, charge, particular functional groups, and so on. Interestingly, once the 19 chemists had made their choices (and reported the criteria they used in doing so), the authors went through the selections using two computational classification algorithms, semi-naïve Bayesian (SNB) and Random Forest (RF). This showed that most of the chemists actually used only one or two categories as important filters, a result that ties in with studies in other fields on how experts in a given subject make decisions. Reducing the complexity of a multifactorial problem is a key step for the human brain to deal with it; how well this reduction is done (trading accuracy for speed) is what can distinguish an expert from someone who's never faced a particular problem before.

But the chemists in this sample didn't all zoom in on the same factors. One chemist showed a strong preference away from the compounds with a higher polar surface area, for example, while another seemed to make size the most important descriptor. The ones using functional groups to pick compounds also showed some individual preferences - one chemist, for example, seemed to downgrade heteroaromatic compounds, unless they also had a carboxylic acid, in which case they moved back up the list. Overall, the most common one-factor preference was ring topology, followed by functional groups and hydrogen bond donors/acceptors.

Comparing structural preferences across the chemists revealed many differences of opinion as well. One of them seemed to like fused six-membered aromatic rings (that would not have been me, had I been in the data set!), while others marked those down. Some tricyclic structures were strongly favored by one chemist, and strongly disfavored by another, which makes me wonder if the authors were tempted to get the two of them together and let them fight it out.

How about the number of compounds passed? Here's the breakdown:

One simple metric of agreement is the fraction of compounds selected by each chemist per batch. The fraction of compounds deemed suitable to carry forward varied widely between chemists, ranging from 7% to 97% (average = 45%), though each chemist was relatively consistent from batch to batch. . .This variance between chemists was not related to their ideal library size (Fig. S7A) nor linearly related to the number of targets a chemist had previously worked on (R2 = 0.05, Fig. S7B). The fraction passed could, however, be explained by each chemist’s reported selection strategy (Fig. S7C). Chemists who reported selecting only the “best” fragments passed a lower fraction of compounds (0.13±0.07) than chemists that reported excluding only the “worst” fragments (0.61±0.34); those who reported intermediate strategies passed an intermediate fraction of compounds (0.39±0.25).

Then comes a key question: how similar were the chemists' picks to each other, or to their own previous selections? A well-known paper from a few years ago suggested that the same chemists, looking at the same list after the passage of time (and more lists!) would pick rather different sets of compounds. Update: see the comments for some interesting inside information on this work.)Here, the authors sprinkled in a couple of hundred compounds that were present in more than one list to test this out. And I'd say that the earlier results were replicated fairly well. Comparing chemists' picks to themselves, the average similarity was only 0.52, which the authors describe, perhaps charitably, as "moderately internally consistent".

But that's a unanimous chorus compared to the consensus between chemists. These had similarities ranging from 0.05 (!) to 0.52, with an average of 0.28. Overall, only 8% of the compounds had the same judgement passed on them by at least 75% of the chemists. And the great majority of those agreements were on bad compounds, as opposed to good ones: only 1% of the compounds were deemed good by at least 75% of the group!

There's one other interesting result to consider: recall that the chemists were asked to state what factors they used in making their decisions. How did those compare to what they actually seemed to find important? (An economist would call this a case of stated preference versus revealed preference). The authors call this an assessment of the chemists' self-awareness, which in my experience, is often a swampy area indeed. And that's what it turned out to be here as well: ". . .every single chemist reported properties that were never identified as important by our SNG or RF classifiers. . .chemist 3 reported that several properties were important, for failed to report that size played any role during selections. Our SNG and RF classifiers both revealed that size, an especially straightforward parameter to assess, was the most important ."

So, what to make of all this? I'd say that it's more proof that we medicinal chemists all come to the lab bench with our own sets of prejudices, based on our own experiences. We're not always aware of them, but they're certainly with us, "sewn into the lining of our lab coats", as Tom Wolfe might have put it. The tricky part is figuring out which of these quirks are actually useful, and how often. . .

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November 16, 2012

Sulfolane

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Posted by Derek

Here's a paper that I missed in Organic Process Research and Development earlier this year, extolling the virtues of sulfolane as a high-temperature polar solvent. I have to say, I've never used it, although I hear of it being used once in a while, mainly by people who are really having to crank the temperature on some poor reaction.

The only bad thing I've heard about it is its difficulty of removal. That high-boiling polar aprotic group all has this problem, of course (DMSO is no treat to get out of your sample sometimes, either, although it's so water-soluble that you always have sheer extraction on your side). But sulfolane is higher-boiling than all the rest (287C!), and it also freezes at about 28C, which could be a problem, too. (The paper notes that small amounts of water lower the freezing temperature substantially, and that 97/3 sulfolane/water is an article of commerce itself, probably for that reason). It has an unusual advantage, though, from a safety standpoint: it stands out from all the other polar aprotics as having remarkably poor skin penetration (as contrasted very much with DMSO, for example). It's more toxic than the others, but the skin penetration makes up for that, as long as you're not ingesting it some other way, which is Not Advised.

The paper gives a number of examples where this solvent proved to be just the thing, so I'll have to keep it in mind. Anyone out there care to share any hands-on experiences?

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November 5, 2012

Caring About Yields?

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Posted by Derek

The discussion here last week about exaggerated reaction yields has gotten me thinking. I actually seem to go for long periods without ever calculating (or caring much) about the yields of my reactions.

That's largely because of the sort of medicinal chemistry work that I do - very early stage stuff, about as far back as you can get. For that work, I like to say that there are really only two yields: enough, and not enough. And if you can get product into a vial, or intermediate sufficient to make more needed analogs, then you have enough. I'd prefer that reactions work well, of course, but "well" is defined in my mind as much (or more) by how clean the product is than how much of it gets produced. A lower-yielding reaction whose product falls out ready to use seems nicer than a higher-yielding one that needs careful chromatography to get the red stuff out of it.

That's the opposite of the way I used to think when I was doing my grad school work, of course. Twenty-seven steps in a row will get you thinking very hard indeed about yields, especially later on in the synthesis. It occurs to you pretty quickly that if you take a 50% yield on something that took you two months to make, that you're pouring a month's effort into the red waste can. If you're going to take a nasty yield in a long sequence, it's much better to get it over with in step one. You'll see this effect at work in papers that just start off from a literature reference intermediate (the "readily available compound 3" syndrome), which can mean that compound 3 is a nasty prep which would besmirch the rest of the sequence were it included.

I'd certainly think differently were I in process chemistry, too, of course. And when I have to work downstream on a project, I do spare a thought for the ease of the chemistry, because that's closer to the point where my optimization colleagues will have to deal with what we produce. But back at the early stage, I have to admit, I really don't care all that much. The vast majority of the compounds that get made back there are not going to go anywhere, so whatever gets them made and tested quickly is a good thing. The elegant synthesis is the one that gets it out of the lab and down the hall, whatever the yield might be.

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October 24, 2012

Chem Coach Carnival: A Few Questions

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Posted by Derek

Over at Just Like Cooking, See Arr Oh has been organizing a "Chem Coach Carnival". He's asking chemists (blogging and otherwise) some questions about their work, especially for the benefit of people who don't do it (or not yet), and I'm glad to throw an entry into the pile:

Describe your current job
My current job is titled "Research Fellow", but titles like this are notoriously slippery in biotech/pharma. What I really do is work in very early-stage research, pretty much the earliest that a medicinal chemist can get involved in. I help to think up new targets and work with the biologists to get them screened, then work to evaluate what comes out of the screening. Is it real? Is it useful? Can it be advanced? If not, what other options do we have to find chemical matter for the target?

What do you do in a standard "work day?"
My work day divides between my office and my lab. In the office, I'm digging around in the new literature for interesting things that my company might be able to use (new targets, new chemistry, new technologies). And I'm also searching for more information on the early projects that we're prosecuting now: has anyone else reported work on these, or something like them? And there are the actual compound series that we're working on - what's known about things of those types (if anything?) Have they ever been reported as hits for other targets? Any interesting reactions known for them that we could tap into? There are broad project-specific issues to research as well - let's say that we're hoping to pick up some activity or selectivity in a current series by targeting a particular region of our target protein. So, how well has that worked out for other proteins with similar binding pockets? What sorts of structures have tended to hit?

In the lab, I actually make some of the new compounds for testing on these ongoing projects. At this stage in my career (I've been in the industry since 1989), my main purpose is not cranking out compounds at the bench. But I can certainly contribute, and I've always enjoyed the physical experience of making new compounds and trying new reactions. It's a good break from the office, and the office is a good break from the lab when I have a run of discovering new ways to produce sticky maroon gunk. (Happens to everyone).

This being industry, there are also meetings. But I try to keep those down to a minimum - when my calendar shows a day full of them, I despair a bit. Most of the time, my feelings when leaving a meeting are those of Samuel Johnson on Paradise Lost: "None ever wished it longer".

Note: I've already described what happens downstream of me - here's one overview.

What kind of schooling / training / experience helped you get there?
I have a B.A. and a Ph.D., along with a post-doc. But by now, those are getting alarmingly far back in the past. What really counts these days is my industrial experience, which is now up to 23 years, at several different companies. Over that time, I don't think I've missed out on a single large therapeutic area or class of targets. And I've seen projects fail in all sorts of ways (and succeed in a few as well) - my worth largely depends on what I've learned from all of them, and applying it to the new stuff that's coming down the chute.

That can be tricky. The failings of inexperience are well known, but experience has its problems, too. There can be a tendency to assume that you really have seen everything before, and that you know how things are going to turn out. This isn't true. You can help to avoid some of the pitfalls you've tumbled into in the past, but drug research is big enough and varied enough that new ones are always out there. And things can work out, too, for reasons that are not clear and not predictable. My experience is worth a lot - it had better be - but that value has limits, and I need to be the first person to keep that in mind.

How does chemistry inform your work?
It's the absolute foundation of it. I approach biology thinking like a chemist; I approach physics thinking like a chemist. One trait that's very strong in my research personality is empiricism: I am congenitally suspicious of model systems, and I'd far rather have the data from the real experiment. And those real experiments need to be as real as possible, too. If you say enzyme assay, I'll ask for cells. If you have cell data, I'll ask about mice. Mice lead to dogs, and dogs lead to humans, and there's where we really find out if we have a drug, and not one minute before.

In general, if you say that something's not going to work, I'll ask if you've tried it. Not every experiment is feasible, or even wise, but a surprising amount of data gets left, ungathered, because someone didn't bother to check. Never talk yourself out of an easy experiment.

Finally, a unique, interesting, or funny anecdote about your career
People who know me, from my wife and kids to my labmates, will now groan and roll their eyes, because I am a walking collection of such things. Part of it's my Southern heritage; we love a good story well told. I think I'll go back to grad school for this one; I'm not sure if I've ever told it here on the blog:

When I first got to Duke, I was planning on working for Prof. Bert Fraser-Reid, who was doing chiral synthesis of natural products using carbohydrate starting materials. In most graduate departments, there's a period where the new students attend presentations by faculty members and then associate themselves with someone that they'd like to work for. During this process, I wanted to set up an interview with Fraser-Reid, so I left a note for him to that effect, with my phone number. His grad students told me, though, that he was out of town (which was not hard to believe; he traveled a great deal).

That night I was back in my ratty shared house off of Duke's East Campus, which my housemates and I were soon to find out we could not afford to actually heat for the winter (save for a coal stove in the front room). And at 9 PM, I was expecting a call from a friend of mine at Vanderbilt, a chemistry=major classmate of mine from my undergraduate school (Hendrix) who knew that I was trying to sign up with Fraser-Reid's group. So at 9 PM sharp, the phone rings, and I pick it up to hear my friend's voice, as if through a towel held over the phone, saying that he was Dr. Fraser-Reid, at Duke.

Hah! Nice try. "You fool, he's out of town!" I said gleefully. There was a pause at the other end of the line. "Ah, is this Derek Lowe? This is Dr. Fraser-Reid, at Duke." And that's when it dawned on me: this was Dr. Fraser-Reid. At Duke. One of my housemates was in the room while this was going on, and he told me that he'd thought until then that watching someone go suddenly pale was just a figure of speech. The blood drained from my brain as I stammered out something to the effect that, whoops, uh, sorry, I thought that he was someone else, arrgh, expecting another call, ho-ho, and so on. We did set up an appointment, and I actually ended up in his group, although he should have known better after that auspicious start. This particular mistake I have not repeated, I should add. Ever restless and exploring, I have moved on to other mistakes since then.

Comments (7) + TrackBacks (0) | Category: General Scientific News | Graduate School | Life in the Drug Labs

September 11, 2012

Careers, And Those Words "Stuck" and "Advance"

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Posted by Derek

A recent comment to another post prompts this entry. Regarding getting a chemistry PhD and getting a job, it reads:

. . .However, transitioning into corporate pharma was a big if not bigger challenge in some ways. It took a while to figure out how the system works and how to advance one's career and not get stuck in the lab.

Now this is a touchy subject, and it's two words in it that make it so: "advance" and "stuck". Pick one hundred chemists who start out in, say, industrial drug research at any given time (I know, bear with me - it's a thought experiment). Now observe them at the five year mark, the ten, and the twenty. What will you find? Some of them will no longer be employed, for sure - recent years make that certain, but honestly, it's always been certain. Some of that, remember, is voluntary. Some people find out, in any profession (once they start practicing it) that it's not actually what they want to do with their lives. It's better to find that out earlier than later. Or something that's clearly better might come along; there are any number of reasons for people to exit a field on their own power. But others true will have been acted on by an outside force, whether that force is their own difficulty in holding on to their position, or the industry's difficulty in holding on to as many people as it used to.

So among those still employed, what will you have? Some of them will have more direct reports than others, or more responsibility in other ways. People's abilities, opportunities, and motivations vary. As time goes on, some of the initial cohort will have definitely moved "out of the lab". But there are different reasons for this. The most common is what's usually called something like "the managerial track". Depending on the company, it's often the case that as people move to higher positions on the org chart, that they'll spend less time actually in the lab as opposed to their offices. In the traditional European drug research labs (especially the German and Swiss ones), this process started very quickly, sometimes on day one. And in general, the larger the company, the more likely it is that people have desk-only jobs as they move along.

But most companies like this also have a "scientific track", although it's sometimes used as a bit of dumping ground for people who (for whatever reason) are definitely not on the managerial track. That does tend to cut into the definition between the two, but the idea is to have somewhere to advance/promote people who don't want to head in the desk/management direction. It's here, I think, that the hard feelings start, because of this blurred boundary.

It's safe to say that some people who move into the managing-the-organization side of the business don't miss the lab work all that much, although some of them certainly do. And it's also safe to say that some of the people who stay on the scientific side would very much rather not have to deal with a stack of performance reviews, budget spreadsheets, making sure that everyone's up to date in the internal training database, and the like - but then again, some of them wouldn't mind that stuff at all, if anyone would give them a chance to mind it. To further complicate things, not everyone on the managerial side of the business is necessarily a good manager, just as not everyone on the lab side of it is a wonderful scientist. And people with longtime desk/office jobs are sometimes heard to say that they miss lab work, in a sort of "good old days" tone.

So you can get some pretty dismissive stuff, from both sides. These would include (but are not limited to) statements about being someone being "stuck in the lab" (as opposed to doing the really important work), or someone else being nothing but a paper pusher who's forgotten how research works (or perhaps never really knew to start with). I try to stay away from those sorts of statements, myself, but everyone in industry will know the sort of thing I'm talking about.

My own preferences? I have a hood, and I work in it. I'm not there all the time, but I'm expected (as are others like me) to produce in the lab as well as at my desk. And I do spend time at the desk, too, although I try to spend it on scientific issues - how do we prosecute the project for Target X? What are the chances for Project Y, and what do we do if it doesn't work out? What technology do we have (or does anyone have) to go after Target Z? Managerially, I've never had a long list of direct reports, nor a list of people reporting to me who also have people reporting to them, etc. I've been, it's fair to say, on the scientific ladder. But "stuck in the lab" is not a phrase I've ever applied to myself.

The key, I think, is to continue to learn and to keep up, no matter which side of the divide you might be. You should be performing at a level that you couldn't have earlier in your career, either way - dealing with issues that you wouldn't have been able to handle, bringing your experience to bear on new situations. The danger in having been around the block a number of times is that you can start to feel as if you know more than you do, or that you've seen pretty much everything before (neither of those is true). But you should definitely know more than you used to!

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August 24, 2012

The Good Ol' Diels-Alder

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Posted by Derek

Over at Chemistry Blog, there's a post by Quintus on the synthesis of a complex natural product, FR-182877. The route is interesting in that it features a key Diels-Alder reaction, and the post mentions that this isn't a reaction that gets used much in industry.

True enough - that one and the Claisen rearrangement are the first reactions I think of in the category of "taught in every organic chemistry course, haven't run one in years". In the case of the Claisen, the number of years is now getting up to. . .hmm, about 26, I think. The Diels-Alder has shown up a bit more often for me, and someone in my lab was running one last year, but it was the first time she'd ever done it (after many years of drug discovery experience).

Why is that? The post I linked to suggested a good reason that one isn't done too often on scale: it can be unpredictably exothermic, and some of the reactants can decide to polymerize instead, which you don't want, either. That can be very exothermic, too, and leaves you with a reactor full of useless plastic gunk which will have to be removed with tools ranging from a scoop to a saw. This is a good time to adduce the benefits of flow chemistry, which has been successfully applied in such cases, and is worth thinking about any time you have a batch reaction that might take off on you.

But to scale something up, you need to have an interest in that structure to start with. There's another reason that you don't see so many Diels-Alders in drug synthesis, and it has to do with the sorts of molecules we tend to make. The cycloaddition gives you a three-dimensional structure with stereocenters, and medicinal chemistry, notoriously, tends to favor flat aromatic rings, sometimes very much to its detriment. Many drug discovery departments have taken the pledge over the years to try to cut back on the flatness and introduce more sp3 carbons, but it doesn't always take. (For one thing, if your leads are coming out of your screening collection, odds are you'll be starting with something on the flat end of the scale, because that's what your past projects filled the files with).

I think that fragment-based drug discovery has a better chance of giving you 3-D leads, but only if you pay attention while you're working on it. Those hits can sometimes be prosecuted in the flat-and-aryl style, too, if you insist. And I think it's fair to say that a lot of fragment hits have an aryl (especially a heteroaryl) ring in them, which might reflect the ease of assembling a fragment-sized library of compounds full of such. Even the fragment folks have been talking over the years about the need to get more three-dimensionality into the collections, and vendors have been pitching this as a feature of their offerings.

The other rap on the classic Diels-Alder reaction is that it gives you substituted cyclohexanes, which aren't always the first place you look for drug leads. But the hetero-Diels-Alder reactions can give you a lot of interesting compounds that look more drug-like, and I think that they deserve more play than they get in this business. I'll go ahead and take a public pledge to run a series of them before the year is out!

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August 22, 2012

Watch that Little Letter "c"

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Posted by Derek

Hang around a bunch of medicinal chemists (no, really, it's more fun than you'd think) and you're bound to hear discussion of cLogP. For the chemists in the crowd, I should warn you that I'm about to say nasty things about it.

For the nonchemists in the crowd, logP is a measure of how greasy (or how polar) a compound is. It's based on a partition experiment: shake up a measured amount of a compound with defined volumes of water and n-octanol, a rather greasy solvent which I've never seen referred to in any other experimental technique. Then measure how much of the compound ends up in each layer, and take the log of the octanol/water ratio. So if a thousand times as much compound goes into the octanol as goes into the water (which for drug substances is quite common, in fact, pretty good), then the logP is 3. The reason we care about this is that really greasy compounds (and one can go up to 4, 5, 6, and possibly beyond), have problems. They tend to dissolve poorly in the gut, have problems crossing membranes in living systems, get metabolized extensively in the liver, and stick to a lot of proteins that you'd rather they didn't stick to. Fewer high-logP compounds are capable of making it as drugs.

So far, so good. But there are complications. For one thing, that description above ignores the pH of the water solution, and for charged compounds that's a big factor. logD is the term for the distribution of all species (ionized or not), and logD at pH 7.4 (physiological) is a valuable measurement if you've got the possibility of a charged species (and plenty of drug molecules do, thanks to basic amines, carboxylic acids, etc.) But there are bigger problems.

You'll notice that the experiment outlined in the second paragraph could fairly be described as tedious. In fact, I have never seen it performed. Not once, and I'll bet that the majority of medicinal chemists never have, either. And it's not like it's just being done out of my sight; there's no roomful of automated octanol/water extraction machines clanking away in the basement. I should note that there are other higher-throughput experimental techniques (such as HPLC retention times) that also correlate with logP and have been used to generate real numbers, but even those don't account for the great majority of the numbers that we talk about all the time. So how do we manage to do that?

It has to do with a sleight of hand I've performed while writing the above sections, which some of you have probably already noticed. Most of the time, when we talk about logP values in early drug discovery, we're talking about cLogp. That "c" stands for calculated. There are several programs that estimate logP based on known values for different rings and functional groups, and with different algorithms for combining and interpolating them. In my experience, almost all logP numbers that get thrown around are from these tools; no octanol is involved.

And sometimes that worries me a bit. Not all of these programs will tell you how solid those estimates are. And even if they will, not all chemists will bother to check. If your structure is quite close to something that's been measured, then fine, the estimate is bound to be pretty good. But what if you feed in a heterocycle that's not in the lookup table? The program will spit out a number, that's what. But it may not be a very good number, even if it goes out to two decimal places. I can't even remember when I might have last seen a cLogP value with a range on it, or any other suggestion that it might be a bit fuzzy.

There are more subtle problems, too - I've seen some oddities with substitutions on saturated heterocyclic rings (morpholine, etc.) that didn't quite seem to make sense. Many chemists get these numbers, look at them quizzically, and say "Hmm, I didn't know that those things sorted out like that. Live and learn!" In other words, they take the calculated values as reality. I've even had people defend these numbers by explaining to me patiently that these are, after all, calculated logP values, and the calculated log P values rank-order like so, and what exactly is my problem? And while it's hard to argue with that, we are not putting our compounds into the simulated stomachs of rationalized rodents. Real-world decisions can be made based on numbers that do not come from the real world.

Comments (39) + TrackBacks (0) | Category: Drug Assays | In Silico | Life in the Drug Labs

July 26, 2012

Amines and the Landscape of Chemical Stink

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Posted by Derek

I was using a tertiary amine the other day when the thought occurred to me: these things all smell the same. The amine smell is instantly recognizable, fishy and penetrating, in the same way that sulfur smells are also easy to pick out (rotten egg/skunk/burning rubber and worse). But as the triethylamine smell wafted along, I began to think that the sulfur stenches cover a wider range than the amine ones.

Is that so? Sulfur compounds certainly have the bigger reputation for strong smells, and it's well earned. But I still have the impression that various thiols or low-molecular sulfides are easier to distinguish from each other. They all have that sulfur reek to them, but in subtle and ever-varying ways. I sound like a wine critic. Amines, though, tend to be a big more one-note. Fish market, they say. Low tide. I'm not sure I could tell triethylamine from Hünig's base from piperidine in a blind snort test, not that I'm totally motivated to try.

There are exceptions. The piperazines often take on a musty, dirt-like smell that overrides the fishy one. (Note, however, that the classic "dirt" smell is largely produced by a compound that has no nitrogen atoms in it at all). And when they first encounter pyrrolidine, chemists (especially male ones) are generally taken aback. (Now that I think about it, does piperdine smell more like pyrrolidine or like the generic tertiary amines?) The straight-chain diamines should be singled out, too, for their famously stinky qualities. If you've never encountered them, the mere existence of compounds with names like putrescine and cadaverine should be warning enough.

We should probably leave pyridine out of the discussion, since as an aromatic ring it's in a different class. But it has to be noted that its odor is truly vile and alien, smelling (fortunately) like nothing on earth except pyridine. These examples are enough, though, to make me wonder if I'm short-changing the amines when I don't rate them as highly for range and versatility in the chemical odor department. Examples are welcome in the comments of amines that go beyond the Standard Mackeral. . .

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July 19, 2012

Come Back Thiophene; All Is Forgiven

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Posted by Derek

A couple of commenters took exception to my words yesterday about thiophene not being a "real" heterocycle. And I have to say, on reflection, that they're right. When I think about it, I have seen an example myself, in a project some years ago, where thiophene-for-phenyl was not a silent switch. If I recall correctly, the thiophene was surprisingly more potent, and that seems to be the direction that other people have seen as well. Anyone know of an example where a thiophene kills the activity compared to a phenyl?

That said, the great majority of the times I've seen matched pairs of compounds with this change, there's been no real difference in activity. I haven't seen as many PK comparisons, but the ones I can think of have been pretty close. That's not always the case, though: Plavix (clopidogrel) is the canonical example of a thiophene that gets metabolically unzipped (scroll down on that page to "Pharmacokinetics and metabolism" to see the scheme). You're not going to see a phenyl ring do that, of course - it'll get oxidized to the phenol, likely as not, but that'll get glucuronidated or something and sluiced out the kidneys, taking everything else with it. But note also that depending on things like CYP2C19 to produce your active drug for you is not without risks: people vary in their enzyme profiles, and you might find that your blood levels in a real patient population are rather jumpier than you'd hoped for.

So I'll take back my comments: thiophene really is (or at least can be) a heterocycle all its own, and not just a phenyl with eye makeup. But one of the conclusions of that GSK paper was that it's not such a great heterocycle for drug development, in the end.

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July 18, 2012

The Best Rings to Put in Your Molecules?

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Posted by Derek

Here's a paper from some folks at GlaxoSmithKline on what kinds of rings seem to have the best chances as parts of a drug structure. They're looking at replacements for plain old aryl rings, of which there are often too many. Pulling data out of the GSK corporate collection, they find that the most common heteroaromatic rings are pyridine, pyrazole, and pyrimidine - together, those are about half the data set. (The least common, in case you're wondering, are 1,3,5-triazine, 1,3,4-oxadiazole, and tetrazole). In marketed drugs, though, pyridine is more of a clear winner, and both pyrrole and imidazole make the top of the charts as well.

When they checked the aqueous solubility of all these compounds, the 1,2,4-triazoles came out on top, and the 1,3,5-triazines were at the bottom, which sounds about right. Other soluble heterocycles included 1,3,4-oxadizole and pyridazine, and other bricks were thiazole and thiophene (not that that last one really counts as a heterocycle in my book). Update: I've revised my thoughts on that! Now, you might look at these and say "Sure, and you could have saved yourself the trouble by just looking at the logD values - don't they line up?" They do, for the most part, but it turns out that the triazines are unusually bad for their logDs, while the five-membered rings with adjacent nitrogens (all of 'em) were unusually good.

The next thing the team looked at was binding to human serum albumin. The 1,3,4-thiadiazoles emerged as the losers here, with by far the most protein binding, followed by thiazoles and 1,2,4-oxadiazoles. Imidazoles had the least, by a good margin, followed by pyrazine and pyridazine. Those last two were better than expected compared to their logD values.

And the last big category was CYP450 inhibition. Here, thiophene, tetrazole, and 1,2,3-triazole were the bad guys, and pyridazine, 1,3,4-thiadizole, and pyrazine (and a few others) were relatively clean. The people at AstraZeneca have published a similar analysis, and the two data sets agree pretty well, with the exception of oxazole and tetrazole. The AZ oxazoles all had open positions next to the ring nitrogen, which seems to have opened them up to metabolism, but the difference in tetrazoles (AZ good, GSK bad) is harder to explain.

The take-home? Pyridazine, pyrazine, imidazole and pyrazole look like the winners from an overall "developability" score. Thiophene brings up the rear, but since I still think that one shouldn't count update (it's a benzene in disguise), the ones to worry about are then thiazole, 1,2,3-triazole, and tetrazole (that last one with an asterisk, due to the CYP data discrepancy).

The paper tries to do the same analysis with heteroaliphatic rings, but the authors admit that they had a much smaller data set to work with, so the conclusions aren't as strong. There was also a higher correlation with plain ol' logD values across all three categories (not as many surprises). The winners turned out to be piperidine NH and morpholine N-alkyl, with imidazoline and piperidine N-alkyl right behind. The losers? Piperidine N-sulfonamide, followed by pyrrolidine N-sulfonamide, and then 1,3-thiazolidine. (Sulfonamides continue to live up - or down - to their reputation as Bad News).

There are, naturally, limitations to this sort of thing. Ceteris paribus is a mighty difficult state of affairs to achieve in medicinal chemistry, and other factors can rearrange things quickly. But if you're just starting out in an SAR series, it sounds like you might wand to give the pyrazines and pyridazines a look.

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July 3, 2012

They Don't Make These Things to Have Dichloromethane Poured on 'Em

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Posted by Derek

With all the electronic notebooks around these days, and the ubiquity of computer hardware and keyboards around the HPLCs, LC/mass specs, and so on, I'm surprised that we don't see more of this. But that is the first keyboard I've seen melted in a lab setting - perhaps I'm just leading a sheltered life.

But ginger ale in an Apple wireless keyboard? I can get that at home, courtesy of my kids. (The hardware survived, although some of the keys were a bit crunchy for a while. . .)

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June 29, 2012

Odd Functionality in Drugs: A Bis-N-Oxide

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Posted by Derek

There are a number of structures that I've never been quite able to make up my mind about in medicinal chemistry. One of those is the pyridine N-oxide. You really don't see those in drugs (at least, no examples come to mind), but you don't see many people trying to advance them as drugs, either. Note: the first comment points out the two key examples I'd forgotten: librium and minoxidil. Once in a while they turn up in the literature, often never to be seen again. I believe that one problem with them is that they present in a living system as mild oxidizing agents, which is the sort of thing that cells try to avoid, and I can't imagine that their pharmacokinetics are very appealing either. There are quite a few pyridine derivatives that are turned into their N-oxides on the way to being excreted, which makes you think that bringing one in from the the start is greasing the skids for fast clearance. But I've never seen one dosed, so how would I know for sure?

These thoughts are prompted by this paper from J. Med. Chem., which has an even stranger-looking benzotriazine bis-oxide. These compounds seem quite active against drug-resistant tuberculosis strains (and it's always good to see something that can kill those guys off), but I'll watch with interest to see if they can be developed into drugs. Anyone else out there ever had the nerve to push an N-oxide forward?

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June 21, 2012

Dead Reagents, Dead Reactions

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Posted by Derek

Chemistry moves on, and it doesn't always take everything with it. There are reagents and reactions that used to be all over the literature, but have fallen out of use, superseded by easier or more reliable alternatives. The first thing I think of in this category is pyridinium chlorochromate (PCC), which I wrote about here. That was all the rage in the late 1970s and into the 1980s, but I don't know when I've last seen a bottle of the stuff.

And since that post itself is seven years old now, I wanted to throw the floor open again for a discussion of dead reagents and dusty reactions. There are plenty of obscure ones, of course, and plenty that don't get much use but still have their place in special situations. But I'm wondering about the ones that used to be big and now are disappearing. What are some that you used to use, but never expect to again?

For my part, other than PCC, I don't ever see doing a vanadium-catalyzed epoxidation, even though I did a few in grad school. And I recall doing a Jones oxidation - does anyone use that one any more? Another reagent that had a vogue in the late 1980s and early 1990s, but I don't recall seeing any time recently, was tris(trimethylsilyl)silane (a replacement for tri-n-butyltin hydride). So those are my nominees - what else?

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May 11, 2012

Desperation In the Lab

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Posted by Derek

You chemists may have really stretched things to get a reaction to work, but here's a good set of "Conditions You'll Probably Never Be Desperate Enough to Try". Bone meal? Ground carrots? I think he has a point.

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May 1, 2012

Chemists and Biologists, In Detail

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Posted by Derek

Let's file this one under "Cultural Differences Between Chemists and Biologists". Have any of my chemistry colleagues out there noticed the difference in presentation detail between the two disciplines?

It's struck me several times over the years. Biologists seem, on average, to go into much more granular detail about their experiments when presenting to a mixed audience than do most chemists. Buffers, buffers that worked a little better, buffers that worked a bit worse, the brand of the sizing column, western blot after western blot. The usual chemistry comment was always "Hey, I don't show pictures of my TLC plates", but eventually I suppose we'll need to come up with another line as LC/MS takes over the world.

Even presenting among their own tribe, most chemists don't (to me) seem to go to the level of detail that I often see from protein purification people or pharmacologists. My theory is that most forms of biology still have so many hidden variables in them (since it's an intrinsically more complex and less understood science) that all the details need to be specified. Organic chemistry, for all its troubles, still tends to be more reproducible, on average, than molecular biology, and at a less picky level of detail

That's why chemists don't often feel the need to go into details even in a room full of chemists: "We had the bromide, so we made these coupled products, and then we made these by reductive amination. . ." substitutes for "We had the aryl bromide, so we reacted it with a list of boronic acids under palladium-catalyzed coupling conditions to give these products, each of which still has the aldehyde in the 3-position, which we purified by chromatography in an ethyl acetate/hexane gradient over 8-gram ISCO silica gel cartridges. We then reacted them with a list of amines using sodium triacetoxyborohydride in dichloromethane at room temperature, followed by a chromatography in 1 to 5% methanol/dichloromethane. . . ". Each of those steps has plenty of other options - different reagent combinations, solvents, etc., and if some colleague needs to reproduce your work, they'll check your notebook or ask you "Hey, what did you guys use for those Suzukis? Dppf? Yuck."

We certainly won't go into that level of detail in a room half full of biologists - it's mostly "We made these, and these, and these", which spares everyone. No TLC plates, no LC/MS traces, no NMR spectra. But they're available if you want 'em.

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April 25, 2012

Drug Company Culture: It's Not Helping

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Posted by Derek

I wanted to call attention to a piece by Bruce Booth over at Forbes. He starts off from the Scannell paper in Nature Reviews Drug Discovery that we were discussing here recently, but he goes on to another factor. And it's a big one: culture.

Fundamentally, I think the bulk of the last decade’s productivity decline is attributable to a culture problem. The Big Pharma culture has been homogenized, purified, sterilized, whipped, stirred, filtered, etc and lost its ability to ferment the good stuff required to innovate. This isn’t covered in most reviews of the productivity challenge facing our industry, because its nearly impossible to quantify, but it’s well known and a huge issue.

You really should read the whole thing, but I'll mention some of his main points. One of those is "The Tyranny of the Committee". You know, nothing good can ever be decided unless there are a lot of people in the room - right? And then that decision has to move to another room full of people who give it a different working-over, with lots more PowerPoint - right? And then that decision moves up to a group of higher-level people, who look at the slides again - or summaries of them - and make a collective decision. That's how it's supposed to work - uh, right?

Another is "Stagnation Through Risk Avoidance". Projects go on longer, and keep everyone busy, if the nasty issues aren't faced too quickly. And everyone has room to deflect blame when things go wrong, if plenty of work has been poured into the project, from several different areas, before the bad news hits. Most of the time, you know, some sort of bad news is waiting out there, so you want to have yourself (and your career) prepared beforehand - right? After all, several high-level committees signed off on this project. . .

And then there's "Organizational Entropy", which we've discussed around here, too. When the New, Latest, Really-Going-to-Work reorganization hits, as it does every three years or so, things slow down. They have to. And a nice big merger doesn't just slow things down, it brings everything to a juddering halt. The cumulative effect of these things can be deadly.

As Booth says, there are other factors as well. I'd add a couple to the list, myself: the tendency to think that If This Was Any Good, Someone Else Would Be Doing It (which is another way of being able to run for cover if things don't work out), and the general human sunk-cost fallacy of We've Come This Far; We Have to Get Something Out of This. But his main point stands, and has stood for many years. The research culture in many big drug companies stands in the way of getting things done. More posts on this to follow.

Comments (36) + TrackBacks (0) | Category: Drug Industry History | Life in the Drug Labs | Who Discovers and Why

April 5, 2012

What Makes a Beautiful Molecule?

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Posted by Derek

A reader sent along this question for the medicinal chemists in the crowd: we spend a lot of time thinking about what makes a molecule ugly (by our standards). But what about the flip side? What makes a molecule beautiful?

That's a hard one to answer, because, well, eye of the beholder and all that. One answer is that if it works well as a drug, how ugly can it be? (See the recent post here about the ugliest drugs in that light). Then there are all sorts of striking molecular structures that have nothing to do with medicinal chemistry, but for the purposes of today's discussion, I think we should rule those out. So, what makes a drug molecule (or candidate molecule) beautiful?

Size matters, for one thing. It may be my bias towards ligand efficiency, but I'm more impressed with potent, selective molecules that can get the job done with lower molecular weight. And you know that in a huge structure, a lot of the atoms are just scaffolding to get the business end(s) of the molecule in the right place, and I can't see giving points for that.

Points should also go for originality. I enjoy seeing a functional motif that hasn't turned up in a dozen other drugs. That may be because I can imagine that the team that developed the compound probably ran through the more usual stuff first and ended up having to go with the newer-looking group, in spite of their own reservations about what might happen. For similar reasons, I also have a bias towards three-dimensional character. Drug binding pockets are generally 3-D (and chiral), so a compound that takes advantage of those seems more elegant than a completely flat structure. (Although you can argue that a flat structure that works is easier to make, and that's definitely not a trivial consideration).
Escitalopram.png
These tend to lead me, when I look though tables of drugs, to CNS ligands, and perhaps that reflects the influence of my first few years in the industry. But for whatever reason, something like escitalopram just looks like a drug molecule to me. As came up in the "ugly drug" post, though, it's instructive to look over a list of, say, the 200 biggest-selling compounds and realize how many structures a person can find aesthetic fault with. Which shows you how far you can get with aesthetics in this business. . .

Which reminds me: coming soon is a large post with graphics of many of the nominated compounds in the "ugliest drug" category. It'll be worth looking them over, and reflecting that they're out there treating patients and making money.

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March 28, 2012

Winning Ugly and Failing Gracefully

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Posted by Derek

A recent discussion with colleagues turned around the question: "Would you rather succeed ugly or fail gracefully?" In drug discovery terms, that could be rephrased "Would you rather get a compound through the clinic after wrestling with a marginal structure, worrying about tox, having to fix the formulation three times, and so on, or would you rather work on something that everyone agrees is a solid target, with good chemical matter, SAR that makes sense, leading to a potent, selective, clean compound that dies anyway in Phase II?"

I vote for option number one, if those are my choices. But here's the question at the heart of a lot of the debates about preclinical criteria: do more programs like that die, or do more programs like option number two die? I tend to think that way back early in the process, when you're still picking leads, that you're better off with non-ugly chemical matter. We're only going to make it bigger and greasier, so start with as pretty a molecule as you can. But as things go on, and as you get closer to the clinic, you have to face up to the fact that no matter how you got there, no one really knows what's going to happen once you're in humans. You don't really know if your mechanism is correct (Phase II), and you sure don't know if you're going to see some sort of funny tox or long-term effect (Phase III). The chances of those are still higher if your compound is exceptionally greasy, so I think that everyone can agree that (other things being equal) you're better off with a lower logP. But what else can you trust? Not much.

The important thing is getting into the clinic, because that's where all the big questions are answered. And it's also where the big money is spent, so you have to be careful, on the other side of the equation, and not just shove all kinds of things into humans. You're going to run out of time and cash, most likely, before something works. But if you kill everything off before it gets that far, you're going to run out of both of those, too, for sure. You're going to have to take some shots at some point, and those will probably be with compounds that are less than ideal. A drug is a biologically active chemical compound that has things wrong with it.

There's another component to that "fail gracefully" idea, though, and it's a less honorable one. In a large organization, it can be to a person's advantage to make sure that everything's being done in the approved way, even if that leads off the cliff eventually. At least that way you can't be blamed, right? So you might not think that an inhibitor of Target X is such a great idea, but the committee that proposes new targets does, so you keep your head down. And you may wonder about the way the SAR is being prosecuted, but the official criteria say that you have to have at least so much potency and at least so much selectivity, so you do what you have to to make the cutoffs. And on it goes. In the end, you deliver a putative clinical candidate that may not have much of a chance at all, but that's not your department, because all the boxes got checked. More to the point, all the boxes were widely seen to be checked. So if it fails, well, it's just one of those things. Everyone did everything right, everyone met the departmental goals: what else can you do?

This gets back to the post the other day on unlikely-looking drug structures. There are a lot of them; I'll put together a gallery soon. But I think it's important to look these things over, and to realize that every one of them is out there on the market. They're on the pharmacy shelves because someone had the nerve to take them into the clinic, because someone was willing to win with an ugly compound. Looking at them, I realize that I would have crossed off billions of dollars just because I didn't feel comfortable with these structures, which makes me wonder if I haven't been overvaluing my opinion in these matters. You can't get a drug on the market without offending someone, and it may be you.

Comments (36) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs

March 19, 2012

Dealing with the Data

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Posted by Derek

So how do we deal with the piles of data? A reader sent along this question, and it's worth thinking about. Drug research - even the preclinical kind - generates an awful lot of information. The other day, it was pointed out that one of our projects, if you expanded everything out, would be displayed on a spreadsheet with compounds running down the left, and over two hundred columns stretching across the page. Not all of those are populated for every compound, by any means, especially the newer ones. But compounds that stay in the screening collection tend to accumulate a lot of data with time, and there are hundreds of thousands (or millions) of compounds in a good-sized screening collection. How do we keep track of it all?

Most larger companies have some sort of proprietary software for the job (or jobs). The idea is that you can enter a structure (or substructure) of a compound and find out the project it was made for, every assay that's been run on it, all its spectral data and physical properties (experimental and calculated), every batch that's been made or bought (and from whom and from where, with notebook and catalog references), and the bar code of every vial or bottle of it that's running around the labs. You obviously don't want all of those every time, so you need to be able to define your queries over a wide range, setting a few common ones as defaults and customizing them for individual projects while they're running.

Displaying all this data isn't trivial, either. The good old fashioned spreadsheet is perfectly useful, but you're going to need the ability to plot and chart in all sorts of ways to actually see what's going on in a big project. How does human microsomal stability relate to the logP of the right-hand side chain in the pyrimidinyl-series compounds with molecular weight under 425? And how do those numbers compare to the dog microsomes? And how do either of those compare to the blood levels in the whole animal, keeping in mind that you've been using two different dosing vehicles along the way? To visualize these kinds of questions - perfectly reasonable ones, let me tell you - you'll need all the help you can get.

You run into the problem of any large, multifunctional program, though: if it can do everything, it may not do any one thing very well. Or there may be a way to do whatever you want, if only you can memorize the magic spell that will make it happen. If it's one of those programs that you have to use constantly or run the risk of totally forgetting how it goes, there will be trouble.

So what's been the experience out there? In-house home-built software? Adaptations of commercial packages? How does a smaller company afford to do what it needs to do? Comments welcome. . .

Comments (66) + TrackBacks (0) | Category: Drug Assays | Drug Development | Life in the Drug Labs

March 9, 2012

Double-Bond-S

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Posted by Derek

The carbonyl group is one of the most fundamental structure in organic chemistry: C-double-bond-O. But you can substitute that oxygen with a sulfur and get to a whole new series of compounds - so how come we don't see so many of those in drugs?

Well, not all of them are stable. Plain old thioketones are pretty reactive, not to mention their appalling stink. And even though they're not as bad as thioketones, the corresponding thioamides and thioureas are known to be more lively than their oxygen counterparts. Many medicinal chemists avoid them because of a reputation for trouble, which I think is probably earned and not just an irrational prejudice. But there are drugs and pharmacological tools with these structures, still.

The thiocarbonyl shows up in a number of heterocycles, too, and there the situation gets a bit murkier. The highest-profile member of this group, unfortunately, may well be the rhodanines, which have come up several times on this blog, most recently here. I'm not a fan of those guys, but here's a question: are there thiocarbonyl structures that are better behaved? Do people like me look down on the whole functional group because of a few (well, more than a few) bad actors?

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March 2, 2012

A Response From Sanofi

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Posted by Derek

The large number of comments on yesterday's post on Sanofi CEO Chris Viehbacher's relentless candid interview included a response from someone at the company itself. At least, I have to assume that it is indeed Jack Cox, Senior Director of Public Affairs and Media Relations (as his LinkedIn profile has it), since the name and position match up, and the IP address of the comment resolves to Sanofi-US. I wanted to highlight his response - in the interest of fairness - and the responses to it, without having everything buried in the triple-digit comments thread to the previous post. Says Mr. Cox:

Anyone who has followed Chris in recent months will have heard some variation of these comments, but within the broader context that unfortunately didn't make it into the Q&A you reference.

Chris has consistently said that his vision for Sanofi's R&D organization is one of open collaboration, in which our own researchers increasingly partner with external teams. This is consistent with a comment you've included: "We're not going to get out of research. We believe we do things will in research but we want to work with more outside companies, startup biotechs, with universities."

In an interview with Luke Timmerman published by Xconomy in January Chris explained how this is working in practice:

"In Cambridge, you've got all those things. Being the No. 1 life sciences employer in Boston is great, but we didn't want to just do the same thing we did everywhere else, having everybody inside our walls. So we created this concept of a hub. There's a core, with a lot of competencies that a big organization can bring, but the idea of a hub is that we can manage the relationships we have with everybody from Dana-Farber Cancer Institute to Harvard to MIT to the Joslin Diabetes Center to some of the biotechs we work with. And we put our own oncology research team in Cambridge. There's a whole ecosystem in Boston, and we feel integrated and at the center of it."

Seeking external expertise, particularly when it concerns emerging technologies, contributes to the creativity and innovation we have within. The key to our approach, however, is that we don't want to simply be investors, but true partners. Again, consider the broader context as shared with Luke:

"The Warp Drive Bio project is interesting because it demonstrates where we want to go. It was very much on the basis of saying we want to work with (Harvard University chemical biologist) Greg Verdine. Someone like that isn't going to come work for Big Pharma, but we liked the science he was doing. We have a strong interest and expertise in natural products, and he had a genomics screening tool.

We will contribute expertise. I don't want to be a venture capitalist, or have a venture fund, like some other companies do. But I want to actually partner, where we bring some of what we know, and combine it with what Warp Drive has. The fact that we are trying to bring people from Sanofi into the collaboration, at such an early stage of research, is unusual. The single factor for success will be whether you can take a company like Warp Drive, with a handful of people, and make it work with an organization of 110,000 people without smothering it."

I believe your readers will agree that in this case the context really matters. Relying on one incomplete source doesn't do justice to the overall approach Chris has been describing.

If you want to truly understand the vision Chris has for Sanofi's research organization, I invite you to catch one of his public speaking engagements in the Boston area.

Kind Regards,

Jack Cox
Sanofi US

One has to wonder if the main difference between the two interviews was that Viehbacher spent more time considering his replies to Xconomy. I take it that since there's been no attempt to deny the earlier quotes in MedCityNews, that they're authentic. And the problem is, even some of his less popular statements in that interview are not false. It really is harder to innovate in a big company compared to a smaller one, for example. But while not false, they're also not the sort of thing one would expect the CEO of a major drug company to just blurt out, either, especially considering the likely effects of such statements on his own company's morale. I believe, in fact, that some current and (recently) ex-Sanofi employees have comments to make on that issue.

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March 1, 2012

What Sanofi Thinks About You

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Posted by Derek

In case you're a scientist, and especially if you're a scientist at Sanofi, their CEO Chris Viehbacher would like you to know some things. What things are those, you ask? Well, how about your position in the world, and especially your position at Sanofi itself?

"What Sanofi is doing is reducing its own internal research capacity. The days when we locked all of our scientists up in a building and put them on a nice tree-lined campus are done. We will do less of our own research. We’re not going to get out of research. We believe we do certain things well in research but we want to work with more outside companies, startup biotechs, with universities."

You know, people with real ideas, innovative stuff, that kind of thing. When asked if this was cheaper, Viehbacher replied:

"It is cheaper. But research and development is either a huge waste of money or too, too valuable. It’s not really anything in between. You don’t really do things because it’s cheaper. The reality is the best people who have great ideas in science don’t want to work for a big company. They want to create their own company. So, in other words, if you want to work with the best people, you’re going to have go outside your own company and work with those people … And, you want to work with them, why do they want to work with you? The reality over the last 10 years is, (a small biotech) wouldn’t get caught dead working with one of these big cumbersome pharma companies. Once you have a funding gap, suddenly there’s a much greater willingness of earlier-stage companies to work with Big Pharma. We’re looking earlier and people who are early need help.

So, if you're one of Sanofi's dwindling number of internal scientists, at least now you know what you're being treated the way you are. It's because you're, well, you're not the sharpest tool in the shed. If your company really wants something to happen, they'll need to bypass you and find someone good. Sticking you in a nice building and telling you to discover stuff hasn't worked out, clearly, and blame must be attached somewhere. Right?

At least Viehbacher has enough self-knowledge to know what people outside his company thinks of it (and its ilk). But hey, now that the people who can actually discover things are desperate, opportunity knocks! This is a business plan known as "So, you need a deal real bad? Well, here's a really bad deal!" And it's the sort of arrangement that just makes everyone happy all around. When asked about working with venture capital firms (as Sanofi recently did with the unfortunately named Warp Drive Bio), the response was:

"There’s two reasons I like (working with venture capital firms). One is, they can sometimes bring competencies we don’t have, like for instance in how to help a startup company. The second thing is to give you a second opinion. Somebody in your company is going to love the science and be championing this internally. But you want to have a second opinion. If you have a venture capital company that’s willing to put money in, that kind of gives a little validation of that."

Those people in his own company again! Nothing but trouble. You wonder, though, what happens when someone inside Sanofi thinks that some hot startup deal might not be a good idea. I wonder if everyone was in love with Warp Drive Bio, for example? No matter - a VC firm was willing to put actual money into the thing, so that's pretty much all the validation anyone needs. Investors in the public markets, though, are apparently fools, because they think that because a big pharma company is interested, that means that a small company might have something going for it:

"The new model, where we’re trying to go, we believe that Big Pharma has competencies in validation. So, if a Big Pharma company does a deal with a smaller company, the smaller company’s share price goes up because people believe that Big Pharma has depth of competencies to judge whether this science is any good or not. Now big companies, and not just Big Pharma, big companies I believe, are not any good at doing innovation. There has to be some element of disruptive thinking to have innovation and I can tell you that big companies do everything to avoid any disruptive thinking in their companies."

Hah! The investors should read Viehbacher's interview, and realize that the sort of scientists who work inside a big company like his wouldn't know an innovation if it slithered up their leg.

Now, there are points to be made about large organizations, and about disruptive thinking, and about various models for drug discovery and for funding ideas. But you know, at the moment, I'm too disgusted to make them.

Update: comments have been disabled now, due to the large volume of them and the follow-up post. Any thoughts can be directed over there - thanks!

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February 22, 2012

Scaling Up a Strange Dinitro Compound (And Others)

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Posted by Derek

I wrote here about a very unusual dinitro compound that's in the clinic in oncology. Now there's a synthetic chemistry follow-up, in the form of a paper in Organic Process R&D.
dinitro.png

It's safe to say that most process and scale-up chemists are never going to have to worry about making a gem-dinitroazetidine - or, for that matter, a gem-dinitroanything. But the issues involved are the same ones that come up over and over again. See if this rings any bells:

Gram quantities of (3) for initial anticancer screening were originally prepared by an unoptimized approach that was not suitable for scale-up and failed to address specific hazards of the reaction intermediates and coproducts. The success of (3) in preclinical studies prompted the need for a safe, reliable, and scalable synthesis to provide larger supplies of the active pharmaceutical ingredient (API) for further investigation and eventual clinical trials.

Yep, it's when you need large, reliable batches of something that the inadequacies of your chemistry really stand out. The kinds of chemistry that people like me do, back in the discovery labs, often has to be junked. It's fine for making 100mg of something to put in the archives - and tell me, when was the last time you put as much as 100 milligrams of a new compound into the archives? But there are usually plenty of weak points as you try to go to gram, then hundreds of grams, then kilos and up. Among them are:

(1) Exothermic chemistry. Excess heat is easy to shed from a 25-mL round-bottom flask. Heat is not so easily lost from larger vessels, though, and the number of chemists who have had to discover this the hard way is beyond counting. The world is very different when everything in the flask is no longer just 1 cm away from a cold glass wall.

(2) Stirring. This can be a pain even on the small scale, so imagine what a headache it is by the kilo. Gooey precipitates, thick milkshake-like reactions, lumps of crud - what's inconvenient when small can turn into a disaster later on, because poor stirring leads to localized heating (see above), incomplete reactions, side products, and more.

(3) Purification. Just run it down a column? Not so fast, chief. Where, exactly, do you find the columns to run kilos of material across? And the pumps to force the stuff through? And the wherewithal to dispose of all that solid-phase stuff once you've turned it all those colors and it can't be used again? And the time and money to evaporate all that solvent that you're using? No, the scale-up people will go a long way to avoid chromatography. Precipitations and crystallizations are the way to go, if at all possible.

Reproducibility. All of these factors influence this part. One of the most important things about a good chemical process is that it works the same flippin' way every single time. As has been said before around here, a route that generates 97% yield most of the time, but with an occasional mysterious 20% flop, is useless. Worse than useless. Squeezing the mystery out of the synthesis is the whole point of process chemistry: you want to know what the side products are, why they form, and how to control every variable.

Oh yeah. Cost.Cost-of-goods is rarely a deal-breaker in drug research, but that's partly because people are paying attention to it. In the med-chem labs, we think nothing of using exotic reagents that the single commercial supplier marks up to the sky. That will not fly on scale. Cutting out three steps with a reagent that isn't obtainable in quantity doesn't help the scale-up people one bit. (The good news is that some of these things turn out to be available when someone really wants them - the free market in action).

There are other factors, but those are some of the main ones. It's a different world, and it involves thinking about things that a discovery chemist just never thinks about. (Does your product tend to create a fine dust on handling? The sort that might fill a room and explode with static electricity sparks? Can your reaction mixture be pumped through a pipe as a slurry, or not? And so on.) It looks as if the dinitro compound has made it through this gauntlet successfully, but every day, there's someone at some drug company worrying about the next candidate.

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February 16, 2012

When Reagents Attack!

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Posted by Derek

Well, since I was just talking about a reagent that can potentially take off without warning, I wanted to solicit vivid experiences from the crowd. What's a compound that you've made that did something violently unexpected? I can recall making some para-methoxybenzyl chloride in grad school (for a protecting group; I was running out of orthogonal protecting groups by that time). It's not hard - take the benzyl alcohol and some conc. HCl and swoosh 'em around. But the product you get by that method isn't the cleanest thing in the world, and on storage, well. . .a vial of it blew out in my hood after the acid had had a chance to work on it.

My most vivid reagent-gone-bad story is probably this one; that's a time I literally came down counting fingers. What other things have you had turn on you?

Comments (78) + TrackBacks (0) | Category: How Not to Do It | Life in the Drug Labs

February 1, 2012

Potassium Hydride Is Not Your Friend

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Posted by Derek

Noted chem-blogger Milkshake seems to have had a close call with a fire started by a tiny potassium hydride residue. It looks like he made it through without serious injury, but that sort of thing will definitely shake a person up.

I hate potassium hydride. Its relative sodium hydride is a common reagent, but it's much tamer (and even so, can cause interesting fires - I knew someone who ignited a heap of it on the pan of a balance while he was weighing it out, which slowed things down a bit). Sodium hydride is usually sold as a 60% dispersion, a dark grey powder soaked with mineral oil to keep it from deteriorating too quickly (and to keep it from setting everything on fire). You can buy 95% sodium hydride, the dry stuff, and there are people who swear by it, but I tend to sweat at it. You never know if it's been stored properly; you may be adding a slug of sodium hydroxide to your reaction without knowing it. And there's the fire part. You'll want to move briskly if you're using the 95%, and I'd pick a day when the humidity is low.

But potassium hydride, that's another beast entirely. It makes the sodium compound look like corn meal, in terms of how forgiving it is. You can't get away with the clumpy oily powder form at all - traditionally, KH is sold as a gooey dispersion of grey powder sitting under a few inches of mineral oil. If it's well dispersed, it's supposed to be 35%. You shake the stuff up until you think it's even mixed, then pipet out the amount of gunk that corresponded to the KH contained therein. Sure you do. What actually happens is that you pipet out the stuff, noticing while you do that it's already settling out inside the pipet, thereby to clog it up when you try to transfer it. No fun.

It's becoming available now dispersed in a block of wax, which is not such a bad idea at all. Wax isn't any harder to get out of your reaction than oil is, and you can carve off chunks and weigh them without so many what-am-I-doing moments. But Milkshake worries that this ease of use will lead to more fires during workups (which is where his reaction ran into trouble), and he may well be right. If you're going to use KH, don't let your guard down.

Comments (47) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs | Safety Warnings

January 31, 2012

The Future of Pharma? Yikes.

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Posted by Derek

Someone has been soaking up the atmosphere at a large pharma company, for sure. "Look, I'm a chemist. I thought you hired me to do chemistry. But so far, all I've heard is gibberish. . .don't you do chemistry here?".

Some of you may enjoy that, but for others, it might just be a bit too realistic to be amusing. . .

The same user has several other videos on YouTube, such as this one, which (in addition to a few four-letter words), features the phrase "Get off the Kool-Aid!" Clearly someone needs to go through some more training. (Thanks to Pharmalot for the original link).

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January 26, 2012

Putting a Number on Chemical Beauty

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Posted by Derek

There's a new paper out in Nature Chemistry called "Quantifying the Chemical Beauty of Drugs". The authors are proposing a new "desirability score" for chemical structures in drug discovery, one that's an amalgam of physical and structural scores. To their credit, they didn't decide up front which of these things should be the miost important. Rather, they took eight properties over 770 well-known oral drugs, and set about figuring how much to weight each of them. (This was done, for the info-geeks among the crowd, by calculating the Shannon entropy for each possibility to maximize the information contained in the final model). Interestingly, this approach tended to give zero weight to the number of hydrogen-bond acceptors and to the polar surface area, which suggests that those two measurements are already subsumed in the other factors.

And that's all fine, but what does the result give us? Or, more accurately, what does it give us that we haven't had before? After all, there have been a number of such compound-rating schemes proposed before (and the authors, again to their credit, compare their new proposal with the others head-to-head). But I don't see any great advantage. The Lipinski "Rule of 5" is a pretty simple metric - too simple for many tastes - and what this gives you is a Rule of 5 with both categories smeared out towards each other to give some continuous overlap. (See the figure below, which is taken from the paper). That's certainly more in line with the real world, but in that real world, will people be willing to make decisions based on this method, or not?
QED%20paper%20chart%20png.png
The authors go for a bigger splash with the title of the paper, which refers to an experiment they tried. They had chemists across AstraZeneca's organization assess some 17,000 compounds (200 or so for each) with a "Yes/No" answer to "Would you undertake chemistry on this compound if it were a hit?" Only about 30% of the list got a "Yes" vote, and the reasons for rejecting the others were mostly "Too complex", followed closely by "Too simple". (That last one really makes me wonder - doesn't AZ have a big fragment-based drug design effort?) Note also that this sort of experiment has been done before.

Applying their model, the mean score for the "Yes" compounds was 0.67 (s.d.0.16), and the mean score for the "No" compounds was 0.49 (s.d. 0.23, which they say was statistically significant, although that must have been a close call. Overall, I wouldn't say that this test has an especially strong correlation with medicinal chemists' ideas of structural attractiveness, but then, I'm not so sure of the usefulness of those ideas to start with. I think that the two ends of the scale are hard to argue with, but there's a great mass of compounds in the middle that people decide that they like or don't like, without being able to back up those statements with much data. (I'm as guilty as anyone here).

The last part of the paper tries to extend the model from hit compounds to the targets that they bind to - a druggability assessment. The authors looked through the ChEMBL database, and ranked the various target by the scores of the ligands that are associated with them. They found that their mean ligand score for all the targets in there is 0.478. For the targets of approved drugs, it's 0.492, and for the orally active ones it's 0.539 - so there seems to be a trend, although if those differences reached statistical significance, it isn't stated in the paper.

So overall, I find nothing really wrong with this paper, but nothing spectacularly right with it, either. I'd be interested in hearing other calls on it as it gets out into the community. . .

Comments (22) + TrackBacks (0) | Category: Drug Development | Drug Industry History | In Silico | Life in the Drug Labs

January 25, 2012

Open Office Plans - A Question or Two

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Posted by Derek

As a follow-up to that post on open offices (and the others referenced in it), I've had a letter from a reader who wonders the following:

(1) How many recent research buildings have been built with open offices, as opposed to cubicles or actual office space? Is this the wave-of-the-future, or is it just a few high-profile examples getting attention?

(2) Does anyone know of any examples where a research department has tried an open-office plan and moved back from it after the experience?

Just to clarify, I don't mean large, relatively open lab spaces (those are pretty common, and often seem to work just fine). What's in question are the wide-open no-walls office and desk areas, with the extreme being the ones where no one has any actual assigned space at all. Thoughts?

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January 23, 2012

This All Too Open Office

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Posted by Derek

Since the topic of open offices in lab design has come up around here several times, I thought I'd point out this op-ed from the New York Times. It's from the author of a new book, Quiet: The Power of Introverts in a World That Can't Stop Talking, and you can guess her point from that title:

SOLITUDE is out of fashion. Our companies, our schools and our culture are in thrall to an idea I call the New Groupthink, which holds that creativity and achievement come from an oddly gregarious place. Most of us now work in teams, in offices without walls, for managers who prize people skills above all. Lone geniuses are out. Collaboration is in.

But there’s a problem with this view. Research strongly suggests that people are more creative when they enjoy privacy and freedom from interruption. And the most spectacularly creative people in many fields are often introverted, according to studies by the psychologists Mihaly Csikszentmihalyi and Gregory Feist. They’re extroverted enough to exchange and advance ideas, but see themselves as independent and individualistic. They’re not joiners by nature.

Well, I wish that I could describe myself as "spectacularly creative", but the rest of that last sentence sounds pretty much like me, anyway. I have no problem talking with people when I meet them. I speak up at meetings, and I really enjoy giving talks to audiences. At the same time. I find that my best thinking is done very much alone. Once I've got something worked out in my head, I'm fine with roaming up and down the halls telling people about it and hearing the reaction. But that working-out has to be done in silence. The phone rings, and my thoughts all take off like like a flock of pigeons. Getting to settle back into their assigned places is not the work of a moment.

For all I know, the new book addresses this problem, but we really need a wider spectrum of words other than "introvert" and "extrovert". There are people who absolutely need human company, human noises and chatter around them. Others would rather have a bit of that, but feel it can be overdone, or just need it in defined amounts, like a meal. And some people don't mind much one way or another, while others are irritated or even panicked by it. You can sort people out, in similar fashion, by their responses to solitude and silence. Given that any research organization is going to have a variety of types in it, you'd think that there would need to be some places where the quiet types could hang out, just as there should be some where the gregarious ones can find what they need.

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January 3, 2012

The Research World Staggers Back to Work

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Posted by Derek

Let's see here. . .145 messages in the work e-mail queue, but most of them are automated reminders that reminded me of the same thing every day of the break. Now to the lab bench. . .now, that was a good idea, making sure that everything was labeled before leaving. As I've said here before, too many times you come back to a bunch of stuff that you were just sure that you're remember every detail of, and feel like a moron as you look at the label on the vial or flask: "Second batch". "Mostly clean". "Large run". Fascinating! Large run of what, exactly? I have, in years past, been reduced to running NMR and LC/MS on my own reactions just to try to figure out what they were, and that's not right.

Reagents that I'd ordered back before the break have come in, and I do recall why I ordered them, at least. You don't want to put in a request for anything sensitive in late December, though, not if it's going to sit out on your bench at RT for a week or ten days. I'm glad I'm not a cell-culture person or a rodent-raiser; my stuff doesn't need to be fed, washed, or watered, and I have the luxury of just walking away from it.

Big pile of junk on the desk, though, some of which never should have stopped there on its way to the recycling bin. I saved this for this morning, since I thought clearing things off would be a good way to jump-start my brain into work mode again. It's different now than it used to be, though - paper's more ephemeral. I have the PDFs of these papers stored, so the hard copy's just a convenience, and if I can't figure out what use it is by looking it it, into the bin it goes without a worry. In the days of paper files, I had to spend a bit more time wondering if I'd regret tossing something that was hard to obtain and actually useful. No more: if it looks useless or unrecognizable, into the blue bin it goes.

And then, for those of us in industry, the company starts waking up. Meeting invitations begin to arrive, to fill out the new year's calendar. Looking at your own schedule, you see the first repeating meetings from last year starting to show up, although some of these will get canceled because there's nothing to talk about yet. People who wanted something from you back in December will start to remember what it was, at about the same time that you remember the people that you wanted something from.

Time, shortly, for the first reaction, the first LC/MS trace, the first NMR, the first lab assay result of the new year. And for some of us, the first blog post. Welcome back!

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December 9, 2011

Uranium, Eh?

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Posted by Derek

For those of you keeping count of how many elements you've used in your chemical careers, you now have another possibility. This paper suggests that uranyl anions are good for epoxide polymerization, so who knows, they may be good for something else as well. I don't anticipate adding this one to my life list, but there's at least a chance of it now. . .

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November 7, 2011

Rating A Massive Pile of Compounds

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Posted by Derek

Here's an interesting exercise carried out in the medicinal chemistry departments at J&J. The computational folks took all the molecules in the company's files, and then all the commercially available ones (over five million compounds), minus natural products, which were saved for another effort, and minus the obviously-nondruglike stuff (multiple nitro groups, solid hydrocarbons with no functionality, acid chlorides, etc.) They then clustered things down into (merely!) about 20,000 similarity clusters, and asked the chemists to rate them with up, down, or neutral votes.

What they found was that the opinions of the med-chem staff seemed to match known drug-like properties very closely. Molecular weights in the 300 to 400 range were most favorably received, while the likelihood of a downvote increased below 250 or above 425 or so. Similar trends held for rotatable bonds, hydrogen bond donors and acceptors, clogP, and other classic physical property descriptors. Even the ones that are hard to eyeball, like polar surface area, fell into line.

It's worth asking if that's a good thing, a bad thing, or nothing surprising at all. The authors themselves waffle a bit on that point:

The results of our experiment are fully consistent with prior literature on what confers drug- or lead-like characteristics to a chemical substance. Whether the strategy will yield the desired results in the long term with respect to quality, novelty, and number of hits/leads remains to be seen. It is also unclear whether this strategy can lead to sufficient differentiation from a competitive stand-point. In the meantime, the only undeniable benefits we can point to is that we harnessed our chemists’ opinions to select lead-like molecules that are totally within reasonable property ranges, that fill diversity holes, and that have been purchased for screening, and that we did so in a way that promoted greater transparency, greater awareness, greater collaboration, and a renewed sense of involvement and engagement of our employees.

I'll certainly give them the diversity-of-the-screening-deck point. But I'm not so sure about that renewed sense of involvement stuff. Apparently 145 chemists participated in total (this effort was open to everyone), but no mention is made of what fraction of the total staff that might be. People were advised to try to vote on at least 2,000 clusters (!), but fewer than half the participants even made it that far. Ten people made it halfway through the lot, and 6 lunatics actually voted on every single one of the 22,015 clusters, which makes me think that they had way too much time on their hands and/or have interesting and unusual personality features. A colleague's reaction to that figure was "Wow, they'll have to track those people down", to which my uncharitable reply was "Yeah, with a net".

So while this paper is interesting to read, I can't say that I would have been all that happy participating in it (although I've certainly had smaller-scale experiences of this type). And I'd like to know what the authors thought when they finally assembled all the votes and realized that they'd recapitulated a set of filters that they could have run in a few seconds, since they're surely already built into their software. And we all should reflect on how thoroughly we seem to have incorporated Lipinski's rules into our own software, between our ears. On balance, it's probably a good thing, but it's not without a price.

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October 27, 2011

Fish Nor Fowl

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Posted by Derek

Talking about hydrogenation here the other day brought up another thought: there's a point where lab work becomes quite difficult, and there are not a lot of good options to help with that. I'm talking about scale-up work, the grey zone between benchtop synthesis and production.

The first of those is where I spend my time. I've often said that there are really only two yields to be calculated in medicinal chemistry: enough and not enough. For some cases, "enough" can be two milligrams, if all you need is one assay (although you're not adding to the screening collection that way). Twenty is plenty for a new compound; it'll be in stock for years at the usual rates of screening.

But later on, when you start to get interested in a particular molecule, those numbers inflate quickly. In vivo tests, PK, toxicology - all these can start to chew up much larger amounts of compound. Hundreds of mgs, then grams, tens of grams, hundreds of grams to get through preclinical because it turns out that you need another large-animal run - those of you in the labs will be familiar with the progression. And well downstream of people like me, there's pilot plant work and real commercial production, where things are measured in kilos and up.

Those folks have a tricky job, but they have one advantage: they know what compound they're making, and eventually they've settled on a route that works. (If you can't do that, well, you don't have a drug). And for a real money-making compound, it's worth investing in dedicated equipment, whole dedicated facilities if need be, just to make it correctly. Earlier in the process, though, you have to be ready for all kinds of chemistries to make all kinds of compounds.

The medium-scale is where those two worlds collide. A medicinal chemist can generally make things up to the tens of grams, maybe a hundred or two, using roughly the same techniques that are used on the smaller scale: round-bottom flasks, suction filtration, magnetic stirring, standard-sized rotary evaporators, silica gel columns. Everything gets bigger and more unwieldy, and it always takes more time (and more solvent) than you thought, but it can get done. Some of the more exotic small-scale chemistries do start to break down on you, which also also adds to the time needed when you have to come up with alternatives.

But if you're always having to work on roughly the hundred-gram scale, you're straddling two regimes. The size of the glassware gets hard to manage - things are heavy, they tip over, they crack - and you really have to have more serious capacity for things like solvent evaporation. But this is way too small for industrial-plant equipment, the kind of thing where you design the process to start on the third floor to take advantage of gravity as you pump the contents of the big batch reactor downstairs for the next step. And it's getting too big for scaled-up versions of standard equipment, but at the same time, you need the versatility that general-purpose labware provides.

Some kinds of gear help to bridge this gap - overhead mechanical stirrers, outboard circulating chillers, and large-capacity rota-vaps come to mind. But there are many other cases where something that's neither benchtop nor pilot plant is needed, and doesn't necessarily exist. Hydrogenation is a case in point. It's done on an industrial scale; that's where all that partially hydrogenated vegetable oil comes from, for one thing. And hydrogenation is common on the gram scale or below. But hydrogenating three hundred grams of something can be a real pain in many labs. The common solution is roll-your-eyes-and-split-it-into-batches, but that gets old fast. . .

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October 24, 2011

Tossing Out the 1920s Hydrogenators: Can It Be Done?

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Posted by Derek

We organic chemists have always liked the hydrogenation reaction. Take your compound up in a solvent, add a pinch of black catalyst powder, and put some hydrogen gas into the vessel. Come back a few hours later, filter off the catalyst, and there's your cleanly reduced compound, ready for the next step, often looking even better than it did before you ran the reaction.

For many decades, the standard ways to run these reactions have been to either take a balloon of hydrogen gas and attach it to the top of your round-bottom flask (as in this video clip), or run it on a "Parr shaker". That last piece of equipment has been with us, essentially unchanged, since the 1920s. It's simplicity itself: a thick-walled glass bottle for your reaction, a tube and stopper running into it (with a framework to hold it down under pressure), a hydrogen reservoir, and a motor to shake the bottle around. Its relentless dackadackadackadacka noise is one of the standard sounds of organic chemistry. These things are always off in separate hydrogenation rooms, and when you have several of them running in there at once the out-of-phase clatter makes sequential thought almost impossible. I wish that there were an audio file I could link to, but working organic chemists will all know the tune.

There are newer ways to run the reaction, and flow chemistry is the obvious choice. The "H-Cube" was an early entry into this space, and many of them are to be found around the chemistry world. Unfortunately, many of them are also found gathering dust. Uptake of the machine has been uneven, despite some obvious advantages. That's because the first-generation machine has some obvious disadvantages, too: you have to change the catalyst cartridge every time you want to try something different, because there's only one at a time. The cartridges themselves are not too large, so if your reaction isn't efficient enough, you can have a problem with not being able to run everything in one-time-through mode. And there's no liquid handling - you have to load your sample and collect it in whatever means you see fit. Various people have modified the machine over the years to get around these limitations, and the company now sells a machine incorporating many of these ideas. And there are competitors out there as well.

So here's my question for the chemical audience: has anyone had enough nerve to ditch the Parr shakers completely? I've heard of places that have done it, but when you inquire closely, you often find that there are still a couple around that do a disproportionate share of the hydrogenations. Are there any flow solutions that work well enough to get away with this? You'd think that there would be advantages to a walk-up instrument, if it were robust enough - put your starting solution in position A-3 on the rack, tell it what pressure and temperature you want, which catalyst to use, and add your run to the queue. Come back after lunch and there it is, eluted into another container, ready for you to pick up. NMR machines work this way, and so do microwave reactors. But do hydrogenators? Today, in the real world? Experiences with such things welcome in the comments. . .

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September 13, 2011

Fifty Years of Med-Chem Molecules: What Are They Telling Us?

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Posted by Derek

I wanted to send people to this 50-year retrospective in J. Med. Chem.. It's one of those looks through the literature, trying to see what kinds of compounds have actually been produced by medicinal chemists. The proxy for that set is all the compounds that have appeared in J. Med. Chem. during that time, all 415, 284 of them.

The idea is to survey the field from a longer perspective than some of the other papers in this vein, and from a wider perspective than the papers that have looked at marketed drugs or structures reported as being in the clinic. I'm reproducing the plot for the molecular weights of the compounds, since it's an important measure and representative of one of the trends that shows up. The prominent line is the plot of mean values, and a blue square shows that the mean for that period was statistically different than the 5-year period before it (it's red if it wasn't). The lower dashed line is the median. The dotted line, however, is the mean for actual launched drugs in each period with a grey band for the 95% confidence interval around it.
Molecular%20weight.png
As a whole, the mean molecular weight of a J. Med. Chem. has gone up by 25% over the 50-year period, with the steeped increase coming in 1990-1994. "Why, that was the golden age of combichem", some of you might be saying, and so it was. Since that period, though, molecular weights have just increased a small amount, and may now be leveling off. Several other measures show similar trends.

Some interesting variations show up: calculated logP, for example, was just sort of bouncing around until 1985 or so. Then from 1990 on, it started a steep increase, and it's hard to tell if that's leveling off or not even now. At any rate, the clogP of the literature compounds has been higher than that of the launched drugs since the mid-1980s. Another point of interest is the fraction of the molecules with tetrahedral carbons. What you find is that "flatness" in the literature compounds held steady until the early 1990s (by which point it was already disconnected from the launched drugs), but since then it's gotten even worse (and further away from the set of actual drugs). This, as the authors speculate, is surely due to metal-catalyzed couplings taking over the world - you can see the effect right in front of you, and so far, the end is not in sight.

Those two measures are the ones moving the most outside the range of marketed drugs. And despite my shot at early combichem molecules, it's also clear that publication delays mean that some of these things were already happening even before that technique became fashionable (although it certainly revved up the trends). Actually, if you want to know When It Changed in medicinal chemistry, you have to go earlier:

It is worth noting that these trends seemed to accelerate in the mid-1980s, indicating that some change took place in the early 1980s. The most likely explanations for an upward change in the early 1980s (before the age of combinatorial chemistry or high-throughput screening) seem to be advances in molecular biology, i.e., understanding of receptor subtypes leading to concerns about specificity; target-focused drug design and its corresponding one-property-at-a-time optimization paradigm (possibly exacerbated by structural biology); and improvements in technologies which enabled the synthesis and characterization of more complex molecules.

Target-based drug design, again. I'm really starting to wonder about this whole era. And if you'd told me back in, say, 1991 about these doubts that I'd be having, I'd have been completely dumbfounded. But boy, do I ever have them now. . .

Comments (26) + TrackBacks (0) | Category: Chemical News | Drug Industry History | Life in the Drug Labs

September 12, 2011

From the RSC/SCI Symposium: A Med-Chem Anomaly

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Posted by Derek

Well, actually, this might not be an anomaly. Medicinal chemists will have heard of the "magic methyl" effect, where small changes can make a big difference in affinity for a drug candidate. This morning I heard an interesting talk by Phil Sanderson of Merck on allosteric Akt inhibitors for cancer. I won't go into all the kinase-ness, although it was definitely worth hearing about. What caught my eye was something he mentioned at the end of the talk. The first compound below was an early screening hit in their work, something that had been in Merck's files since the early 1970s. After a huge amount of work over many years, which you can follow though the literature if you like with a search for "allosteric" and "Akt", they found that four-membered rings were very useful in the structures. Going back to the original structure and adding that same modification to it improved its potency by roughly 100-fold.
MRK%20starting%20point.pngMRK%20ending%20point.png
One methylene group! You wonder what might have happened if they'd done that early in the project, but as Sanderson correctly noted, no one would have done that (it's synthetically tricky; no one would have put in the time). And they don't have any structural information that seems to explain this effect, he says. So if you're looking for an illustration of what makes medicinal chemistry the wild ride it is, you've got an excellent one here.

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August 24, 2011

Disappearing Information, Courtesy of Aldrich Chemical

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Posted by Derek

I've been in the lab all afternoon setting up reactions, and that prompts me to write about something that I've been noticing. Is it just me, or does Aldrich seem to be abandoning the practice of putting any useful information on their labels?

This has been creeping up for a while, but I worry that instead of an anomaly it's the way of the future. I just got in several bottles of reagents from Aldrich, and basically all they have on their labels are the names of the compounds. No molecular weight, no density, no melting or boiling point: nothing but a line of type surrounded by an Aldrich label. And while I can go look these things up, and while my electronic notebook often is able to provide the information, it would still be a lot more convenient to have it on the label as well. You know, like it used to be.

I assume that this is a cost savings. As a rule, I assume that the most likely answer to any question that starts out "I wonder how come they. . ." is "money". But it's a shame.

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August 9, 2011

Drug Research Areas You Wish You'd Never Heard Of

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Posted by Derek

A conversation the other day got me to thinking: over the course of my career, I've worked in the following therapeutic areas (more or less in chronological order): CNS (dementia, then Alzheimer's), diabetes, osteoporosis, obesity, oncology, anti-bacterials, multiple sclerosis, and antivirals. That covers a fair amount of ground, but there are still areas I've never really touched on - not much that would qualify as cardiovascular and not much inflammation, for example. So I'm sure that there are readers out there who have seen more drug discovery territory than I have - anyone who thinks that they have the local record, feel free to leave details in the comments.

A second question is whether there are therapeutic areas that you'd always wanted to try but never have. (Anti-infectives would have been in that category for me until the last few years). The opposite of that is well worth asking, too: are there disease areas that you regret ever having touched on? For my part, I learned a lot doing my Alzheimer's work, but in retrospect, much of it was a ferocious waste of effort, considering the results, so I'd probably put that one at the top. Other candidates?

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June 15, 2011

High Pressure - The Good Kind

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Posted by Derek

I was talking with some colleagues about underused synthetic chemistry technologies the other day, and one that came up was high pressure. Here's a new paper from JACS looking at pressure effects on a common reaction (Michael addition), and there are quite a few others like it scattered around the literature. In general, reactions that have a lot of steric congestion, or whose transition state occupies less volume than the starting complex, will show some effects as you go to higher pressure.

But no one ever does it. Well, not quite "no one", but pretty damned few people do. I think the problem is that you need special equipment, for the most part, and you also need to have the idea of using high pressure. Both of those are in short supply. But I wonder if someone were to make a lab-friendly high pressure reactor, if it might get taken up a bit more. (Note to equipment manufacturers: I am not promising to buy the thing if you make it. But it's a thought).

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June 10, 2011

Chem-Geekery: Name Reactions You've Never Run

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Posted by Derek

A colleague of mine is running a Diels-Alder reaction this morning, and turned out to have never run one before, despite many years of experience in chemistry. (I'd bet, though, that a fair number of chemists who have run the reaction did it in an undergraduate lab and never have since). I've run them - although it's been a while - and I've done the Claisen rearrangement (ditto), the Knoevenagel condensation, the Barbier reaction, and the Henry reaction. I've done plenty of Horner-Emmons-Wadsworth reactions (although not in the last few years), Jones oxidation, Birch reduction, the Arbuzov reaction, and a Chichibabin pyridine synthesis, many years ago. And I've done a Cannizzaro, the Gabriel synthesis, Ferrier rearrangements, the Shapiro reaction, Peterson olefination, and Lindlar reduction. I've run Sandmeyer reactions, the Prins, Staudinger reduction, Ullmann coupling, and Weinreb ketone synthesis. I've done the Wolff–Kishner reduction (once) and Wurtz coupling (once), a Dakin-West (once), a Darzens (once), and a Delepine reaction (once).

But I've never done a straight aldol condensation, at least, not on purpose. And I've never, as far as I can recall, actually done a Fischer indole synthesis, or the lovely Skraup reaction. I've never run a Bayliss-Hillman, a Ritter reaction, a Cope rearrangement, a Julia olefination, a Pictet-Spengler, a Nazarov cyclization, nor a pinacol, and I don't think I've ever set up an ene reaction.

So what's on your list? What's the most famous reaction you've never run? Is there some reaction you've always sort of wanted to do, but never had the reason?

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June 6, 2011

Underused Lab Solvents

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Posted by Derek

Interesting post from Milkshake over at Org Prep Daily on solvents that don't get used as much as they might in synthetic chemistry. Among them: trifluoroethanol, methyl t-butyl ether, and 1-methoxy-2-propanol. Definitely worth a look for those of us who are trying to get things to work at the bench - other nominations welcomed in the comments.

And if you're looking for someone to do that, I believe that Milkshake himself is still looking for a position (unpaid advertisement!)

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May 26, 2011

Pfizer's Brave New Med-Chem World

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Posted by Derek

OK, here's how I understand the way that medicinal chemistry now works at Pfizer. This system has been coming on for quite a while now, and I don't know if it's been fully rolled out in every therapeutic area yet, but this seems to be The Future According to Groton:

Most compounds, and most actual chemistry bench work, is apparently going to be done at WuXi (or perhaps other contract houses?) Back here in the US, there will be a small group of experienced medicinal chemists at the bench, who will presumably be doing the stuff that can't be easily shipped out (time-critical, difficult chemistry, perhaps even IP-critical stuff, one wonders?) But these people are not, as far as I can tell, supposed to have ideas of their own.

No, ideas are for the Drug Designers, which is where the rest of Pfizer's remaining medicinal chemistry head count are to be found. These are the people who keep trac of the SAR, decided what needs to be made next, and tell the folks in China to make it. It's presumably their call, what to send away for and what to do in-house, but one gets the sense that they're strongly encouraged to ship as much stuff out as possible. Cheaper that way, right? And it's not like there's a whole lot of stateside capacity, anyway, at this point.

What if someone working in the lab has (against all odds) their own thoughts about where the chemistry should go next? I presume that they're going to have to go and consult a Drug Designer, thereby to get the official laying-on of hands. That process will probably work smoothly in some cases, but not so smoothly in others, depending on the personalities involved.

So we have one group of chemists that are supposed to be all hands and no head, and one group that's supposed to be all head and no hands. And although that seems to me to be carrying specialization one crucial step too far, well, it apparently doesn't seem that way to Pfizer's management, and they're putting a lot of money down on their convictions.

And what about the whole WuXi/China angle? The bench chemists there are certainly used to keeping their heads down and taking orders, for better or worse, so that won't be any different. But running entire projects outsourced can be a tricky business. You can end up in a situation where you feel as if you're in a car that only allows you to move the steering wheel every twenty minutes or so. Ah, a package has arrived, a big bunch of analogs that aren't so relevant any more, but what the heck. And that last order has to be modified, and fast, because we just got the assay numbers back, and the PK of the para substituted series now looks like it's not reproducing. And we're not sure if that nitrogen at the other end really needs to be modified any more at this point, but that's the chemistry that works, and we need to keep people busy over there, so another series of reductive aminations it is. . .

That's how I'm picturing it, anyway. It doesn't seem like a particularly attractive (or particularly efficient) picture to me, but it will at least appear to spend less money. What comes out the other end, though, we won't know for a few years. And who knows, someone may have changed their mind by then, anyway. . .

Comments (117) + TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History | Life in the Drug Labs

May 20, 2011

What Would You Get Rid Of?

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Posted by Derek

Here's a general question for all you lab types, prompted by some rearranging that I've been doing over at my bench: what piece of equipment do you get the least use out of for the space it takes up? Those dusty items that haven't been touched in a couple of years are obvious candidates, but feel free to add some instruments that work, but crowd out other useful items. . .

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May 10, 2011

A Complete Diversion: Purple Compounds

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Posted by Derek

I had to use some potassium permanganate a little while back - first time in years I'd had any of it out in the lab, and I was reminded of just what a spectacular purple color the stuff has.
KMNO4.jpg
There's some of it dissolving in water, via Flickr, and it's hard to beat for sheer purplelosity. But the solid doesn't look as impressive; it's quite dark (which is probably how it makes such an intense color on dissolution). So what's the best purple solid in the lab?
Chromium%28III%29-chloride-purple-anhydrous-sunlight.jpg

I have to promote my personal favorite, chromium (III) chloride (image courtesy of the Wikipedia entry).

That's a pretty good shot, but it really should be experienced in person. The stuff is metallic purple flakes, weirdly reflective - it looks like it should be the color of a custom racer's hood, rather than anything you'd actually order from a chemical supply house. Now all I have to do is find a use for it in the lab. . .

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May 9, 2011

What Medicinal Chemists Really Make

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Posted by Derek

Chemists who don't (or don't yet) work in drug discovery often wonder just what sort of chemistry we do over here. There are a lot of jokes about methyl-ethyl-butyl-futile, which have a bit of an edge to them for people just coming out of a big-deal total synthesis group in academia. They wonder if they're really setting themselves up for a yawn-inducing lab career of Suzuki couplings and amide formation, gradually becoming leery of anything that takes more than three steps to make.

Well, now there's some hard data on that topic. The authors took the combined publication output from their company, Pfizer, and GSK, as published in the Journal of Medicinal Chemistry, Bioorganic Med Chem Letters and Bioorganic and Medicinal Chemistry, starting in 2008. And they analyzed this set for what kinds of reactions were used, how long the synthetic routes were, and what kinds of compounds were produced. Their motivation?

. . .discussions with other chemists have revealed that many of our drug discovery colleagues outside the synthetic community perceive our syntheses to consist of typically six steps, predominantly composed of amine deprotections to facilitate amide formation reactions and Suzuki couplings to produce biaryl derivatives. These “typical” syntheses invariably result in large, flat, achiral derivatives destined for screening cascades. We believed these statements to be misconceptions, or at the very least exaggerations, but noted there was little if any hard evidence in the literature to support our case.

Six steps? You must really want those compounds, eh? At any rate, their data set ended up with about 7300 reactions and about 3600 compounds. And some clear trends showed up. For example, nearly half the reactions involved forming carbon-heteroatom bonds, with half of those (22% of the total) being acylations. mostly amide formation. But only about one tenth of the reactions were C-C bond-forming steps (40% of those were Suzuki-style couplings and 18% were Sonogoshira reactions). One-fifth were protecting group manipulations (almost entirely on COOH and amine groups), and eight per cent were heterocycle formation, and everything else was well down into the single digits.

There are some interesting trends in those other reactions, though. Reduction reactions are much more common than oxidations - the frequency of nitro-to-amine reductions is one factor behind that, followed by other groups down to amines (few of these are typically run in the other direction). Among those oxidations, alcohol-to-aldehyde is the favorite. Outside of changes in reduction state, alcohol-to-halide is the single most favorite functional group transformation, followed by acid to acid chloride, both of which make sense from their reactivity in later steps.

Overall, the single biggest reaction is. . .N-acylation to an amide. So that part of the stereotype is true. At the bottom of the list, with only one reaction apiece, were N-alkylation of an aniline, benzylic/allylic oxidation, and alkene oxidation. Sulfonation, nitration, and the Heck reaction were just barely represented as well.

Analyzing the compounds instead of the reactions, they found that 99% of the compounds contained at least one aromatic ring (with almost 40% showing an aryl-aryl linkage) and over half have an amide, which totals aren't going to do much to dispel the stereotypes, either. The most popular heteroaromatic ring is pyridine, followed by pyrimidine and then the most popular of the five-membered ones, pyrazole. 43% have an aliphatic amine, which I can well believe (in fact, I'm surprised that it's not even higher). Most of those are tertiary amines, and the most-represented of those are pyrrolidines, followed closely by piperazines.

In other functionality, about a third of the compounds have at least one fluorine atom in them, and 30% have an aryl chloride. In contrast to the amides, there are only about 10% of the compounds with sulfonamides. 35% have an aryl ether (mostly methoxy), 10% have an aliphatic alcohol (versus only 5% with a phenol). The least-represented functional groups (of the ones that show up at all!) are carbonate, sulfoxide, alkyl chloride, and aryl nitro, followed by amidines and thiols. There's not a single alkyl bromide or aliphatic nitro in the bunch.

The last part of the paper looks at synthetic complexity. About 3000 of the compounds were part of traceable synthetic schemes, and most of these were 3 and 4 steps long. (The distribution has a pretty long tail, though, going out past 10 steps). Molecular weights tend to peak at between 350 and 550, and clogP peaks at around 3.5 to 5. These all sound pretty plausible to me.

Now that we've got a reasonable med-chem snapshot, though, what does it tell us? I'm going to use a whole different post to go into that, but I think that my take-away was that, for the most part, we have a pretty accurate mental picture of the sorts of compounds we make. But is that a good picture, or not?

Comments (24) + TrackBacks (0) | Category: Chemical News | Drug Development | Life in the Drug Labs | The Scientific Literature

April 20, 2011

Return of the Magic Methyl Group

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Posted by Derek

Well, I've been traveling this week, but have found a bit of time to blog. Today we have something new about SAR, courtesy of the BASF marketing department.

Medicinal chemists are all familiar with the "magic methyl group" effect - the phenomenon of a single methyl sending a compound over the top in terms of activity, selectivity, PK, or what have you. I've seen it several times myself. Usually you starting wondering why you didn't just put the thing in six months before, but that's rarely the way things work out.

Well, we're not the only people who notice such things. Check out this ag-chem ad from BASF for their Kixor herbicide (sent along by an alert reader). Scroll down to the bottom of the page, and you'll find:

Methyl groups serve as "metabolic handles" in crops delivering crop safety and giving you confidence knowing you have made the right choice"

There you have it! Methyl groups add confidence! Now that's worth knowing - and you have to wonder what secrets other functional groups hold. Do carboxylic acids put a spring in your step? Do para-fluoros freshen the breath? Will a sulfonamide help you make the big sale? Someone in the advertising department might believe it - as Dilbert put it, marketing people even believe marketing surveys, so what's the limit?

Comments (18) + TrackBacks (0) | Category: Life in the Drug Labs

April 5, 2011

In Which I Reminisce About the Prins Reaction, Chemical Abstracts, and John Keats

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Posted by Derek

Well, this post needs updating. In it I mentioned never running a Prins reaction again since the 1980s, nor any photochemistry, and today what do I find myself doing? Both of them, although not at the same time.

I am, fortunately, not running the Prins this way. But even bringing it up at all recalls to me a key part of my education. When I first joined my graduate school research group, I was put to making some tetrahydropyran systems. I was handed a synthesis, drawn up before my arrival, of how to make the first one, and like most first-year grad students, I gamely dug and and started to work on it.

I should have devoted a bit more thought to it. I won't go into the details, but it was a steppy route that relied, in the final ring-closure step, on getting the cyclic ether to form where one of the partners was a neopentyl center. The organic chemists in the audience will immediately be able to guess just how well that went.

So I beat on it and whacked at it, getting nowhere as I used up my starting material, until I was finally driven to the library. In the spring of 1984, that was a different exercise than it is now, involving the 5-year Chemical Abstracts indices and an awful lot of page flipping. (I haven't so much as touched a bound volume of CA in I don't know how many years now). If you were a nomenclature whiz, you could try looking up your compound, or something like it, in the name index, but a higher-percentage move was often to look up the empirical formula. That gave you a better shot, because (if it was there at all) you could see how CA named your system and work from there.

To my great surprise, the second set of collective indices I checked (the good ol' 9th), yielded a direct hit on an empirical formula, and the name looked like exactly what I had been trying to make. The reference was in Tetrahedron, which we most certainly had on the shelf, and I zipped over to see if there was any detail on how to make the stuff.

There was indeed. A one-stepper Prins cyclization gave just the ring system I'd been trying to make, and that was one step from the intermediate I needed. I just stared at the page, though. I honestly couldn't believe that this was real (as I mentioned, I was in about my second month of grad school lab work). Surely the synthesis I'd been given was the way to make this stuff? Surely the people responsible for it had checked the literature before drawing it up? (After all, it had only taken my a few minutes to find the stuff myself). Surely I couldn't just make the ring in one afternoon using two starting materials I could buy cheaply from Aldrich?

Well, surely I could. And that's just what I did, and got my project moving along until the next interesting difficulty came up a couple of months later. But I still recall standing there in the Duke chemistry library, looking at that journal article "with a wild surmise" that perhaps I should check things out for myself next time instead of just taking everyone else's word. It took a couple more lessons for me to really grasp that principle (Nullius in verba!, but it's helped me out a great deal over the years. I have the 27-year-old photocopy I made that afternoon in front of me now. It's a good reminder.

Comments (15) + TrackBacks (0) | Category: Graduate School | Life in the Drug Labs | The Scientific Literature

April 4, 2011

Surely You Have Something Else to Do

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Posted by Derek

Here's a question for all the organic chemists out there. A discussion with some colleagues the other day got me to thinking about the reactions that we all tend to underuse. The category I offered up was gaseous reagents. Outside of hydrogenation, I think that many of us sort of go "Ehh. . ." when we come across transformations that need lecture bottles, cylinder, regulators, and so on.

Add to that the unpleasant nature of many of the gases themselves, and it's easier to find something else to do. But there are a lot of good reactions and reagents in this category - metal-catalyzed CO insertions, reactions with ammonia, acetylene, sulfur dioxide, etc. There's just a bit of a higher activation barrier to getting around to running them.

I'd say that photochemistry and electrochemistry are in this "rather do something else" category as well. Other nominations welcome!

Comments (37) + TrackBacks (0) | Category: Life in the Drug Labs

March 22, 2011

A 200-Proof Shot of Medicinal Chemistry

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Posted by Derek

For the chemists out there in the crowd: have you been looking for a paper to read that's filled, beginning to end, with good, solid, old-fashioned medicinal chemistry? Look no further than this one, on recent reports of isosteres. This sort of thing is still the heat of med-chem as it's practiced in the real world - messing around with the structure of an active molecule to see what you can improve and what you can get away with.

If you're not a medicinal chemist, the idea of a bioisostere is some chemical group that can substitute for another one. Classic examples are things like swapping in a tetrazole ring for a carboxylic acid or an oxadiazole for an ester. Here are some examples - even if your organic chemistry is shaky, you can see the similarities across these structures. If it works, you can change the other properties of your molecule (solubility, stability, selectivity) for the better while still keeping the key features that made the original group valuable for activity. It's not something that just automatically comes through every time - sometimes there just is no substitute - but it works enough of the time to be one of the essential techniques.

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March 18, 2011

Brave New Office

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Posted by Derek

Management fads are truly a bad sign. I don't think that there's anyone out there in the working world who doesn't realize this, on some level, but it's worth keeping in mind. When some higher-up at your company decides "You know, we'd make a huge leap in productivity if we just did everything totally differently than we've ever done them before - I read this great article!", then you really need to hunker down until the fit passes.

Well, some of the folks at GlaxoSmithKline down in Research Triangle are probably looking for somewhere to hide. Because according to this article, the company is (yes!) at the forefront of a movement that's (yes!) sweeping the nation: open office space. No assigned desks, no permanent locations, just everyone floating around in a cloud of happy productivity. Jim Edwards at Bnet is right when he calls this "slightly insane".

Um. . .haven't we been hearing about this wonderful innovation for years now? And haven't several companies tried it and abandoned it, because (strangely enough) their employees didn't like the idea of putting their possessions into lockers every morning, wandering (or scrambling) around for desk space, and being unable to leave the slightest sign of anything personal around their work area? Here are some tempting details:

All employees are assigned a storage unit where they can keep files, a keyboard, a power pack and a mouse. There will also be group storage spaces where files that need to be accessed by more than one person can be kept. Any files that are not accessed regularly will be stored off-site. GSK's document retention policy isn't changing; it just may end up being followed more closely.

Gosh, that does sound like what I've been yearning for all these years. Making the transition to this wonderful environment isn't easy, though:

The larger move will ultimately include an extensive education campaign to prepare employees for their new surroundings.

Employees will work in neighborhoods, each of which includes meeting rooms and quiet areas. They'll attend etiquette workshops, and each neighborhood will adopt a set of policies to deal with hypothetical situations that may come up.

The groups that are moving to the new layout are those whose managers embraced the change. (Admin Shelby) Bryant now sits at a desk directly across from her boss, David Bishop, GSK's director of site operations in RTP.

Bishop said as the move gets closer, more and more departments are expressing interest in unchaining themselves from their desk.

"I don't believe we will ever get to where everybody wants it," he said.

Maybe not! But that'll be their loss, won't it, not having to go through all that education, and attend those etiquette workshops, and then throw out all their stuff. Honestly, I think I'd rather chew on glass than attend a series of workplace etiquette seminars and get re-educated by someone who tells me that I'm not going to have a desk any more. And those meetings to set behavior policies, those will be delightfully excruciating, for sure. What on earth is the company thinking?

Well, they're thinking about how this will allow them to vacate several buildings, because housing the employees this way takes up less room. So once again, this conforms to a rule that has seldom let me down: any question that starts out with "I wonder how come they. . ." can be answered with the word "Money".

Comments (149) + TrackBacks (0) | Category: Business and Markets | Life in the Drug Labs

March 2, 2011

It's Worth It to Know That There Are Others

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Posted by Derek

So, when it comes to sitting through inane meetings and pointless presentations, it isn't just me. . .what a relief!

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January 19, 2011

Dogs and Ponys

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Posted by Derek

Here's a problem that I've seen at every company I've worked at, and there are good reasons to believe that it afflicts every company out there. That's because I think it's grounded in human nature: dog-and-pony-itis.

That's the phrase I use for what happens to meetings over time. Many readers will be familiar with the process: a company gradually accumulates regular meetings on its internal calendar - project team meetings, individual chemistry and biology meetings inside that, overall review meetings, resourcing, planning, interdisciplinary meetings. . .everyone who's anyone, in some companies, has to be calling a meeting of their very own.

Eventually, someone says "Enough!" and purges the schedule, replacing the tangle of overlapping meetings with A Brand New Meeting or two. These will actually discuss issues, for once, and people are encouraged to actually say what's really going on with their projects. For once. And who knows, maybe that's the case (for once) - but it doesn't last.

Because every time, in my experience, the Brand New Meeting itself starts to collect barnacles. Over time, it becomes less useful, and more of a show. The music starts up, the Pomeranian dogs start hopping around and barking, and the trained horses make their entrance from the wings. It becomes more expedient to just get up and tell people the broad strokes of a project, especially the broad strokes that are actually working, and leave the messy details out. And gradually, other meetings spring up to try to take up the slack, since nothing ever seems to get done at the Brand New. . .

The thing is, I don't know how to stop this from happening. It comes on like rust. I've lost count of the we've-got-to-get-rid-of-this-stupid-meeting initiatives I've seen over the years, and every time the cycles eventually repeats. So here's a question: has anyone broken out? And if you have, how? Suggestions welcomed in the comments. . .

Comments (54) + TrackBacks (0) | Category: Life in the Drug Labs

December 8, 2010

Fluorination Without Tears. Or Panicked Shouts.

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Posted by Derek

One of the comments to this post brought my attention to this paper in JACS on a new fluorinating agent. I just finished writing a column on fluorinated drugs for Chemistry World, so the subject is on my mind.

I have to say, this looks like it could be a very useful reagent. I've never worked with any arylsulfur trifluorides, but that looks to change soon, since I'd guess that this stuff will shortly be commercialized. An air-stable, non-runaway reactive fluorinating reagent would hit the spot. It would be fine with me if I never open another bottle of DAST again, and my experiences with the likes of xenon difluoride haven't been wonderful, either. If anyone gets a chance to try this compound out, let us know if it's all it's billed to be!

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December 6, 2010

A Quick Glassware Question

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Posted by Derek

Here's a lab equipment question that someone probably knows the answer to, but that someone isn't me. Anyone know where you can buy Corex glass? I'm looking for a tube of the stuff, about 3cm by 28cm, but the only thing I can find are centrifuge tubes. The stuff is (or at least was) made by Corning. It's an aluminosilicate and it's mechanically quite strong, so the centrifuge use makes sense, but no one seems to sell a plain tube of the stuff. Any ideas?

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November 19, 2010

Novartis and the Labs of the Future

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Posted by Derek

Here's a look (PDF) at the Novartis "Labs of the Future". This looks like another one of these "open lab" concepts, and it appears that Basel has really bought into the idea. The interview with the two biologists helping to head the project is. . .well, it's very Swiss, that's the best description. When asked "What indicators would you select to measure improvement?" after people move in, the answer is:

Bouwmeester: That depends on the monitoring period. I am assuming that one or two months after we move into the building, the employees will already be experiencing a new dynamic. If they report a positive difference, that will be a first measure of success. It is important that the people in the LOTF develop some
kind of ownership regarding their role in the building. It will be a more active role than usual. The LOTF is basically an open space where you can observe your peers across the hierarchies. This is a different type of social architecture compared to 10 years ago, or even today still. Everybody will be more under observation and observing more than before. The dynamism of the interaction between people will increase. The employees themselves will have to decide what is common practice on their floor. Of course the concept will need to be adapted over time; I would be surprised
if all concepts materialize exactly as anticipated.

I would be, too. In fact, I'd like to propose that last sentence be printed up on T-shirts, coffee mugs, and posters, but that's probably not going to happen. More on what this is actually going to look like:

Korthäuer: (There will be) big screens, placed where people typically pass by. There will be video cameras installed on each laptop, allowing easy and informal contacts. The information technology concept is an important part of it. We have also designed special furniture that serves the same goal. We want to get rid of functional cells such as coffee rooms, writing rooms, lab rooms etc. Our aim is to bring the walls down. But of course we still need differentiation. In the LOTF
there are still compartmentalized areas with particular qualities, constructed according to people’s needs and workflow requirements. . .

Korthäuer: On the information technology side, we are trying to implement a few applications which really support the concept. There will be videoconferences, ‘smart’ whiteboards that allow notes to be captured electronically. We focus on proven technologies. Gradually, we will bring new technologies into the building such as haptic interfaces. Removing the walls in a building can bring about big changes. There will be much less storage room. Therefore, a little robot operating in an elevator shaft will transport materials ordered by laptop up from the basement to the floors. . .

Bouwmeester: We have already implemented Virtual Reality Rooms with ultra-high-resolution video screens, so that the quality is as though you were in a real-life meeting; the effect is quite spectacular. As with any global project, it will all require a certain attitude, a set of skills that people will have to develop. Much energy and time will be needed to communicate efficiently between places as different as Basel, Cambridge and Shanghai. . .

Allow me to note a few difficulties. For one, those high-res video conference venues still have to deal with switching and transmission delays, especially across the distances that the Novartis guys are talking about. So if you try to have a spirited real-time discussion, you'll mostly be getting very clear, sharp, high-fidelity views of people interrupting each other and pausing awkwardly. (Update: see the comments section - some users are reporting more successful experience.) I have a more macro-scale worry about this sort of thing, too, having to do with my suspicion of plans that depend on people finally shaping up and acting the way that they're supposed to. As with any global project, y'know.

I think that I'll let Tom Wolfe have the last word here, since what he wrote in From Bauhaus to Our House is still applicable, over thirty years later:

I once saw the owners of such a place driven to the edge of sensory deprivation by the whiteness & lightness & leanness & cleanness & bareness & spareness of it all. They became desperate for an antidote, such as coziness & color. They tried to bury the obligatory white sofas under Thai-silk throw pillows of every rebellious, iridescent shade of magenta, pink, and tropical green imaginable. But the architect returned, as he always does, like the conscience of a Calvinist, and he lectured them and hectored them and chucked the shimmering little sweet things out.

Every great law firm in New York moves without a sputter of protest into a glass-box office building with concrete slab floors and seven-foot-ten-inch-high concrete slab ceilings and plasterboard walls and pygmy corridors. . .Without a peep they move in!—even though the glass box appalls them all. . .

I find the relation of the architect to the client in America today wonderfully eccentric, bordering on the perverse. . .after 1945 our plutocrats, bureaucrats, board chairmen, CEO's, commissioners, and college presidents undergo an inexplicable change. They become diffident and reticent. All at once they are willing to accept that glass of ice water in the face, that bracing slap across the mouth, that reprimand for the fat on one's bourgeois soul, known as modern architecture.

And why? They can't tell you. They look up at the barefaced buildings they have bought, those great hulking structures they hate so thoroughly, and they can't figure it out themselves. It makes their heads hurt.

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November 11, 2010

Comment of the Day: Outsourcing and Architecture

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Posted by Derek

From reader Jose, in the comments thread to the most recent post:

"Published I find it ironic that so many pharma sites who hired hotshot architects to design labspaces that foster as much personal interaction as possible, are now pumping the virtues of collaborations across 10 time zones."

Comments (1) + TrackBacks (0) | Category: Business and Markets | Drug Industry History | Life in the Drug Labs

November 2, 2010

Good Old Medicinal Chemistry: What Can You Get Away With?

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Posted by Derek

Medicinal chemists spend an awful lot of time working with SAR, structure-activity relationship(s). That's how we think: hmm, what happens if I put a chloro there? If I make that ring one size larger? If I flip that stereocenter/add a nitrogen/tie back that chain? Ideally, you pick up on a trend that you can exploit to give you a better compound, but the problem is, no SAR trend lasts forever. Methyl's good, ethyl's fine, anything bigger falls off the cliff - that sort of thing.

Activity "cliffs" of this sort are the subject of a paper earlier this year in the Journal of Chemical Information and Modeling. (For some earlier approaches to this same type of question, see here, here, here, and especially here).This group (from Germany) looked over several public SAR databases and used a new algorithm to extract "matched molecular pairs", which are compounds that differ only at one point in their structure. And what they were looking for wasn't the orderly progressions; they were after the changes that tended to suddenly change the activity of a compound by at least 100-fold. Were there, they wondered, functional group shifts that have a greater or lesser chance of doing that, over a wide range of targets and compound classes?

It looks like there are, and they're the transformations that you might well imagine. Messing around with a carboxyl group, for example, seems rarely to be a neutral event. Carboxylates are so relentlessly polar and hydrogen-bonding that your SAR is probably going to love 'em or hate 'em. The next two liveliest groups were carbonyls (in general) and amines. Of less interest (but equally believable) is the transformation from methyl to bulky alkyl (or vice versa, which is the direction I'd recommend people try to go if at all possible - other things being equal, no one should grease up their compounds unless there's absolutely no choice).

Well, it needs no ghost come from the grave to tell us this, either. How about any surprises? Adding a secondary hydroxyl group was surprisingly silent, compared to what you might picture. And switching from secondary to tertiary amines (just with methyl groups) is a much less conservative switch than you might imagine, with several huge activity shifts across different target classes. Introduction of methyl ethers rarely affected things much one way or another, and that might account for the low tendency of dimethylamine-to-morpholine doing anything. Small halogens on aryl rings (fluorine, chlorine) had low potential to cause big shifts, with ortho-chloros showing no examples of that happening at all. Oddly (at least to me) was the fact that morpholine-to-alkylpiperazine showed almost no big changes, either.

But it has to be emphasized that these are (1) averages and (2) averages over a large (but not gigantic) data set. For example, one of the "no changes at all" transformations is a favorite med-chem isostere, thiophene for phenyl. And that's true - most of the time, that does nothing. But I've seen two examples in my career when that one actually caused a big change in activity, so it's rare, but not impossible. That's the thing that makes med-chem so enjoyable and so frustrating at the same time. It's full of things (like actually discovering a drug) that are rare, but not quite impossible.

Comments (19) + TrackBacks (0) | Category: Life in the Drug Labs

October 28, 2010

Shine A Light

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Posted by Derek

I'm enjoying myself very much in the lab today, doing something I haven't done in 20 years: photochemistry. I did some during my post-doc (with Bernd Giese, which is also the last time I've done free radical chemistry, at least on purpose). Since then, though, it's one of those things that's never come up. We had a mercury lamp apparatus in my grad school group, which I saw used a few times - one of which resulted in one of those nose-wrinkling "What's that funny smell?" moments, when the person running it forgot to turn on the cooling water. Don't do that. Medium-pressure mercury lamps can get pretty toasty. (They'll also permanently tan your eyeballs if you're so foolish as to look at them, I should also note, so don't do that, either!)

Most synthetic chemists will have had a brief experience with the technique - it's very appealing to think of doing chemistry just by shining a light on the reaction. But there can be a lot of variables - the sort of lamp you use (and thus the wavelengths and energy flux), various filters, sensitizing additives, hardware setups. Many people find that they use it for one reaction at some point, to make a specific compound, and never quite find a use for it again. In my experience, every decent-sized chemistry department has a photochemical rig of some sort, and no one quite knows where all its parts are.

That's probably a shame. There are a lot of unusual and interesting reactions that can be done photochemically - if you like 3- and 4-membered rings, this is certainly a field you should look into. I can recommend this recent bookas a general review of the field, for anyone who's thinking about it. We'll see how much use I get out of my current setup, but for now, I'm happily blasting away with the ultraviolet. . .

Update: blasting away is right! My cooling water dribbled down and then cut out on me after I tried to turn it down a bit, and, well. . . now I'm cleaning melted goo off of the quartz. A razor blade is working pretty well, but that's no way to treat a working piece of equipment.

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October 26, 2010

Enthalpy and Entropy Again

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Posted by Derek

Earlier this year, I wrote here about using calorimetry in drug discovery. Years ago, people would have given you the raised eyebrow if you'd suggested that, but it's gradually becoming more popular, especially among people doing fragment-based drug discovery. After all, the binding energy that we depend on for our drug candidates is a thermodynamic property, and you can detect the heat being given off when the molecules bind well. Calorimetry also lets you break that binding energy down into its enthalpic (delta-H) and entropic (T delta-S) components, which is hard to do by other means.

And there's where the arguing starts. As I mentioned back in March, one idea that's been floating around is that better drug molecules tend to have more of an enthalpic contribution to their binding. Very roughly speaking, enthalpic interactions are often what med-chemists call "positive" ones like forming a new hydrogen bond or pi-stack, whereas entropic interactions are often just due to pushing water molecules off the protein with some greasy part of your molecule. (Note: there are several tricky double-back-around exceptions to both of those mental models. Thermodynamics is a resourceful field!) But in that way, it makes sense that more robust compounds with better properties might well be more enthalpically-driven in their binding.

But we do not live in a world bounded by what makes intuitive sense. Some people think that the examples given in the literature for this effect are the only decent examples that anyone has. At the fragment conference I attended the other week, though, a speaker from Astex (a company that's certainly run a lot of fragment optimization projects) said that they're basically not seeing it. In their hands, some lead series are enthalpy-driven as they get better, some are entropy-driven, and some switch gears as the SAR evolves. Another speaker said that they, on the other hand, do tend to go with the enthalpy-driven compounds, but I'm not sure if that's just because they don't have as much data as the Astex people do.

So as far as I'm concerned, the whole concept that I talked about in March is still in the "interesting but unproven" category. We're all looking for new ways to pick better starting compounds or optimize leads, but I'm still not sure if this is going to do the trick. . .

Comments (17) + TrackBacks (0) | Category: Analytical Chemistry | Drug Assays | Life in the Drug Labs

October 25, 2010

Settle A Bet

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Posted by Derek

I had an email this morning asking me to settle a bet on lab technique. I'm not sure I know the answer myself, so I figured I'd throw the question out to the readership.

So here goes: in your vacuum cold trap, which I'll assume is cooled by dry ice (and not liquid nitrogen, for the most part), what solvent do you use: acetone or isopropanol? (If you use something else, feel free to add it to the list, but I think you'll be in a distinct minority). As for me, I used acetone back in grad school, but switched over to isopropanol years ago, because I didn't have to change it (or add to it) so often.

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If You're Not Excited, Sit Down

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Posted by Derek

Mat Todd of the University of Sydney looks over the SciFoo conference that we both attended during the summer, and contrasts that to an ACS meeting. The comparison isn't kind, as you'd imagine:

. . .with a few very notable exceptions the talks I saw were a) presented in a dull Powerpoint-heavy series of slides with verbal commentary about what was on the slides where even the presenter was visibly bored with what they were saying and b) on published material that was c) way too predictable and incremental. So both the presentational style and the content were disappointing. So many talks at the ACS would have been more interesting if the speaker had simply given out paper copies of their latest paper and given us 10 minutes to read it in silence then 10 minutes to talk about it. Now of course specialism necessitates incrementalism in content, but it’s no good if the meeting becomes a chore to sit and listen to. Nor is it good if the talks come out of the Powerpoint Machine (the genius of the “Chicken Talk” is that you can kind of follow the talk structure without listening to the content – it sounds exactly like most academic talks right up to the last supplementary slide in response to the second question at the end). In maybe 80% of the talks I attended nobody asked questions, or nobody was allowed to, or people asked “pity questions” just to break the awkward silence, but which were in no way interesting in themselves.

"A chore" is exactly what I find too many presentations and conferences to be, unfortunately. If we limited presentations, as Mat suggests, to people who are excited about their results, we'd have a lot of short meetings in this field. . .

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October 22, 2010

Keeping Track Of All Those Chemicals

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Posted by Derek

Here's something that you don't think about until you actually work in a department full of chemists: how do you keep track of who's got what, and where it is? Everyone has reagents on their bench, and hidden away under the fume hood, and they're ordering more (and using up the current bottles) all the time. And people are wandering from lab to lab, borrowing and pilfering, sometimes when the original owners are there, and sometimes not. So how do you know what you have?

I've seen a number of approaches to this chemical inventory problem. The essential thing is that every bottle of every reagent be trackable. That means some sort of bar-coding system, most likely. Those bar codes need to go on when the compounds come in the door, ideally, so there aren't a lot of invisible reagents floating around. I think the best way to do this is to have the shipping and receiving people involved - if you trust the chemists to bar-code things, many of them just won't quite get around to it.

The next big question is whether you're going to have a centralized chemical stockroom or not (I've worked under both systems). The stockroom probably makes it easier to keep track of things, in general, since otherwise the available reagents are distributed throughout the labs at all times (instead of the ten per cent or so that are actually in active use). And it helps to have some place to send all those bottles back to - when you clean up your bench, you know that there's one thing you can do immediately, which helps keep the chemicals homing back to the central location.

A stockroom, though, requires dedicated space and dedicated head count, and neither of those are always feasible. The spread-throughout-the-labs approach puts the work back on the chemists. Its biggest disadvantage is entropy: bottles move around, get silently consumed, or get just plain lost. (That happens with a stockroom system, too, but at a slower rate). After a while, your map of the chemical inventory is useless - and for popular reagents, "a while" might be about two weeks.

That brings up the moving-chemicals problem, and to be honest, I've never seen a good solution to that one. Ideally, any time a person borrows some reagent from its known location, they scan the bar code so the system knows that it's moved. In practice, you know, you're just using it for a couple of days. Or you're just running one reaction, and you're going to take it right back. It's just right down the hall; the folks down there know where it is. Right. A stockroom system keeps this from randomizing things as quickly, but no matter what, this sort of Brownian motion is going to scramble things eventually.

So there has to be a regular inventory taken, no matter whose system you're using. Whether that's someone from the stockroom coming through and scanning all the benches and cabinets, or whether you declare Inventory Day and make all the chemists do it themselves, it has to be done. Twice a year is not too often, in my experience.

If anyone has solutions to some of these problems that I haven't touched on, feel free to share them in the comments. But please, no "Just Make Everyone Act Responsibly For Once" recommendations. Let's assume that people are intrinsically looking for the easy ways out, and work from that - it's a worldview that has never disappointed me.

Comments (44) + TrackBacks (0) | Category: Life in the Drug Labs

October 18, 2010

Palladium Couplings: You Can't Run Them All

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Posted by Derek

This year's Nobel for palladium-catalyzed coupling reactions highlighted how useful these have become. But what every practicing organic chemist knows is how complicated they can be, particularly when you first couple of favorite recipes don't work. I've long thought that almost any metal-catalyzed transformation can be optimized, if you're just willing to devote enough of your life to it. But you have to have a good reason to wade into the swamp, because there sure are a lot of variables that can be tweaked. Here's a good case in point, recently published in Organic Letters. A perfectly reasonable reaction (C-H arylation of a chloropyrazole, which had been demonstrated before) was run through the statistical wringer to track down the best conditions.

They looked at 6 solvents, 10 bases, 4 catalysts, 5 ligands, and 4 additives, which would give you 7200 combinations if you ran the whole shebang. A Design of Experiments approach cut the number of actual runs down significantly, and then (fortunately) some of the variables turned out to be pretty insensitive. So this one wasn't as bad as some of them get - the ligand didn't seem to have too much effect, for example, whereas in some other Pd couplings it's crucial. (The choice of base had a much bigger effect, in case you're wondering). Their best set of conditions seems to work reasonably well across a range of possible substrates.

DoE is worth a post of its own, and that'll be a timely thing for me. After brushing up against it for years, I may finally have a use for the technique soon. For those who don't know it, it's basically a way to figure out how to most efficiently sample "experiment space", by getting the most information out of each different run. And then you use principal components analysis (or something similar) to see what the most important changes were, and how they correlate to each other. It's asking, mathematically, what a synthetic chemist wants to know about a complicated reaction recipe: what changes are responsible for most of the variation in the results, and how can I track them down by running a reasonable number of experiments? In the drug industry, process chemists think about this sort of thing a lot more than discovery chemists do, but it's worth keeping an eye out for any time the approach could be helpful.

Comments (20) + TrackBacks (0) | Category: Life in the Drug Labs

October 14, 2010

Conference Thoughts

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Posted by Derek

Update: here's a trip report on this conference over at Practical Fragments

I'm back from Philadelphia and the FBLD conference. I'm not going to put a trip report up on the blog - although I'm certainly writing one up for my colleagues at work - but a number of people at the meeting asked me what I might say about it here.

Well, I enjoyed it. I tend to like more focused conferences like this one, anyway, where most of the people doing the best work in a field can attend what's still a fairly small meeting. It probably helps that this isn't a very old series of meetings, too. Over time, some sort of scientific entropy sets in, and the topics covered can begin to smear out a bit. Some of the longer-running Gordon Conferences are (to me, anyway) a little blurry about what they're trying to cover.

That same tendency can affect individual talks. We medicinal chemists are particularly guilty of that, since our discipline spreads over a pretty wide area. At a meeting like this one, which was all about fragment-based techniques, people had to resist the temptation to keep going past the fragment-based parts of their talk. Once you get up toward 400 molecular weight, you're not talking about fragments any more - you're doing good old medicinal chemistry. Maybe it's structure-based at that point, maybe not, and maybe you're using some of the biophysical techniques that help out with moving fragment leads forward - but the fragment techniques are what got you to that point, not what's carrying you forward through the concerns about PK, formulations, polymorphs, and all the other later-stage worries of a drug program.

The speakers at this meeting generally did a good job avoiding this pitfall, but I have to admit that the few times I saw PK data come up on the screen, I stopped taking notes. I didn't stop listening, on the chance that there might be something interesting, but it certainly wasn't what I was there to focus on. One could imagine a whole meeting about solving PK problems in drug development - there probably is one, actually. But at that one, you'd have to make sure that the speakers didn't spend time telling you about the neat fragment-based techniques that led to their drug candidate.

As I said, though, there were a lot of interesting speakers at this one, and not a single talk was anything close to a complete waste of time. How many meetings can you say that about? Things ran smoothly, and with notably better food than some of the other conferences I've attended. Some meetings just pitch a bunch of Wissenschaftlerfutter out onto the tables, figuring that people will deal with it - and to be honest, they're usually right. We'll eat most anything in this field, although I've been told that physicists are even less discriminating, so at least we have that.

Comments (5) + TrackBacks (0) | Category: Life in the Drug Labs | The Scientific Literature

September 27, 2010

Workhorse Reactions

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Posted by Derek

A group at GSK has published a paper in Angewandte Chemie on the kinds of reactions that medicinal chemists use, and why they use them. The conclusions will come as no surprise to anyone practicing in the field. The workhorse reactions were condensations (amides, etc.), palladium-catalyzed couplings, and alkylations. And if you look at the reactions used to generate arrays (small libraries) of compounds simultaneously, those reactions almost take over the list.

Why is that? Well, for one thing, because those reactions tend to work. You'll almost always get product out of them - no small thing. You really, really don't want to spend time tweaking a reaction just to make it produce something, not when the odds of any individual product working are still small. And you can also get a good amount of structural diversity off-the-shelf, by using the huge numbers of commercial amines, acids, aryl boronic acids, and so on. They're also fast reactions, for the most part: set 'em up one day, work 'em up the next, and on to the next analogs.

The authors list some criteria that new reactions would need to order to make the list: not fussy about conditions (temperature, time, order of addition, atmosphere, etc.), compatible with polar solvents, tolerant of a wide range of functional groups, easy to dispense, easy to clean up, and so on. They mention that there's been funding in the UK over the last few years (as there has been here) for discovery of new chemistries that would meet this standards, but (reading between the lines) it doesn't seem as if anything major has made it up the charts yet.

Their other take-home is that people who specialize in running arrays can usually do them more efficiently than those who set them up just once in a while. They suggest that it takes a slightly different sort of person to be good at this:

. . . Owing to their focus on and expertise with arrays, we have found that the array chemists can make, purify, analyze, and register array compounds more efficiently than the program medicinal chemists. They are frequently also more effective in delivering a higher percentage of products from the array in greater yield and purity.

The team has a unique skill set and mindset. We have found that an array chemist should be highly organized, show attention to detail, be manually dexterous, be comfortable with repeatedly delivering to deadlines, and have an ability to work with often introverted and occasionally obstreperous program chemists ! This combination of characteristics is uncommon amongst chemists.

As an obstreperous program chemist myself, I should resent that remark. But you know, they're probably right. . .

Comments (9) + TrackBacks (0) | Category: Life in the Drug Labs

September 17, 2010

Put In Another Methyl Group: A Villanelle

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Posted by Derek

A comment to the most recent post on puns mentioned the famous JOC paper in verse from the 1970s, and prompted another comment that "If you have to report your results as a villanelle, I think we'll see fewer methyl, ethyl, butyl, futile papers. . ."

Well, it's not a whole paper, for sure. But here's the best that I can do in thirty minutes:

Put In Another Methyl Group: A Villanelle

I shouldn't have to put a methyl there
No matter what the modeling group might say
So it docks to perfection: I don't care.

The project head gave me an evil glare
When I spoke up at our review today.
I shouldn't have to put a methyl there.

"The glutamate will pick up that lone pair".
Who knows? That might be right; I couldn't say.
So it docks to perfection: I don't care.

How do these really bind? We don't know where.
It's not like we can get a good X-ray.
I shouldn't have to put a methyl there.

Quaternary chiral centers? I don't dare.
I'd need two months if I needed a day.
So it docks to perfection: I don't care.

But no one ever said research was fair.
I'm going to have to come up with a way.
I shouldn't have to put a methyl there.
So it docks to perfection: I don't care.


Update: yes, I'm going to give the molecular modelers their own poem. It's only fair!

Comments (21) + TrackBacks (0) | Category: Life in the Drug Labs | The Scientific Literature

September 16, 2010

Six Sigma in Drug Discovery? Part One - Are Chemists Too Individual?

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Posted by Derek

I had an interesting email about a 2009 paper in Drug Discovery Today that has some bearing on the "how much compound to submit" question, as well as several other areas. It's from a team at AstraZeneca, and covers their application of "Lean Six Sigma" to the drug discovery process. I didn't see it at the time, but The title probably made me skip over it even if I had.

I'll admit my biases up front: outside of its possible uses in sheer widget-production-line settings, I've tended to regard Six Sigma and its variants as a buzzword-driven cult. From what I've been able to see of it, it generates a huge number of meetings and exhortations from management, along with a blizzard of posters, slogans, and other detritus. On the other hand, it gives everyone responsible a feeling that they've Really Accomplished Something, which is what most of these managerial overhauls seem to deliver before - or in place of - anything concrete. There, I feel better already.

On the other hand, I am presumably a scientist, so I should be willing to be persuaded by evidence. And if sensible recommendations emerge, I probably shouldn't be so steamed up about the process used to arrive at them. So, what are the changes that the AZ team says that they made?

Well, first off is a realization that too much time was being spent early on in resynthesis. The group ended up recommending that every lead-optimization compound be submitted in at least a 30 to 35 mg batch. From my experience, that's definitely on the high side; a lot of people don't seem to produce that much. But according to the AZ people, it really does save you time in the long run.

A more controversial shift was in the way that chemistry teams work. Reflecting on the relationship between overall speed and the amount of work in progress, they came up with this:

Traditionally, chemists have worked alongside each other, each working on multiple target compounds independently from the other members in the team. Unless managed very carefully by the team leader, this model results in a large, and relatively invisible, amount of work in progress across a team of chemists. In order to reduce the lead time for each target, it was decided to introduce more cooperative team working, combined with actively restricting the work in progress. The key driver to achieve and sustain these two goals was the introduction of a visual planning system that enables control of work in progress and also facil-
itates work sharing across the team. Such a visual planning system also allows the team to keep track of ideas, arrival of starting materials, ongoing synthesis and compounds being purified. It also makes problems more readily recognizable when they do occur.

We have reflected on why chemistry teams have always been organized in such an individual-based way. We believe that a major factor lies in the education and training of chemists at universities, in particular at the doctoral and postdoctoral level, which is always focused on delivery of separate pieces of work by the students. This habit has then been maintained in the pharmaceutical industry even though team working, with chemists supporting each other in the delivery of compounds, would be beneficial and reduce synthesis lead times.

OK, that by itself is enough to run a big discussion here, so I think I'll split off the rest of the AZ ideas into another post or two. So, what do you think? Is the "You do your compounds and I'll do mine" style hurting productivity in drug research? Is the switch to something else desirable, or even possible? And if it is, has AstraZeneca really accomplished it, or do they just say that they have? (Nothing personal intended there - it's just that I've seen a lot of "Now we do everything differently!" presentations over the years. . .) After all, this paper is over a year old now, and presumably covers things that happened well before that. Is this how things really work at AZ? Let the discussion commence!

Comments (50) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs | Who Discovers and Why

September 15, 2010

Intermediates

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Posted by Derek

Talking about the amounts of compound to submit as a medicinal chemist brings up another topic. In every med-chem department I've worked in, there have been periodic exhortations for the chemists to register their intermediates. But too few people do.

For those outside the field, what I'm referring to are the "stepping stone" compounds along the way to structures that you're actually targeting. We try not to have these pathways go on too long, but there are often compounds that lack a key methyl group, or don't have the right stuff on the nitrogen yet, and so on. From the way that the compounds in a project have been running, you can be pretty sure that these things aren't going to be of much use for your current biological target - but the point is that they could be useful for someone else.

I've always been surprised by how many compounds sit on the benches, or in drawers, and never quite make it into the compound repository. To be sure, there are plenty of intermediates that shouldn't go in there - anyone who compound-codes a red-hot acid chloride should be whacked over the head. But plenty of things that people think of as "just starting material" or "just an intermediate" have nothing wrong with them, and should be added. I don't even mind a Boc group on an amine - t-butyl's not anyone's favorite, but there are plenty of drugs out there with carbamates on them. Fmoc is where I'd draw the line, though, since I think there's too much of a possibility for the binding to be driving by that big ol' fluorenyl, which is the first thing you'd want to get rid of if the compound hits. I don't think I'd go for any silyl groups on the alcohols, but benzyls and the like are fine.

So do a good deed today if you're in the lab: clear out a few of those compounds you have sitting around and put numbers on 'em. In your heart, you know it's the right thing to do!

Comments (16) + TrackBacks (0) | Category: Life in the Drug Labs

September 14, 2010

How Much Compound?

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Posted by Derek

Here's a question for those of you out in the industry: how much compound do you make, when you make a new one? Sometimes this question is equivalent to asking "How little will they let you get away with?" Different organizations have different requirements, on paper and for real, as to what that amount is. Five mg? Ten?

I've worked with people who kept coding these little 1.5mg amounts on most of their compounds, but I only do that if I'm desperate. That's really only going to do the immediate project any good, and not much, at that, if you want to do anything beyond the first in vitro assays. You'd like to have something living in the screening files so it can perhaps do some good later on. I try to aim for 10 to 20mg of compound, myself, although I don't always make it. And you?

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August 31, 2010

Nanopowders?

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Posted by Derek

Here's a lab question for everyone. I have a bottle of Aldrich copper oxide nanopowder on my lab bench; I've been meaning to try it out for some Ullmann reactions. I note that Aldrich (and others) are now selling a variety of such nanopowders, mostly metals and insoluble metal compounds.

And that makes sense, because these are the things that tend to react at their surfaces, and you'd have to think that a real nanopowder would have a tremendous surface area. My question is: does this really work out? Has anyone noticed a difference between the nanopowder form of a particular reagent and its more traditional one? I can imagine there being one - but I can also imagine the particles clumping up under some conditions and giving you back the equivalent of the cheaper stuff, too. Any hands-on experience out there?

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June 16, 2010

Sparteine and Other Fine Chemical Shortages

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Posted by Derek

One of the folks over at Chemistry Blog has run into a shortage: he and his labmates have tried to order (-) sparteine from every supplier in the book, and there's none to be had. So if anyone has a big dusty bottle of it sitting around, you might drop these desperate chemists a line. But that got me thinking about the way things suddenly dry up like this.

The situation is different than for an industrial chemical shortage, like the acetonitrile crunch that we went through a while back (and which has long since eased up). It's quite unusual for a bulk chemical like that to go down; several factors hit all at once in that case, and it affected an awful lot of people who needed the solvent. But fine chemicals are much weirder. When you trace some of them back to their real sources, you sometimes find that there are really only a couple of people in the world at any given time making some of these things. Or, in many cases, you find that there's no one making it at all - someone made a bunch a few years ago for some reason, sold the excess to a supplier, and everyone else has been buying it from that same bottle ever since.

So when one of these small-scale itemsevaporates, the reason can be supply: no one makes it any more. Or it can be demand-driven: a single drug company's scale-up group can deplete the world's commercial supply of some strange little molecule when they suddenly switch to a 500-gram run. Everyone working in such a group knows to call all the suppliers when they have a prep calling for some weirdo starting material, and they'll often take the precaution of ordering whatever's out there to be had. (That serves as a cushion while they contract someone else to crank out a batch or figure out how to make it themselves). Naturally, you'd rather have your drug candidates depend only on things that can be ordered in tank car lots, but that's just not always possible.

So it could be that someone needed a lot of (-) sparteine for an asymmetric synthesis recently, and bought up the existing world stocks. But this one sounds like more of a supply problem. There would appear to be customers out there, who have been draining the existing stocks, but no one's been able to replenish them. TCI apparently stated that it's the starting material for (-) sparteine that has become unavailable, but that sounds a bit funny, since it would surprise me if the material on the market is synthetic. Sparteine is a naturally occurring alkaloid, found in several species of plant, and it's very hard to compete with isolation of the natural product in those cases.

Perhaps TCI means that the usual plant source is unavailable - that's happened before, too. A spike in Tamiflu demand a few years ago suddenly sent the price of star anise up to record levels, since the chiral starting material (shikimic acid) in the usual synthesis was most conveniently isolated from that source. But for sparteine, it looks as if the isolation comes from plants in the broom family, which are not exactly rare shrubs, so I'm not sure what's going on. Any ideas?

Comments (19) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs

May 12, 2010

A Quick And Nerdy Question

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Posted by Derek

As a brief followup to my "Elements I Have Yet to Use" post, I note this new paper on cleavage of molecular nitrogen by a hafnium complex. And to get right down to organic synthesis, here's a paper from last year that used hafnium triflate as a Lewis acid.

OK, here goes: has anyone out there ever used hafnium for anything? Anything at all? I sure haven't. (N.b. - ordering some on purpose to raise your desktop monitor or prop the door open does not count).

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April 29, 2010

Curse of the Plastic Tubes

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Posted by Derek

In keeping with the problem discussed here ("sticky containers"), there's a report that a lot of common spectrometric DNA assays may have been affected by leaching of various absorbing contaminants from plastic labware. If the published work is shown relative to control tubes, things should be (roughly) OK, but if not, well. . .who knows? Especially if the experiments were done using the less expensive tubes, which seem to be more prone to emitting gunk.

We take containers for granted in most lab situations, but we really shouldn't. Everything - all the plastics, all the types of glass, all the metals - is capable of causing trouble under some conditions. And it tends to sneak up on us when it happens. (Of course, there are more, well, noticeable problems with plastics in the organic chemistry lab, but that's another story. Watch out for the flying cork rings!)

Comments (12) + TrackBacks (0) | Category: Biological News | Life in the Drug Labs

March 29, 2010

Compounds and Proteins

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Posted by Derek

For the medicinal chemists in the audience, I wanted to strongly recommend a new paper from a group at Roche. It's a tour through the various sorts of interactions between proteins and ligands, with copious examples, and it's a very sensible look at the subject. It covers a number of topics that have been discussed here (and throughout the literature in recent years), and looks to be an excellent one-stop reference.

In fact, read the right way, it's a testament to how tricky medicinal chemistry is. Some of the topics are hydrogen bonds (and why they can be excellent keys to binding or, alternatively, of no use whatsoever), water molecules bound to proteins (and why disturbing them can account for large amounts of binding energy, or, alternatively, kill your compound's chances of ever binding at all), halogen bonds (which really do exist, although not everyone realizes that), interactions with aryl rings (some of which can be just as beneficial coming in 90 degrees to where you might imagine), and so on.

And this is just to get compounds to bind to their targets, which is the absolute first step on the road to a drug. Then you can start worrying about how to have your compounds not bind to things you don't want (many of which you probably don't even realize even are out there). And about how to get it to decent blood levels, for a decent amount of time, and into the right compartments of the body. And at that point, it's nearly time to see if it does any good for the disease you're trying to target!

Comments (5) + TrackBacks (0) | Category: Drug Assays | In Silico | Life in the Drug Labs

March 26, 2010

Privileged Scaffolds? How About Unprivileged Ones?

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Posted by Derek

The discussion of "privileged scaffolds" in drugs here the other day got me to thinking. A colleague of mine mentioned that there may well be structures that don't hit nearly as often as you'd think. The example that came to his mind was homopiperazine, and he might have a point; I've never had much luck with those myself. That's not much of a data set, though, so I wanted to throw the question out for discussion.

We'll have to be careful to account for Commercial Availability Bias (which at least for homopiperazines has decreased over the years) and Synthetic Tractability Bias. Some structures don't show up much because they just don't get made much. And we'll also have to be sure that we're talking about the same things: benzo-fused homopiperazines (and other fused seven-membered rings) hit like crazy, as opposed to the monocyclic ones, which seem to be lower down the scale, somehow.

It's not implausible that there should be underprivileged scaffolds. The variety of binding sites is large, but not infinite, and I'm sure that it follows a power-law distribution like so many other things. The usual tricks (donor-acceptor pairs spaced about so wide apart, pi-stacking sandwiches, salt bridges) surely account for much more than their random share of the total amount of binding stabilization out there in the biosphere. And some structures are going to match up with those motifs better than others.

So, any nominations? Have any of you had structural types that seem as if they should be good, but always underperform?

Comments (9) + TrackBacks (0) | Category: Drug Assays | Drug Industry History | Life in the Drug Labs

March 19, 2010

The Chemical Suppliers: Customer Reviews

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Posted by Derek

Update, March 19: I've added a few more suppliers to the list, and broken out a third category for the mixed reviews. And I note in the comments that someone claiming to be Kathy Yu from 3B Chemicals is threatening me with legal action. The IP address resolves only to AT&T Internet Services, but there does appear to be someone from that name who works at 3B. I hope, for her sake and that of the company, that this is someone impersonating her, because whoever is leaving these comments is doing 3B no favors.

And since I am reporting opinions, both my own and those of other contributors that I have no reason to doubt, and am doing so without malicious intent, I will cheerfully ignore all legal threats.

OK, here are the lists of good companies and not-so-good companies, based on my experience and those of readers. I've had some personal communications, too, which I've added to the data set. As more reports come in, this will be the post that's updated, so it can serve as a reference.

I should note up front that I'm not listing the Big Guys, since (while they can have their ups and downs), you generally know that they're going to send you something. What we're looking at are the companies that you might not have dealt with, but want to know if they're reliable. And that brings us to the:

Good Suppliers
ABCR: good prices and hit rate on orders. Very professional.
Activate: expensive, but what's there is there, and it's the right stuff.
Adesis: not cheap, but very reliable and willing to work with customers to deliver similar compounds.
Advanced Chem Tech: recommended for peptide/amino acid stuff.
AK Scientific: several good reports on availability and purity.
Alinda: have ordered one thing from them, which was fine.
Anaspec: good reports on reliability
Apollo: good stuff, but catalog needs to be a bit more in line with their real stock.
Array: very pricey, but it's all there.
Astatech: good experience reported
Bionet: interesting catalog, doesn't back-order you.
Chembridge: a big catalog, but it's all real. Occasional purity problem.
Chem/Impex: good hit rate on availability. Some questions on their chiral purities.
Combi-Blocks: good list of useful intermediates, delivers on them.
Enamine: similar to ChemBridge in many ways. Big catalog. Not the fastest out there.
Florida Center for Heterocyclics: occasional purity issues, but they do deliver.
Frontier: great source for boronic acids and the like.
Life Chemicals: have had good experiences with compound purity here.
Lu: good source for custom peptides.
Matrix: interesting catalog, which they will really ship to you.
Maybridge: on the border of being one of the big guys. Very reliable.
Midwest: good reports on reliability.
Netchem: custom synthesis, but (for once!) with good turnaround and purity.
Oakwood/Fluorochem: good prices and reliability.
Peptide Protein Research: good for custom peptides.
Pharmacore: good stock of intermediates.
Rieke: reliable, only game in town for many odd reagents.
Strem: well known for quality inorganics and organometallics.
Synquest: used to be PCR. Good customer service.
Synthonix: stuff is in stock, customer service is responsive.
TCI: has always delivered, and quickly.
Transworld: very reliable and responsive.
Tyger: have never had a problem with them.
Waterstone Chemicals: good experience on pricing and availability

Mixed Reviews
American Custom Chemicals (ACC): several tales of bad purity and customer service, but others have had nothing but good experiences with them.
3B Chemicals: "will lead you on for months". Several bad experiences reported. On the other hand, I've just heard directly from a colleague who's had good luck with them.
J&W Pharmlab: bad experience reported (delays and purity), but others OK.
Ontario: one good report, but others complain of availability and leads times.
SPECS: mixed reports, but overall positive.

The Not So Good:
Ambinter: seems to source a lot of stuff from mystery suppliers. Many delays.
Any supplier, sad to say, with "Hangzhou" or "Shanghai" in the name. Tend to have absolutely nothing on the shelf, and if there's even a listed price, it's science fiction.
Anichem: very bad experience here with unexplained delays.
Beta Pharma: bad experience reported.
ChemMaker: very negative report on customer service and responsiveness.
City Chemicals: several bad experiences reported
Combi-Phos: several reports of purity problems.
Rarechem: haven't come across anyone with a good report here.
UK Green: a bad experience reported.
Uorsy: nothing ever seems to be in stock.
Zelinsky: several bad experiences reported.

Comments (89) + TrackBacks (0) | Category: Life in the Drug Labs

March 18, 2010

Good Suppliers - And The Other Guys

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Posted by Derek

Is it just me, or is the fine chemicals supply business getting even more out of hand than usual? I was just talking with a colleague who'd sourced an interesting intermediate, at the (steep!) price of about $900 for a gram. She placed the order and. . .you guessed it, the supplier immediately back-ordered it, saying the price had changed. It took someone from Purchasing to drag the new quote out of them (they apparently wouldn't give it over the phone). Now (to no one's surprise, I'm sure) the material is over $3000/gram, and will have a lead time of weeks.

This sort of thing has gone one for a long time, of course. But my impression is that there's more of it than ever. When the Chinese and ex-Soviet suppliers began to appear some years ago, they were often a pretty cheap source of some unusual compounds. But that's changed.

My belief - and I'll be glad to hear from people who do more compound purchasing than I do - is that the Chinese outfits especially have decided in recent years that they have some real pricing power, and are pushing it to see how far they can get. Add that to the hand-waving don't-you-worry-now aspect of many of their product lists, and you have a recipe for irritation and wasted time. (Another colleague described some of these online catalogs as "things they wish they sold".)

A previous comment on to a post like this listed some suppliers that had been found to be reliable, and I'll reproduce that here, in no particular order: Maybridge, Enamine, Asinex, Key Organics, ChemBridge, Specs, ASDI Biosciences, InterBioScreen, Vitas M Labs, Life Chemicals, Labotest, and TimTec. Suppliers of weirdo outlier compounds that nonetheless tend to come through were Albany Molecular, Chem T&I, Florida Center for Heterocyclic Compounds, and Princeton Biomolecular. I've used many of those folks myself (and have had particular success with Life Chemicals and Specs, as far as availability and purity). Some of these companies are faster to ship than others. But the thing that stands out with all of them is that they have what they say that they have, and what's more, it costs what it says that it costs.

For intermediates, as opposed to final-compound-like structures, I'd say that I've had good dealings with Apollo, Synthonix, Matrix, Pharmacore, Adesis, Tyger, Fluorochem, Oakwood, and Astatech. There are, I'm sure, several other suppliers in this category, and I'd be glad to list more of them after seeing the comments.

But now let's reverse the polarity. What's a blog for if you can't say what you really think? Here, then, is a preliminary blacklist of suppliers. These people either have product listings that overlay poorly with reality, try to jerk you around on the price, take much longer to deliver than their initial estimates, or (lucky you) can do all of these at once. My personal recommendation is to be quite careful with ChemPacific, Uorsys, CTI, Zelinsky, and everyone with the words "Hangzhou" or "Shanghai" in the company name.

Please feel free to add others to the lists. I'll do a consolidated post reflecting everyone's experience - that way, we can give business to deserving companies you might not have worked with before, and we can perhaps shame some others into acting more reasonably.

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March 17, 2010

Science Buildings: Good, Bad, and Weird

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Posted by Derek

The entries I've done on the "open-plan" Biochemistry building at Oxford (see also Jim Hu) generated a lot of comments from people who've worked in poorly designed science facilities. I've heard from Linda Wang, a reporter at C&E News, who's writing article on this very subject. She's looking for chemists who are willing to talk about both good and bad experiences working in various building designs, so if you fit that description, feel free to email her at l_wang-at-acs.org (email address de-spammified, just substitute the usual symbol) or give her a call at 202-872-4579.

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March 8, 2010

Not Gonna Make That One

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Posted by Derek

A discussion at work the other day got me to thinking: what structures do you medicinal chemists out there just refuse to work on? Any? We all have our own prejudices - in fact, if you get enough chemists into one conference room, one or another of them will probably rule out just about any structure you propose. Try that sometime, and be sure to sneak a few marketed drugs in there to tick people off. Don't like organoazides? Michael acceptors? Nitroaromatics? Epoxides? Chloromethyl ketones? They're out there working in the real world and making real money.

Now, I'm not saying that you should concentrate on these things. The success rate for (say) chloromethyl ketones is surely lower than for a lot of other compound classes, and there's only so much time and money available. That's why I have personal rules like "No Naphthyls". If someone shows me a structure with a raw naphthalene hanging off it that works, well, good for them, and I guess I'd work on it on that basis. But I won't contribute any myself, because I think the odds are too low.

But I have even more deep-seated prejudices. There are some structures that I just don't think have a chance, even if it looks like they work at first. I'd rather kill them immediately than take the (grave) chance of wasting everyone's time. The first thing I can think of on such a list would be quinones and their ilk. There are just too many other bad things that they're capable of. Now that I've said this, I feel sure that someone is come up in the comments with an example of a quinone that's making five hundred million dollars a year or something. But I sure can't think of one myself, and I just don't see the point of trying to make a drug out of such a structure (unless their lively reactivity is part of some nasty mechanism all its own, in which case, good luck to you).

So call me close-minded. But no quinones.

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March 4, 2010

Flowing, Not So Gently

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Posted by Derek

I've written both here and elsewhere about flow chemistry, the technique where you pump your reactions through a reaction tube of some sort rather than mixing them up in a flask. And I freely admit that I have a fondness for the idea, but it's definitely not the answer to every problem.

For one thing, I tend to like the idea of sending reactants over a bed of catalyst or solid-supported reagent (what I call Type II or Type III flow reactions in that 2008 link above). Type I reactions, in my scheme, are the ones where you just use a plain tube or channel, and all the reactants are present in solution. A big advantage of those, as far as I can tell, is to handle tricky intermediates that you wouldn't want to have large amounts of or to control potential runaway exothermic reactions. There's also the possibility of running the reaction stream through some solid-phase purifications and scavengers, the way Steve Ley and his group like to work, which is convenient since you're already pumping the stuff along anyway.

But the sorts of reactions that you often see in the flow-chemistry equipment brochures. . .well, that's something else again. More than one outfit has earnestly tried to sell me a machine based on how well it did a Fischer esterification. My problem wasn't that the reaction was discovered almost in Neanderthal times - it was that Thag run reaction in round bottom flask, work fine, not need flow reactor. I mean, really, this is a nonexistent problem and needs no solution.

So I read this new paper in Angewandte Chemie with interest. The authors are looking at some standard catalytic organic transformations and comparing them carefully between batch mode and a flow setup. They stipulate at the beginning that flow chemistry has the advantages mentioned above, but they're wondering about what it can do for more ordinary chemistry:

"In addition to these developments, general and rather sweeping claims have been made that microreactor systems accelerate organic reactions and that lower catalyst loadings and higher yields can routinely be achieved in these systems compared to those of reactions carried out in flasks. Despite these potential advantages, examples of successful implementation of microflow reaction technologies in either academic organic synthesis or industrial process research and manufacturing remain more isolated than these reports would suggest. However, the implication is that it is only a matter of time before microflow reactors will dominate laboratory studies aimed at both fundamental research and practical applications of complex organic reactions, with our current mode of operation in reaction flasks ultimately becoming a relic of the past. It seems therefore worthwhile to examine the assumptions behind this viewpoint to provide a critical analysis of “flask versus flow” as a means for effecting reactions."

What they find is that there's very little difference. A catalyzed aldol reaction that was studied under flow conditions by the Seeburger lab is shown to perform identically to a batch reaction, if you make sure to run them at the same temperature and with the same catalyst loading. The paper then looks at asymmetric addition of diethyl zinc to benzaldehyde, a model reaction that I often wish would disappear from human consciousness so it would afflict us no more. But here, too, under more challenging heat-transfer conditions, flow showed no differences from batch. The authors point out that this reaction is, in fact, run under industrial conditions, but not in a flow apparatus. Rather, it's done in batch mode, but though good old slow addition of reagent, which also gives you control over exotherms.

The authors specifically exempt all supported-reagent chemistry from their analysis, so that preserves what I like about flow systems. But for homogeneous reactions, the only time they can see an advantage for the flow reactors is when there's a potential for a dangerous rise in temperature. So now we'll see what some of the more flow-oriented people have to say in reply. . .

Comments (28) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs

February 25, 2010

Cranking Away

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Posted by Derek

Not as much time to blog this morning (and it's been hard getting into the site, since there are a lot of people who apparently want to know how to order some dioxygen difluoride). For one thing, I'm clearing a bunch of reactions out, and I've been devoting thought to how to do that in the laziest possible manner.

Maybe I should clarify that. What I mean is, how do I work up all these reactions quickly, in such a way as to make clean compounds that are worth testing, but spend the least amount of effort doing so? There are, of course, all sorts of brute-force ways to bang these things through, some of which would involve me not leaving my lab for the next three days or so, but I have other demands on my time. It's worth thinking about the most efficient way to do it.

Since these things I'm making all have acidic groups hanging off them, the most appealing idea I have right now is to use a basic resin to clean them up - as most med-chem types know, you can generally stick acidic compounds onto such resin, wash a lot of the crud off and throw that away, then bump your desired compounds off with some sort of acidic wash. This sort of solid-phase cleanup became popular in the combichem era, and has persisted for situations like this.

That's probably how I'll go, as opposed to, say, individually loading every single one of the compounds onto the HPLC machine. That would make me rather unpopular with the other people who might want to use that instrument before March is upon us, for one thing, and it would be complete overkill as well. These compounds are all pretty clean looking - a wash-and-rinse protocol should turn them out in good shape, and there's no need to use Super Ultimate Purification on them. (And besides, I'm making them all in reasonable quantity, which would bog down the HPLC even more).

An even more brainless way to do this workup would be to run every single compound through an automated column (like a Biotage). At least the HPLC has a liquid handler on it - I could set the thing up with a few rows of samples to inject, and walk away with some degree of confidence that it would run them. But the Biotage-type machines are usually one-at-a-time things, for larger samples. One batch of five grams of stuff would be perfect - two or three dozen at 100 mgs each, not so.

And all this makes me think of someone who used to work down the hall from me (no more clues than that!) I noticed that he was always cranking away in the lab, every time I went past. I mean, this guy looked like one of those multi-armed Hindu god statues, with each hand holding a round-bottom flask or a TLC plate. Impressive! Until I realized, after dealing with him a while, that the reason he was zipping around in there like a hamster was because he was doing everything in the most brutal and time-wasting way possible. He seemed to pick his reactions and protocols according to how much hand labor they involved: the more, the better.

I took a vow never to be him, and today I plan to live up to that. Measure twice, cut once and all that.

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February 10, 2010

Chemical Supplier Question

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Posted by Derek

Here's a quick question for those of you that order a lot of odd little compounds. A correspondent tells me that he's been ordering resupplies from some of the usual suspects in this area (ChemBridge, ChemDiv - you know the sorts of companies, if you're in the med-chem business). And a higher than usual percentage of compounds are coming back as "Unavailable". . .only to show up available, at a significantly higher price, from Aurora.

Now, I certainly don't know the business arrangements between all these companies. I know that some of the compounds themselves are clearly coming from the same original sources, often somewhere in Russia, and make their way into a number of catalogs at once. But is this Aurora business a coincidence. . .or a business model? Anyone seen this happen personally?

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January 26, 2010

The Infinitely Active Impurity

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Posted by Derek

Yesterday's post touched on something that all experienced drug discovery people have been through: the compound that works - until a new batch is made. Then it doesn't work so well. What to do?

You have a fork in the road here: one route is labeled "Blame the Assay" and the other one is "Blame the Compound". Neither can be ruled out at first, but the second alternative is easier to check out, thanks to modern analytical chemistry. A clean (or at least identical) LC/MS, a good NMR, even (gasp!) elemental analysis - all these can reassure you that the compound itself hasn't changed.

But sometimes it has. In my experience, the biggest mistake is to not fully characterize the original batch, particularly if it's a purchased compound, or if it comes from the dusty recesses of the archive. You really, really want to do an analytical check on these things. Labels can be mistaken, purity can be overestimated, compounds can decompose. I've seen all of these derail things. I believe I've mentioned a putative phosphatase inhibitor I worked on once, presented to me as a fine lead right out of the screening files. We resynthesized a batch of it, which promptly made the assay collapse. Despite having been told that the original compound had checked out just fine, I sent some out for elemental analysis, and marked some of the lesser-used boxes on the form while I was at it. This showed that the archive compound was, in fact, about a 1:1 zinc complex, for reasons that were lost in the mists of time, and that this (as you can imagine) did have a bit of an effect on the primary enzyme assay.

And I've seen plenty of things that have fallen apart on storage, and several commercial compounds that were clean as could be, but whose identity had no relation to what was on their labels (or their invoices for payment, dang it all). Always check, and always do that first. But what if you have, and the second lot doesn't work, and it appears to match the first in every way?

Personally, I say run the assay again, with whatever controls you can think of. I think at that point the chances of something odd happening there are greater than the chemical alternative, which is the dreaded Infinitely Active Impurity. Several times over the years, people have tried to convince me that even though some compound may look 99% clean, that all the activity is actually down there in the trace contaminants, and that if we just find it, we'll have something that'll be so potent that it'll make our heads spin. A successful conclusion to one of these snipe hunts is theoretically possible. But I have never witnessed one.

I'm willing to credit the flip side argument, the Infinitely Nasty Impurity, a bit more. It's easier to imagine something that would vigorously mess up an assay, although even then you generally need more than a trace. An equimolar amount of zinc will do. But an incredibly active compound, one that does just what you want, but in quantities so small that you've missed seeing it? Unlikely. Look for it, sure, but don't expect to find anything - and have 'em re-run that assay while you're looking.

Update: I meant to mention this, but a comment brings it up as well. One thing that may not show up so easily is a difference in the physical form of the compound, depending on how it's produced. This will mainly show up if you're (for example) dosing a suspension of powdered drug substance in an animal. A solution assay should cancel these things out (in vitro or in vivo), but you need to make sure that everything's really in solution. . .

Comments (33) + TrackBacks (0) | Category: Analytical Chemistry | Drug Assays | Life in the Drug Labs

January 21, 2010

In Hoc Signo Non Vinces

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Posted by Derek

I am here to confess to a deep-seated prejudice, one that has been with me for many years now. I know that others feel differently, but I'm sticking to my rule: No Naphthyls.

OK, pile on me now for having a closed mind. I know that there are drugs that are more successful than anything I'll ever make that have a naphthalene in them. (At least that structure's a small one). It's just that I see a naphthyl as the worst sort of "potency through greasiness" move in drug design. They hurt your solubility, drive up your molecular weight, open you to metabolites that you may not care for, and all for what? A little activity in your in vitro assay.

I'm getting close to putting cyclohexyl on the same list, if you want to know the truth. Problem is, people make these things "just as SAR compounds". You know, they'll trowel this hunk of grease onto the side of the molecule, just to see what happens, and if it really looks good, well, they'll. . .find some way to make it better. Right. Tetrahydropyranyl instead, that'll do it. But my attitude is, why not just make the THP derivative in the first place, if that's where you're going to go?

SAR is long, and life is short. There isn't time to make everything. So I decided a long time ago that I'd try to only make structures that I could live with. That still admits a lot of weird stuff, don't get me wrong. I have functional groups on my go-to lists that make people roll their eyes. But I draw the line at flat slabs of lard. No naphthalenes.

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January 19, 2010

What Should Non-Chemists Know About Medicinal Chemistry, Anyway?

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Posted by Derek

It's been a busy day on the front lines of science around here; apologies for not getting anything up until now. Here's a topic that I was discussing with some colleagues not too long ago: how much do we need to know about each other's specialties, anyway? I'm assuming that the answer is "more than nothing", although if someone wants to make the zilch case, I'd be interested in hearing it done.

But once past that, what's the optimum? I (for example) have never done cell culture. Nor do I see myself ever needing to do it (and anyone who needs me to is clearly in a bad way). I know the broad outlines of the field, but almost none of the details, and I'm sure that even my broad outlines have some faint parts in them. So if I'm at some sort of meeting where the problem-of-the-day turns on cell culture issues, I can be of no help at all. Is this a problem? I understand that different cells take to culture conditions differently, have varying growth rates, need media changes and whatnot, can generally only be passaged a certain number of times, etc. In short, I know roughly what to expect from my cell culture colleagues, and what would be silly of me to demand. Is that about right?

After all, I don't expect them to know the ins and outs of medicinal chemistry, particularly the synthetic organic lab part of it. Things like methylene chloride being rather more weirdly polar as a solvent than you'd expect, or the fact that some amines will stick to solid magnesium sulfate drying agent (but not sodium sulfate), or how you can azeotrope out acetic acid with toluene, or how you want palladium tetrakis to be lemon yellow and not orange - these and dozens of others are the tricks of my lab trade, and they don't know mine in the same way that I don't know theirs.

But I do like it when my biology colleagues have the broad outlines - that molecules with chiral centers, other things being equal, are often harder to make than achiral structures, that sticking a lot of cycloalkyl grease on a molecule is asking for metabolic trouble (no matter what it does for the potency in the assays), what sorts of things tend to make a molecule more (or less) soluble, and so on. Those are the equivalent of me knowing that primary cell lines lose some of their functions in culture, the difference between transient transfection and a stable cell line, etc.

It seems to me that each discipline in our business could draw up a list of What Everyone Else In the Company Should Know about their area. So, to start off with, I'm throwing the comments section over to what biologists (and others) should know, at a minimum, about med-chem. Take it away!

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January 18, 2010

Oxford's New Building, One Year Later

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Posted by Derek

About a year ago, I wrote here about the impressive-looking new biochemistry building at Oxford, and wondered if it would work out quite the way the architects intended. Now I see a report from a post-doc who actually works there:

My first thoughts setting foot into the new building were the following: How are we supposed to concentrate with our offices in the atrium? How are we going to manage to work at such tiny desks?
I have to say, these initial concerns were justified. We hear the lab phone of every single floor ringing through the atrium, including people's mobile phones (which also causes envy towards those who actually have reception). When people really need to concentrate on writing, reading or thinking while others are discussing their work or are simply chatting, the atmosphere can get pretty tense. And even if it was completely silent in the atrium, the small size of the desks already makes working difficult. . .I once discussed the lack of space with our head of department. He simply replied: when you have to write a paper, you work from home anyway... I'd say £47 million well spent!

Anyone else over there want to comment?

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December 2, 2009

Data, Raw and Otherwise

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Posted by Derek

Perhaps I should talk a bit about this phrase "raw data" that I and others have been throwing around. For people who don't do research for a living, it may be useful to see just what's meant by that term.

As an example, I'll use some work that I was doing a few years ago. I had an reaction that was being run under a variety of conditions (about a dozen different ways, actually), but in each case was expected to either do nothing or produce the same product molecule. (This was, as you can see, a screen to see which conditions did the best job at getting the reaction to work). I set this up in a series of vials, taking care to run everything at the same concentration and to start all the reactions off at as close to the same time as I could manage.

After a set period, the reaction vials were all analyzed by LC/MS, a common (and extremely useful) analytical technique. I'd already given the folks running that machine a sample of the known product I was looking for, and they'd worked up conditions that reproducibly detected it with high sensitivity. They ran all my samples through the machine, and each one gave a response at the other end.

And those numbers were my raw data - but it's useful to think about what they represented. The machine was set to monitor a particular combination of ions, which would be produced by my desired product. As the sample was pumped through a purification column, the material coming out the far end was continuously monitored for those specific ions, and when they showed up, the machine would count the response it detected and display this as a function of time: a flat line, then a curvy, pointed, peak which went up and then came back down as the material of interest emerged from the column and dwindled away again.

So the numbers the machine gave me were the area under the curve of that peak, and that means, technically, that we're one step away from raw numbers right there. After all, area-under-the-curve is something that's subject to the judgment of a program or a person - where, exactly, does this curve start, and where does it end? Modern analytical machines are quite good at judging this sort of thing, but it's always good to look over their little electronic shoulders to make sure that their calls look correct to you. If you want to be hard-core about it, the raw data would be the detector response for each individual reading, at whatever frame rate the machine was sampling at. That's even more raw than most people need - actually, while writing this, I had to think for a moment to picture the data at that level, because it's not something I'd usually see or worry about. For my purposes, I took the areas that were calculated, since the peak shapes looked good, and the machine's software was able to evaluate them consistently and didn't have to apply any sort of correction to them to meet its own quality standards.

So there's one set of numbers. But the person running the machine had taken the trouble (as they should have) to run a standard curve using my supplied reference compound. That is, they'd dissolved it up to a series of ever-more-dilute solutions, and run those through the machine beforehand. This, plotted as peak area versus the real concentration, gave pretty much a straight line (as it should), and the machine's software was set up to use this information to also calculate a concentration for every one of my product peaks. So the data set that I got had the standard plot, followed by the experiments themselves, with both the peak areas and the resulting calculated amounts. Since these were related by what was very nearly a straight line, I probably could have used either one. But it's important to realize the difference: by using the calculated concentrations, I could either be correcting for a defect in the machine (if its detector response really wasn't quite linear), or I could be introducing error (if the standard solutions hadn't been made up quite right) It's up to you, as a scientist, to decide which way to go. In my case, I worked up the data both ways, and found that the resulting differences were far too small to worry about. So far, so good.

But there's another layer: I had done these experiments in triplicate. There were actually thirty-six vials for the twelve different conditions, because I wanted to see how reproducible the experiments were. For my final plots, then, I used the averages of the three runs for each reaction, and plotted the error bars thus generated to show how tight or loose these values really were. That's what I meant about the area numbers versus the concentration numbers question not meaning much in this case. Not only did they agree very well, but the variations between them were far smaller than the variations between different runs of the same experiments, and thus could safely be put in the "don't worry about it" category while interpreting the data.

What I did notice while doing this, though, was something else that was significant. My mass spec colleague had done something else which was very good practice: including a standard injection every so often during the runs of experimental determinations. Looking these over, I found that this same exact sample, of known concentration, was coming out as having less and less product in it as the process went on. That's certainly not unheard of - it usually means that the detector was getting less sensitive as time went on due to some sort of gradually accumulating gunk from my samples. Those numbers really should have been the same - after all, they were from the same vial - so I plotted out a curve to see how they declined with time. I then produced another column of numbers where I used that as a correction factor to adjust the data I'd actually obtained. The first runs needed little or no correction, as you'd figure, but by the end of the run, there were some noticeable changes.

So now I had several iterations of data for the same experiment. There was the raw raw data set, which I never really saw, and which would have been quite a pile if printed out. This was stored on the mass spec machine itself, in its own data format. Then I had numbers that I could use, the calculated areas of all those peaks. After that I had the corresponding concentrations, corrected for by the standard concentration curve run before the samples where injected. Then I had the values that I'd corrected for the detector response over time. And finally, once all this was done, I had the averages of the three duplicate runs for each set of conditions.

When I saved my file of data for this experiment, I took care to label everything I'd done. (I was sometimes lazier about such things earlier in my career, but I've learned that you can save ten minutes now only to spend hours eventually trying to figure out what you've done). The spreadsheet included all those iterations, each in a labeled column ("Area" "Concentration" "Corrected for response"), and both the standard curves and my response-versus-injection-number plots were included.

So how did my experiments look? Pretty good, actually. The error bars were small enough to see differences in the various conditions, which is what I'd hoped for, and some of those conditions were definitely much better than others. In fact, I thought I saw a useful trend in which ones worked best, and (as it turned out), this trend was even clearer after applying the correction for the detector response. I was glad to have the data; I've had far, far worse.

When presenting these results to my colleagues, I showed them a bar chart of the averages for the twelve different conditions, with the associated error bars plotted, which was good enough for everyone in my audience. If someone had asked to see my raw data, I would have sent them the file I mentioned above, with a note about how the numbers had been worked up. It's important to remember that the raw data are the numbers that come right out of the machine - the answers the universe gave you when you asked it a series of questions. The averages and the corrections are all useful (in fact, they can be essential), but it's important to have the source from which they came, and it's essential to show how that source material has been refined.

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November 28, 2009

Recommended Books For Medicinal Chemists, Part One

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Posted by Derek

I asked recently for suggestions on the best books on med-chem topics, and a lot of good ideas came in via the comments and e-mail. Going over the list, the most recommended seem to be the following:

For general medicinal chemistry, you have Bob Rydzewski's Real World Drug Discovery: A Chemist's Guide to Biotech and Pharmaceutical Research. Many votes also were cast for Camille Wermuth's The Practice of Medicinal Chemistry. For getting up to speed, several readers recommend Graham Patrick's An Introduction to Medicinal Chemistry. And an older text that has some fans is Richard Silverman's The Organic Chemistry of Drug Design and Drug Action.

Process chemistry is its own world with its own issues. Recommended texts here are Practical Process Research & Development by Neal Anderson and Process Development: Fine Chemicals from Grams to Kilograms by Stan Lee (no, not that Stan Lee) and Graham Robinson.

Case histories of successful past projects are found in Drugs: From Discovery to Approval by Rick Ng and also in Walter Sneader's Drug Discovery: A History.

Another book that focuses on a particular (important) area of drug discovery is Robert Copeland's Evaluation of Enzyme Inhibitors in Drug Discovery.

For chemists who want to brush up on their biology, readers recommend Terrence Kenakin's A Pharmacology Primer, Third Edition: Theory, Application and Methods and Molecular Biology in Medicinal Chemistry by Nogrady and Weaver.

Overall, one of the most highly recommended books across the board comes from the PK end of things: Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization by Kerns and Di. For getting up to speed in this area, there's Pharmacokinetics Made Easy by Donald Birkett.

In a related field, the standard desk reference for toxicology seems to be Casarett & Doull's Toxicology: The Basic Science of Poisons. Since all of us make a fair number of poisons (as we eventually discover), it's worth a look.

There's a first set - more recommendations will come in a following post (and feel free to nominate more worthy candidates if you have 'em).

Comments (21) + TrackBacks (0) | Category: Book Recommendations | Drug Development | Life in the Drug Labs | Pharmacokinetics | The Scientific Literature | Toxicology

November 24, 2009

Fear Of Academic Chemistry?

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Posted by Derek

A comment to yesterday's post made a point that seemed instantly familiar, but it's one that my own thoughts had never quite put together. All of us who do medicinal chemistry came out of academic labs; that's where you get the degrees you need to have to be hired. Many of us worked on the synthesis of complex molecules for those degrees, since that's traditionally been a preferred base for drug companies to hire from. (You get a lot of experience of different kinds of reactions that way, have to deal with setbacks and adversity, and have to learn to think for yourself. Plus, if you can put up with some of the people who do natural products synthesis, the thinking goes, you can put up with anything).

Here's the interesting part, though. People who do the glass-filament spiderweb-sculpture work that is total natural product synthesis will defend it on many grounds (some more defensible than others, in my view). They have, naturally enough, a bias in favor of that kind of work. But have those of us who've done that kind of chemistry and then moved on to industry ended up with the opposite bias? Have we reacted against the forced-march experience of some of our early training by resolving never to get stuck in such a situation again (which is reasonable), but at the same time resolved never to get stuck doing fancy synthesis again?

That one may not be so reasonable. And I don't mean that we avoid twenty-step syntheses for irrational reasons, because there are perfectly rational reasons for fleeing from such things in industrial work. But this bias might extend further. Take a workhorse reaction like palladium-catalyzed coupling - that's just what people tend to think of when they think of uninspiring industrial organic synthesis, two or three lumpy heteroaromatics stuck together with Suzuki couplings, yawn. One of my colleagues, though, recently mentioned that he saw too many people sticking with rather primitive conditions for such reactions and taking their 50% yields (and cleanup problems) as just the normal course of events. And he's got a point, I'd say. There really are better conditions to use as your default Pd coupling mixture than the ones from the mid-1990s. You don't have to always clean all the red-brown gunk out from your product after using (dppf) as your phosphine ligand, and good ol' tetrakis is not always the reagent of choice. But a lot of people just take the standard brew, throw their starting materials in there, and bang 'em together. Crank up the microwave some more if it doesn't work.

I can see how this happens. After all, the big point that people have to learn when they join a drug research effort is that chemistry is not an end in itself - it's a tool to make compounds for another end entirely. If you're just making analogs in the early stages of a new project, no one's going to care much if your yields are low, because the key thing is that you made the compounds. I've said myself (many times) that there are two yield in medicinal chemistry: enough, and not enough. Often, perhaps a little too often, five milligrams qualifies as "enough", which means that you can check off a box through some really brutal chemistry.

But at the same time, if you could make simple changes to your reaction conditions, or to the kinds of reactions you tend to run, you could potentially make more compounds (because you're not spending so much time cleaning them up), make them in higher yields (or make your limited amount of starting material stretch further), or make more interesting (and patentable) ones, too. I think that too many of us do tend to get stuck in synthetic ruts of various sorts.

Perhaps the main cause of this is the pressure of normal drug discovery work. But I do have to wonder if some of the problem is a bit of aversion to the latest, hottest reagent or technique coming out of the academic labs. To be sure, a lot of that stuff isn't so useful out here in what it pleases us to call the real world. But there are a lot of things we could stand to learn, as well. Palladium couplings used to be considered kind of out-there, too, you know. . .

Comments (30) + TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs

November 20, 2009

But These Reagents, Where Are They?

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Posted by Derek

I'm home today (sick children, etc.), so I'm blogging from next to my daughter's guinea pig cage rather across the hall from my lab. But I have a lab-based question to throw out: what would you say is the chemistry technique or reagent with the worst publication-to-real use ratio?

I have a couple of nominees to get things rolling. For reagent, I would like to advance the montmorillonite clay stuff. I cannot count how many papers I have seen on its use as a Lewis acid, catalyst, and all-around good thing to have, but I have never used it myself, never spoken with anyone who has, and never (to my recollection) heard it suggested as a possible thing to try when someone encountered a synthetic problem. For all I know it's a fine reagent, but its footprint does not seem to be very large. I actually have used benzotriazole, but I've never seen an actual container of montmorillonite K-10.

For general technique, I'm tempted to nominate ionic liquids. Man, are there ever a lot of publications on those things, but again, I've never actually encountered them in actual practice. I have heard second-hand of people trying them, so I guess that counts for something, but it still seems to be disproportionate compared to the avalanche of literature citations for the things. The craze seems to have peaked, but still not a week goes by that I don't see a paper.

Nominations? As with the book recommendation post, I'll assemble things into master lists.

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November 19, 2009

What Are the Best Med-Chem Books?

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Posted by Derek

I get regular requests to recommend books on various aspects of medicinal chemistry and drug development. And while I have a few things on my list, I'm sure that I'm missing many more. So I wanted to throw this out to the readership: what do you think are the best places to turn? This way I can be more sure of pointing people in the right directions.

I'm interested in hearing about things in several categories - best introductions and overviews of the field (for people just starting out), as well as the best one-stop references for specific aspects of drug discovery (PK, toxicology, formulations, prodrugs, animal models, patent issues, etc.)

Feel free to add your suggestions in the comments, or e-mail them to me. I'll assemble the highest-recommended volumes into a master list and post that. Just in time for the holidays, y'know. . .

Comments (35) + TrackBacks (0) | Category: Life in the Drug Labs | Pharma 101

November 13, 2009

Lumpy Assay Results

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Posted by Derek

When we screen zillions of compounds from our files against a new drug target, what can we expect? How many hits will we get, and what percentage of those are actually worth looking at in more detail?

These are long-running questions, but over the last twenty years some lessons have been learned. A new paper in J. Med. Chem. emphasizes one of the biggest ones: if at all possible, run your assays with some sort of detergent in them.

Why would you do a thing like that? Compound aggregation. The last few years have seen a rapidly growing appreciation of this problem. Many small molecules will, under some conditions, clump together in solution and make a new species that has little or nothing to do with their individual members. These new aggregates can bind to protein surfaces, mess up fluorescent readouts, cause the target protein to stick to their surfaces instead, and cause all kinds of trouble. Adding detergent to the assay system cuts this down a great deal, and any compound that's a hit without detergent but loses activity with it should be viewed with strong suspicion.

The authors of this paper (from the NIH's Chemical Genomics Center and Brian Shoichet's lab at UCSF) were screening against the cysteine protease cruzain, a target for Chagas disease. They ran their whole library of compounds through under both detergent-free and detergent conditions and compared the results. In an earlier screening effort of this sort against beta-lactamase, nearly 95% of the hits (many of them rather weak) turned out to be aggregator compounds. This campaign showed similar numbers.

There were 15 times as many apparent hits in the detergent-free assay, for one thing. Some of these were apparently activating the enzyme, which is always a bit of an odd thing to explain, since inhibiting enzyme activity is a lot more likely. These activators almost completely disappeared under the detergent conditions, though. And even looking just at the inhibitors, 90% of the hit set in the detergent-free assay went away when detergent was added. (I should note that control cruzain inhibitors performed fine under both sets of assays, so it's not like the detergent itself was messing with the enzyme to any significant degree).

They point out another benefit to the detergent assay - it seems to improve the data by keeping the enzyme from sticking to the walls of the plastic tubes. That's a real problem which can kick your data around all over the place - I've encountered it myself, and heard a few horror stories over the years. But it's not something that's well appreciated outside of the people who set up assays for a living (and not always even among some of them).

So, let's get rid of those nasty aggegators, right? Not so fast. It turns out that some of the compounds that showed this problem during the earlier beta-lactamase work didn't cause a problem here, and vice versa. Even using different assays designed to detect aggregation alone gave varying results among sets of compounds. It appears that aggregation is quite sensitive to the specific assay conditions you're using, so trying to assemble a blacklist of aggregators is probably not going to work. You have to check things every time.

One other interesting point from this paper (and the previous one): curators of large screening collections spend a lot of time weeding out reactive compounds. They don't want things that will come in and react nonspecifically with labile groups on the target proteins, and that seems like a reasonable thing to do. But in these screens, the compounds with "hot" functional groups didn't have a particularly high hit rate. You'd expect a cysteine protease to be especially sensitive to this sort of thing, with that reactive thiol right in the active site, but not so. This ties in with the work from Benjamin Cravatt's group at Scripps, suggesting that even fairly reactive groups have a lot of constraints on them - they have to line up just right to form a covalent bond, and that just doesn't happen that often.

So perhaps we've all been worrying too much about reactive compounds, and not enough about the innocent-looking ones that clump up while we're not looking. Detergent is your friend!

Comments (11) + TrackBacks (0) | Category: Drug Assays | Life in the Drug Labs

November 10, 2009

Lab Equipment: Any H-Cube Troubleshooters Out There?

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Posted by Derek

I mentioned the H-Cube hydrogenation machine here a couple of years ago as an early example of a commercial flow chemistry machine. As some readers may have guessed, my recent post on hydrogenations was partly inspired by a recent run of activity on this instrument, which came in quite handy.

Until the last couple of days, that is. Now there's a problem, and I'd be glad to hear from any H-Cube users who might know how to solve it. (If you haven't used one, you can probably bail out right now!) What's going on is: when I try to run a hydrogenation in "Full H2" mode, everything works fine until the H2 valve closes. The pump's fine, the flow through the instrument is fine. . .until the status switches to "Running". At that point the flow stops momentarily, then a gout of solvent runs from the outlet all at once, and then. . .nothing. Well, nothing except hydrogen gas - if I dip the outlet tube below the surface of some solvent, I can see that it's still producing that. But there's no flow. Lifting the solvent inlet from the reservoir, I can see that nothing's being taken up - an air bubble forms at the inlet, and just moves up and down.

So there's something going on when the system starts letting hydrogen into the flow, but I'm not sure what that might be. I can always call in the $250/hr folks, but I thought that throwing my problems out onto the blog was at least worth a try. Just to take care of some obvious fixes, so far I've cleaned the metal frit, replaced the Teflon membrane, sonicated the check valve, and tried changing catalyst cartridges. Anyone got any clues after that?

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October 29, 2009

Four Med-Chem Questions

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Posted by Derek

Here are a few more of those questions that medicinal chemists have to deal with from time to time. Most of these have no definitive answers (which is why they keep coming up!)

1. You're making a compound that looks to be important in the project - maybe even the clinical candidate, if things go right. But there's a step in the synthesis which - while it does work - is clearly not something that's going to scale up too well. You need more compound right now, and you can push things through. But you're eventually going to have to ditch that step (unless this compound gets overtaken by another one), so. . .when's the right time to worry about that?

2. Your compound series is in a pretty crowded patent landscape. In fact, another application has just published that really looks to be breathing down your neck. Of course, that means the work in it was done a year and a half ago (or more). Can you assume that Company X has followed the same course that you have, and has already investigated the series you're working on? Should you drop them, or go in in the chances that six months from now another application will drop that covers you like a tarp?

3. You're finally writing up one of your old projects for publication. But it's been a while, and the details of what happened are not as sharp as they were when thing were going on. What's more, on looking the work over, you realize that there are some obvious gaps in it, stuff that didn't look that way at the time, but sure does so now. You can write things up to make it look more coherent, but only by rearranging the way it really happened. Where do you draw the line?

4. Your lead compound is ready to go into toxicology testing, the last big step before declaring victory and naming it as the development candidate. Trouble is, there's something funny about it in rats. They just don't get the blood levels that mice and dogs do, and your tox people would really, really rather run the tox study in rats (since that's the standard, and what they have the most comparison data for). Update: I mistakenly switched rodents mentally this morning on the train, now they're switched back to what they should be). You can get the blood levels up to where they need to be - but only by using a dosing vehicle that might have problems of its own, and that the toxicologists haven't had much experience with either. What to do?

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October 27, 2009

Reduce Your Number of Reductions, Why Don't You?

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Posted by Derek

I've been occupied all morning with voodoo. Well, the technical name for it is catalytic hydrogenation, but let's call it for what it is: witchcraft. It's a widely used reaction in organic chemistry, and you can use it to reduce all kinds of different functional groups on your molecules. But once you get off the well-traveled roads, it's all jungle drums at midnight.

One reason we chemists like this reaction so much is that it's simple. You add some dark insoluble powder to your compound - which is some metal like palladium, platinum, nickel or the like, adsorbed onto carbon black or another solid. Then you add solvent and put the whole thing under an atmosphere of hydrogen gas. That soaks into the metal particles, your compound sits on them and gets magically reduced, and after a while you filter everything off and there's your clean, transformed product.

Most of the time. You'll note that I've skipped over a lot of variables there. For one thing, there's the choice of metal catalysts. Pt and Pd get the most use, but they come on a variety of solid supports. Carbon, alumina, barium sulfate, calcium carbonate. . .they all act differently. And don't stop with those guys: nickel's not to be ignored, then rhodium's available, and even ruthenium if you want to crank up the pressure. The pressure of all that hydrogen, there's another variable. Just a balloon on top, atmospheric pressure? Or put in a thick glass bottle on a shaker and turn it up to 50 pounds per square inch? Higher, in a metal apparatus? And what temperature did you have in mind? Ambient, or would you like to heat things up? Remember, as the pressure goes up, so does the temperature you can run the solvents up to.

Ah yes, the solvents. A lot of the time you see this work done in methanol or ethanol, but the reactions will often go quite differently in ethyl acetate or even something less polar. I've even seen some done in dichloromethane, although that somehow just seems wrong. Acids often have a profound effect on things, particularly if there's a basic amine in your compound.

And I haven't mentioned poisoned catalysts yet, have I? A bit of lead, or the addition of (non-protonated) amines or sulfur-containing compounds can dial down the reactivity of a lot of these metals - often down to zero, but sometimes to a useful level that you can't reach any other way. And then there's transfer hydrogenation, where you don't use the gas itself, but let some other compound give up hydrogen inside the reaction and transfer it over to your substrate. Paraformaldehyde, formic acid, phosphites, cyclohexene - all of those will work, and they can all work differently.

So. . .how many variations are we up to? Do you want to use 5% palladium on carbon in methanol, room temperature at 50 psi? Or platinum oxide in acetic acid at 50 degrees? Rhodium on alumina, ethanol, 100 psi at 100 C? Or wet 10% platinum catalyst with formic acid? That should get you started on this simple, well-known reaction. I've run 22 of them in the last two days, with the assistance of the H-Cube reactor, and I have to say: I'm about hydrogenated out.

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October 26, 2009

Elements I Have Yet to Use

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Posted by Derek

I wrote about this topic a few years ago, and thought I'd update it. Many chemists find themselves looking at a periodic table and wondering "How many of these things have I personally handled?" My list is up to nearly 45 elements (there are a couple that I've got to think about, one-off catalyst reactions from twenty-two years ago and the like). And there are at least 29 that I hope to never use at all, since they're radioactive and I'm generally not in the mood for that. So what does that leave me?

Well, I've never used beryllium, although it's not that I'm tapping my foot waiting for any. It's pretty toxic stuff, for the most part, and there are hardly any organic chemistry reactions that get near it. That means that I can't even think what I might use it for, and I could easily go my whole career without seeing any.

The next lowest molecule weight element I haven't messed with (excluding unreactive neon, which you at least get to see in its excited state) is probably scandium. That whole first column of transition metals is pretty useless for organic chemists, to be honest (Yttrium? Lanthanum?), and I've never seen any reactions that leapt out at me as things I had to try. No, if the answer is scandium, it must have been a pretty odd question.

Next up, I haven't used either of the G twins, gallium and germanium. They're not too well studied compared to their family members above and below: aluminum and even indium are more widely used than gallium, and silicon and tin show up in organic labs a million times more often than germanium. But with those relatives, you'd have to think that there's something interesting that can be done with these, so it depends on whether anyone finds out what that might be during the rest of my chemistry career.

And right next to these is arsenic, which I've also managed to avoid. It's famously poisonous, although it's really not worse than a lot of other things that get used much more often. But again, there's not a lot of compelling chemistry to be done with the stuff, not that I know of, anyway, and there are always those unfortunate nomenclature problems to be dealt with, especially if you have a British accent.

Krypton I've never had a use for, and I'd have to rate the chances as very low indeed. In the next row, I've handled strontium chloride, but only to make red-colored flames for a school demonstration show. I have yet to touch yttrium, as mentioned above, and I've managed to miss zirconium so far as well. There are actually a number of organometallic reactions that use that one, so it's at least a real possibility. Niobium I have yet to encounter, and at the rate it's used, I probably never will. Cadmium's another toxic beast - there are some old reactions that use organocadmiums, but I can't think when I saw a modern reference that used any of them, and I don't see this one in my future, either. Antimony I might use if I never need some horrible superacid. Tellurium, well. . .there would have to be a pretty good reason, given its reeking, nose-wrinkling sulfur and selenium relatives, but someone might yet come up with one. Can't rule that one out, unfortunately.

Now we're getting into the heavy metals, and a lot of gaps start to appear. Has anyone in an organic chemistry lab ever used hafnium or tantalum? Didn't think so. The best candidate for "something I could use, but haven't" in this bunch is osmium. The tetroxide is a very useful reagent that I just haven't had the need for. It wouldn't surprise me if that's the next addition to my list. I've no desire whatsoever to use thallium. It's part of a short run of nasties that you hit right after the jewelry metals - you have your platinum, then gold, and you think you're in the high-rent district, and suddenly it's mercury, thallium, and lead right in a row. Reminds me of the way towns were stuck next to each other in New Jersey.

And as far as the lanthanides, well, I've used cerium as a TLC stain, and once I used samarium iodide - which, true to its reputation, didn't work. None of the others have I touched, and unless I need some funky NMR shift reagent, which fewer and fewer people do these days, I don't see it happening. There are a lot of funny rare earths down there, but little reason for an organic chemist to go digging around among them.

Weirdest element I actually have handled? Xenon would have to be the winner - I've used the difluoride, and yes, that was the recourse of a desperate chemist. But it did work to turn a silyl enol ether into an alpha-fluoro ketone, so I can't say anything bad about it, other than its rather penetrating smell, which I probably should have taken more care not to experience. . .

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October 14, 2009

Consultants

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Posted by Derek

Most chemistry departments in the drug industry have some academic consultants who come in every so often. The idea is that they'll have some useful suggestions about synthetic problems (there aren't so many academic consultants who are useful on drug discovery questions as opposed to pure chemistry ones). At the companies where I've worked, the consultants will spend the day in a conference room, while project teams troop in and out with presentations.

How useful this process is varies, to say the least. The first variable is the consultant, because some people are just better at that sort of thing. Ideally, you want someone who has a lot of ideas, has them relatively quickly, and enjoys putting them out for people to comment on them. Not everyone fits that description. While those can all be useful qualities, there are plenty of world-class scientists whose working style doesn't fit those requirements, and these people tend to be less valuable for drop-in sessions.

Another variable is the sorts of problems the drug discovery teams are dealing with. We try, in the industry, to reduce our chemistry to the simplest possible routes. Time is money (and money is money, too), and we always need methods that will reliably crank out plenty of different analogs without a lot of work. When that works, it often doesn't lead to especially exciting chemistry - in fact, the Venn diagram would show that "smoothly running project" and "exciting chemistry" don't overlap much. That means that the projects where things are going fine don't have much to talk about when the consultants appear, and those sessions sometimes end up spending more time on peripheral problems.

Much of the time, too, the biggest problems aren't chemical ones. If you're having trouble with metabolism, tox, or absorption, there aren't going to be many consultants who can help you out. Most of the ones who can are ex-industry people. (And with problems like these, sometimes no one can help you out at all). But asking someone about oral bioavailability when their research is all about interesting new synthetic organic methods is a waste of time - yours and theirs.

I've had some useful and interesting consulting sessions over the years, but some really disastrous ones, too. Many of the latter feature those "Well, now what do we talk about?" moments, which seem to be a cue for Satan to emerge and fill out the hour. So plan ahead. Make sure that you've got plenty to talk about. Actually, you'd better have more than you think you'll need, because some of your topics may either get a fast answer, or an equally fast shrug of the shoulders. . .

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October 8, 2009

Hoist, Petard, Etc.

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Posted by Derek

Hmmm. As a colleague just pointed out to me, I've spent some time here defending "me-too" drugs. And just this morning (see the previous post) I take off after what can only be described as "me-too reactions", saying that I don't see the use for so many of them.

Well! The only defense I can offer (until I think of a better one) is that there is no drug category so populated as the aldoxime-to-nitrile conversion is in synthetic chemistry (or acetal formation/deprotection, desilylation, or the other categories I spoke of in that other post). I suppose I might have a tougher time standing up for me-too drugs if there were (say) twenty-nine statins on the market. But still. . ."I'd better put up a post on that", I said. "Better you than someone with a funny pseudonym in your comments section", came the reply.

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Retire These Reactions!

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Posted by Derek

Here's a question you don't hear discussed very often: are there some synthetic organic chemistry reactions that don't need any more work? I'm moved to ask this because I just came across yet another way that someone has reported to dehydrate an oxime to a nitrile. (No, I won't link to it. You don't need it. No one needs it).

If asked to count the number of times I have seen new reagents that dehydrate oximes to nitriles, I would be at a total loss to even try to guess. But I've seen it over and over and over. Is it possible that we now have enough ways to do this? And that anyone who is contemplating adding another one to the list should instead go do something else?

I'll vote for that. And there are several other transformations that could go on the same list. That doesn't mean that I think that our existing methods for these are all perfect, or that they couldn't be improved. I mean, even for forming amides, I would like an inexpensive reagent that never fails, even with crappy unreactive hindered coupling partners, works at room temperature in about five minutes, and has a ridiculously simple workup. We don't quite have that, do we? But no one's publishing on coupling reagents like that, because they're rather hard to realize. What we get are a bunch of things that are about as useful as what we have already.

And I agree that it's worth having multiple methods to accomplish the same reaction. I've been saved several times by being able to move down the list and find something that works. But how long should the list be? Eight reagents? Ten? Twenty? At what point should something like this cease to become an acceptable field for human effort?

My first nomination, then, for the Retirement Home for Organic Transformations is aldoxime to nitrile. I am willing to face the rest of my chemistry career with only the monstrously long list of reagent systems we have today for that reaction. Further nominations can be made in the comments - I'll assemble a list for another post.

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September 22, 2009

Colorful Junk

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Posted by Derek

Last Saturday night I stayed out until 3:30 AM, then slept in the back of our van. Now, that may sound like a pretty good evening for some of you, but it might seem a little odd for a guy like me. There's a good reason, though - I was out at the Connecticut Star Party, a meeting of amateur astronomers out in the boonies of eastern CT. Fall is a good season for those get-togethers - there are a lot of interesting things in the sky, the weather tends to clear out as cold fronts come through (but it's still temperate, overall), and it gets dark at a reasonable hour. Conditions last weekend were about as good as they can get, actually - I won't go into what I observed, unless it turns out that there are a lot of readers to whom phrases like "Minkowski's Footprint" and "G-numbered globulars around M31" mean something.
jupiter_cassini.jpg
There were good views of Jupiter, though, and that always reminds me of the lab. I didn't spend much time looking at the planet (it tends to ruin your night vision for a while!), but the colors of the cloud belts are striking: yellow, brown, orange, tan, and (of course) the Great Red Spot, which is sort of a light brick color these days. (That's about the right color there in the photo, although that's a lot higher-resolution than you can see with the naked eye, taken as it was from the Cassini spacecraft on its way to Saturn. The black dot is the shadow of one of the moons, giving anyone in Jupiter's cloud deck a total solar eclipse).

What it reminds me of are the reactions on my bench (and some of those older stored samples), which are turning the same colors. And they're doing that for the same reasons. Jupiter's a gigantic stew of organic chemicals, which are being run through all kinds of temperatures and pressures (including plenty of conditions that are too bizarre to reproduce - so far - on Earth), being irradiated by the Sun and constantly zapped by huge lightning storms. The side reactions in my lab tend to make yellow, orange, red, and brown stuff, and Jupiter is nothing but side reactions.

So what is all that stuff? It's rather hard to characterize it, naturally, but I've always assumed that they're some sort of high-molecular-weight condensation products. (There's been some work done on trying to figure out what the astronomical versions of it, called tholins, must be). There must be a fair number of double bonds and a lot of conjugation in there, to get all those chromophores which push the transmitted light down to the yellow-orange part of the spectrum. All the higher-energy wavelengths of light, the purple/blue/green stuff, are being soaked up. No organic compound in my experience has ever decomposed to anything colored blue. They start by going yellow and then head down through orange and red, towards deep brown and thence to black.

So when I purify these things, and all the colorful stuff sticks to the top of the chromatography column and makes bands of who-knows-what up there, I often glance up at the stuff I'm throwing away, and think "Jupiter". And that's probably accurate.

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August 12, 2009

Sulfoxides: A Sneaking Affection

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Posted by Derek

Let us now praise sulfur. Well, some kinds of sulfur, anyway. The +2 oxidation state (earlier typo fixed, aargh) is a bit hard to handle, what with all those angry-skunk, burnt-tire overtones. But move up the ladder to +4, and you've got some possibilities.

Those do not include the hideous thioacetone, but bring some oxygen into the picture and you get a sulfoxide. And these guys I like, probably because one of the best compounds I've made in my career had one as a prominent feature.

Not every medicinal chemist shares my enthusiasm, that's for sure. Sulfoxides have a reputation for being potentially metabolically unstable - and they can go either way, being oxidized up to sulfones or reduced back to the parent sulfide. (I believe the former is more common, and is the clearance mechanism for DMSO, among other members of the tribe). But there are some out there in the market, chief among them esomeprazole (Nexium). Then there's armodafinil (Nuvigil), Cephalon's follow-up to Provigil, like Nexium another single-enantiomer-of-a-racemate drug.

But sulfoxides aren't just for extending your patent life and raking in the money. They can make a big difference in activity. The group has a strange character to it, because that oxygen atom is about as close to a naked O-minus as you're going to find. And the tetrahedral geometry of the sulfur means that this electronegative group is held is a very specific orientation relative to the other parts of your molecule. Like a nitrile, a sulfoxide is sui generis: there's nothing else that will do what it does.

And they're chiral. That can either be a bug or a feature, depending on your project and on your view of the world. If your target protein recognizes that chirality, it's probably really going to recognize it, because of that strong character. But that chirality is yet another reason that people avoid the sulfoxide, because that means chiral synthesis, which is a pain. All sorts of methods have shown up - chiral oxidation of sulfides, displacement with inversion at the sulfoxide sulfur - but there's no good general solution. The existence of the commercial drugs shows that this problem can be overcome, but there's no use denying that it's a problem.

All these problems can, at times, blend together. I was told some years ago about a Merck clinical compound that had a chiral sulfoxide. When they checked for metabolites, they found what looked like unchanged drug substance coming back out. A closer look, though showed that this was actually the enantiomer of the starting drug! What happened, as I heard it, was that the sulfoxide was first getting reduced, then oxidized back up to the opposite sulfoxide, when then passed out unchanged. Eating your starting material and collecting your own urine has yet to catch on as a sulfoxide inversion method, though. . .

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August 7, 2009

How A Real Drug Industry Project Meeting Goes

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Posted by Derek

For those who don't work in the industry, and wonder what goes on behind the closed doors of the research buildings, allow me to give you a fly-on-the-wall view of a typical meeting of a drug discovery project team. There are no huge revelations here, and I'm not going to try to reproduce 45 minutes worth of talk, but I think that my industrial readers will find this to be a pretty accurate depiction:

(Camera view of the inside of a small conference room, with six or eight people seated around a table)

CHEMIST A: OK, is this everyone that's going to show up? We have to stop this thing of starting all the meetings fifteen minutes late. (Slide goes up on screen from laptop). All right, here are the two scaffolds, and here's where we were last time with them. You guys should know that at the last Senior Review Meeting everyone kept asking when we were going to narrow down on just one of these, and I kept having to tell them that we're not ready to do it yet. But they're getting tired of hearing that.

CHEMIST B: Not as tired as we are of them asking the question. But I guess you probably didn't say that? OK, I'll do Scaffold 1; my lab's been working on that one the whole time. (New slide goes up). As usual, these things are potent out the wazoo, but we can't shake that Other Enzyme activity, and none of these compounds have the plasma stability that we want.

Last time we said that we were going to hang a bunch of stuff off the 4-position to try to fix that metabolic problem, but we only got a few of the things made. Every time you try to put anything useful out there, you get this side product, and most of the time you can't separate the stuff, you can just see it in the NMR and maybe on the LC/MS trace.

But we've made these four analogs - the potency isn't getting any better, but it isn't getting any worse, and we've put 'em in for PK. If they work, though, we're going to have to find another way to do this stuff.

CHEMIST C: Why don't you try to put in those groups via (obscure name reaction)?

CHEMIST B: Because (obscure name reaction) doesn't flippin' work on this system - we tried that, too, and all we get back is starting material. At least the route we've got gives us something. Sometimes. Sort of.

CHEMIST A: What are we going to do if those come back from PK with the same short half-life?

CHEMIST B: Well. . .work on something else, I guess, because if the problem is out here in the 4-position, you'd think that these changes would fix it. Unless we suddenly made some other part of the molecule more likely to be metabolized by messing with this end of it. But you can assume stuff like that all day, and it doesn't get you anywhere. Keep thinking like that, and you'll never make anything.

CHEMIST A: OK, we'll wait for the numbers. My group's been doing the second scaffold, so I'll take that one. (New slide goes up). These have always been the most selective compounds we've got against That Other Enzyme, and they have pretty good PK numbers, but we keep trying to get more potency. We made this series of amines, trying to pick up a hydrogen bond out there in the far binding pocket, but. . .well, most of them don't seem to work. They're really soluble, though. Every time we make something that's really soluble, it doesn't bind.

BIOLOGIST A: Yeah, those things were nice. Should have known.

CHEMIST A: The outlier is that third one, the piperazine. That looks like it might be picking up something, so we're going to make another series off of that one. What we really need is the piperazine with this funky group on it, and you're supposed to be able to buy it from insert name of fly-by-night supplier, but I don't want to depend on those guys.

CHEMIST D: So how long are we going to keep beating on these things? Have you guys ever made anything that's below, like, fifty or a hundred nanomolar?

CHEMIST A: Well, that thiophene compound was the best, and that's what got us excited, you know, but none of the other aryls seemed to work as well. So we've still got the three-position to try out there, and I think we've got some intermediates that we can use to get some analogs. I don't want to pull the plug until we've made those. And we need to make that piperazine series that's up there.

CHEMIST D: But last time you didn't want to pull the plug until you'd made these compounds. Does the plug ever actually come out, or not?

CHEMIST A: Well, not yet, partly because, hey, when you get down to it, this is probably the best series we have to work on. Nothing else gives us those plasma levels.

CHEMIST B: But there's only so much that blood levels can do for you if the potency isn't there. Would you put a hundred nanomolar compound into the animal model?

BIOLOGIST B: I hope not, because as you guys know, that model is a pain in the neck to run, and we'd rather not spend three or four weeks on it unless you've got something that you think is going to actually work.

CHEMIST C: What if you try to mimic that right-hand part of the first scaffold with some sort of cyclic amine goes to screen and waves hands like over here? Piperidine, pyrrolidine - would that hit the same part? It looks like there's space in the X-ray structure to get over there.

CHEMIST A: You want to try it?

CHEMIST C: Well. . .OK. I'll take a look, see if we can get something like that. You guys have any of the ester left, or did you burn it all up already?

(camera pulls back out of the conference room)

. . .and that's how it goes. In fact, that's almost exactly how it goes, most of the time. That's science as it's being done.

Comments (40) + TrackBacks (0) | Category: Life in the Drug Labs

July 20, 2009

Everything In Its Place

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Posted by Derek

Things are pretty quiet around the industry these days, so my blogging thoughts have been turning to Big General Problems. And here's one that I know that people are working on, but which I think we as chemists are going to have to understand much better: localization.

"Say what?" is the usual response to that, but hear me out. What I mean is the trick that living cells use for their feats of multistep synthesis. Enzymes aren't generally just floating around hoping to bump into things - well, some of them are, but a lot of them are tied to specific regions. They're either membrane-bound, or they're expressed in structures where they don't get a lot of chances to diffuse out into the mix. The interior of a cell, on the whole, is a pretty intensely structured place (as it would have to be).

And that allows specific reactions to take place away from other things that might interfere, which is something that we have a hard time doing in the lab. If you have a five-step synthesis, it's a pretty safe bet that you don't dump the reagents for all five steps into the pot at the same time and hope for the best. No, we generally have to fish out the product and take it on separately. It's often a real achievement (especially on larger scale) to be able to "telescope" two steps into one flask and skip any sort of product isolation between them. Doing it with more than one step is even more rare (and more useful when you can bring it off).

There's been a lot of work on one-pot cascade or domino reaction systems, and that's a step toward what we need. But most of these cases are reaction-driven: people find chemistries that can be run in this fashion, and then try to exploit them to make whatever can be made. Nothing wrong with that, but it would be nice to have product-driven approaches, where you'd look at a particular structure and figure out which multicomponent reaction scheme would work best for it. Generally speaking, we just don't have enough worked-out systems to be able to do that.

And that's where I think that some new technologies could help, specifically flow chemistry and/or microfluidics. Instead of figuring out reactions that can exist while all stirring around together in one pot, this approach takes it as a given that many transformations probably just can't be done that way. And if you can't have one big reactor with multiple things in it, then why not make multiple reactors, each with a different thing in it? Flow systems can, in theory, send compounds through a series of isolated reactions, moving the material physically through various zones and reagents. Not every reaction is perfect of course, but you can often use scavenger reagents along the way to strip out potential interfering impurities before the next step.

I like the idea, but there are a lot of things to be done to make it work. Probably the most advanced organic synthesis that's being done is this style is in Steve Ley's lab at Cambridge. I always enjoy reading their flow papers, which make clear that there's some significant optimization that needs to be done before you can throw the switch and stand back. Some other multistep flow work can be found here and here, and the same comment applies: there's a lot of preparation involved.

My hope is that these kinds of things will eventually move toward more of a plug-and-play system, where you put in the various cartridges and choose a protocol from the list of best-general-fits for your planned reactions. We're quite a ways from that, but I don't see why it wouldn't be possible.

Comments (21) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs

July 14, 2009

RUR

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Posted by Derek

What does it take for a new technology to catch on in the labs? There's an endless stream of candidates (I hope it's endless, anyway), from small gizmos that you can keep in your drawer to multi-hundred-thousand-dollar machines that need their own air handling systems. But all of them start out in the "is this thing any good?" zone, and not all of them emerge, no matter how much they might cost.

That's the first criterion: does the new equipment do anything useful? You'd think that this would have been worked out by, say, the team that developed the product in the first place, but hope does spring eternal. Companies do sometimes get some funny ideas about what their intended markets are clamoring for.

The second test is whether it does its thing in a way that doesn't mess up what you're already doing. "Useful but annoying" is an all-too-well populated category, and if the balance tips too far toward the latter, people will gradually find reasons to stop using the equipment. With some equipment, you start to feel as if you're paying twenty dollars for $20.03 in pennies, putting the whole process into the "not worth the trouble" bin.

Automation is often a factor here. Poorly engineering automation will drive people away like a skunk, of course. Lack of automation won't drive them away, but it won't give them an incentive to come back, either. But do it right, and you lower the perceived cost of using the equipment. Microwave reactors for chemical reactions are a good example of this. The first buckaroos who did these things used kitchen microwave ovens and homebrew reaction vessels. Then there was a generation of reaction carousels that fit into the oven compartment, but that fell into the "annoying" category. The more recent crops of dedicated machines, though, have caught on. They don't look like microwave ovens at all (for example), since the reaction chamber is much smaller (built, in fact, to fit the reaction vials). And they run from a software interface, allowing you to put your tube in the rack, set up your conditions, and walk away.

That phrase "and walk away" is the key idea behind good lab automation. You shouldn't have to stand in front of a machine to make sure that it's going to do what it's supposed to. You can walk away from NMRs, from LC/MS machines, from fraction collectors and many other devices. But if you can't, because the machine hasn't evolved to the point where automation is possible - or worse, if it has automation you can't trust - then the benefit of using the thing had better be substantial.

Lab-scale flow reactors are a good example of equipment that hasn't quite reached the walk-away stage yet (although I have hopes). I know that there are several machines out there that have some ability to do multiple unattended runs, but I'd be interested to know how many users actually manage to leave the things alone while they're doing them. I'm a fan of flow chemistry, but until the machines are more like the microwave reactors, their user base will be confined more to hairy, wild-eyed types like me. The companies in the business seem to realize, though, that my phenotype will not allow them to earn an honest living, and are taking steps.

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June 22, 2009

Funky Carbocycles

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Posted by Derek

Earlier this month I posted about rolofylline, which I noted has a rather unusual noradamantane attached to it. Now check out this ORL-1 compound from Banyu, complete with the not-so-widely-heard-of bicycloheptane-spirocyclopropane group.

This was not arrived at lightly, as you'd imagine. There's a table in the Supporting information for the paper, but I'll quote from the body of the main manuscript:

Various kinds of cycloalkanes, substituted or nonsubstituted cyclopropyl rings to medium sized rings (such as cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl), spiroalkane (such as spiro[2.5]octanemethyl, spiro[3.5]nonanemethyl, spiro[4.5]decanemethyl, spiro[2.4]heptanemethyl, spiro[3.4]octanemethyl, spiro[4.4]nonanemethyl), bicycloheptane (such as methylbicyclo[2.2.1]heptylmethyl, dimethylbicyclo[2.2.1]heptylmethyl, spirocyclopropanebicycloheptanemethyl), and branched alkanes (such as 3,3-dimethylbutane, 3,3-dithylbutane, 1-methylcyclobutaneethyl, 1-methylcyclopentaneethyl, 1-methylcyclohexaneethyl) were tested.

No, that couldn't have been a lot of fun. Anyone else out there found themselves having to optimize grease recently?

Comments (5) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs

June 15, 2009

Ugliness Defined

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Posted by Derek

Yesterday's post on so-called "ugly" molecules seems to have touched a few nerves. Perhaps I should explain my terms, since ugliness is surely in the eye of the beholder. I'm not talking about particular functional groups as much as I'm talking about the whole package.

First off, a molecule that does what it's supposed to do in vivo is (by my definition) not truly ugly. The whole point of our job as medicinal chemists is to make active compounds - preferably with only the activity that we want - and if that's been accomplished there can be no arguing. Of course, "accomplished" has different meanings at different stages of development. Very roughly, the mileposts (for those of us in discovery research) are:

1. Hitting the target in vitro.
2. Showing selectivity in vitro.
3. Showing blood levels in vivo.
4. Showing activity in vivo.
5. No tox liabilities in vivo.

And these all have their gradations. My point is that if you've made it through these, at least to a reasonable extent, your molecule has already distinguished itself from the herd. The problem is that a lot of structures will fly through the first couple of levels (the in vitro ones), but have properties that will make it much harder for them to get the rest of the way. High molecular weight, notable lack of polarity (high logP), and notable lack of solubility are three of the most important warning signs, and those are what (to me) make an ugly molecule, not some particular functional group.

My belief is that, other things being equal, you should guard against making things that have trouble in these areas. You may well find yourself being forced (by the trends of your project) into one or more of them; that happens all the time, unfortunately. But you shouldn't go there if you don't have to. It's also true that there are molecules that have made it all the way through, that are out there on the market and still have these liabilities. But that shouldn't be taken as a sign that you should go the same route.

Ars longa, vita brevis. There's only so much time and so much money for a given project, and your time is best spent working in the space that has the best chance of delivering a drug. A 650 molecular weight compound with five trifluoromethyl groups is not inhabiting that space. It's not impossible that such a compound will make it, but I think we can all agree that its chances are lower compared to something smaller and less greasy. If the only thing you can get to work is a whopper like that, well, good luck to all concerned. But we have to depend on luck too much already in this business, and there's no reason to bring in more.

Comments (13) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs | Pharmacokinetics

Don't Make Them in the First Place?

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Posted by Derek

I've been involved in another outbreak of the perennial debate about what kinds of compounds medicinal chemists should be making. I can summarize the way this usually goes:

Chemist A: "Look at all these ugly molecules! Why can't we institute some sort of "No-Suzuki-Coupling" rule for two days out of every week or something? Failing that, why doesn't everyone at least try to make things that look better from the start?"

Chemist B: "Nice thought - but the most potent molecules tend to be on the uglier end of the spectrum. And once you've made a single-digit nanomolar compound for the first time in a new project, it's impossible to walk away from it. It's almost like you get to choose: good physical properties, or good activity and selectivity."

Chemist A: "Don't look in these places if you don't want to find what's there. I'm tired of people making big insoluble monster compounds "just for SAR purposes". Because then some of them hit, and you're stuck with 'em."

Chemist B: "But I can't go give a project update and say that we found the most potent compound ever, but we're not going to follow up on it. And then spend the rest of the time telling everyone that we made a whole bunch of compounds with great properties, but hey, they have no activity. That's not going to do me (or anyone else) any good, right?"

Chemist A: "That's why you don't make the uglies in the first place, so you don't get put in that bind. Of course, what everyone says to do is to take that potent ugly compound and make it better, now that you've found it. Problem is, most of the time the things you do to make it "better" start to kill the activity. We'd be better off with fewer hot compounds, as long as the ones we had were decent."

And so it goes. This same debate has gone on in my other workplaces, too, and I believe that it's a general one across the industrial labs. Who's winning the argument at your shop?

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June 10, 2009

Random Questions, Answered Randomly

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Posted by Derek

I had some requests to answer my own "Random Questions" from the other day, so here goes:

1. Does it bother you, or by contrast make you a bit proud, when you tell someone that you're a chemist and (as happens in about seven out of ten cases) they say "Oh, that was my hardest/least favorite/most boring subject when I was in school"?

Well, whether it bothers me or not, this happens all the time. Like pretty much every chemist in the world, I get to hear all about how people couldn't stand my subject in school. I take the point that mathematicians have it even worse, but it's not like we miss many of them with chemistry, either.

When people ask me what I do, I tell them "drug discovery", and I mention the diseases that I'm working on. That never fails to get some interest, and only then I spring on my listener the (often unexpected) info that this involves chemistry. Coming at it from that angle almost always leads to a good conversation, while coming at it from the "I'm a chemist" angle often leads to "Hey, look at the time!" effects. It's worth doing it in the right order, though - I like the effect when of showing that this boring/hard/useless subject actually leads to what most people find is a really interesting job.


2. How many thousands (10s, 100s of thousands) of dollars of unused equipment is sitting in dusty, unused storerooms at your company, because someone ordered it years ago and either (1) never got it to work, (2) was the only person ever to get it to work, or (3) found that it worked, but what it did wasn't worth doing that way?

Disused equipment? What is this disused equipment you speak of? Never have I seen such a thing. Why, those elaborate combichem machines in the sub-basement, they're just down there because they're so valuable. That rotating split-and-mix thingamabob and the multichannel parallel doohickey, we guard those closely.

Hah! Actually, I remember a couple of labs where this stuff wasn't in the basement at all. No, it was out there in the hoods, taking up space and slowly gathering dust, a standing reproach to everyone who walked past it. It would have been better off out of sight, but no one quite had the heart. And besides, it would sometimes get turned on for visiting groups - there was that.

3. Have you ever set up a reaction and thought "Boy, I sure hope that this doesn't work"?

I suppose that this is somewhat shameful, but yes, I have set up reactions hoping that they would fail. Usually it's been when I've had to use a particularly distasteful reagent (sodium ethanethiolate, for example), and I don't want to end up using it on a larger scale. I remember a fellow grad student presenting his work while we were trying to get our PhDs, and he detailed a deoxygenation step which only worked when his intermediate was made using a hefty excess of thiophosgene. "As fate would have it", said his long-suffering labmate from the back of the room.

And I've had less honorable instances, dating back to grad school or early in my industry career, when I was more or less forced to run a reaction a particular way even though I felt there was no chance for it to work. So yeah, in those cases I did look forward to saying "Yes, I tried your idea. And no, it didn't work any better than mine."

4. For the drug discovery people out there, what per cent of compounds you've made over the years would you guess dissolve in plain water to any real extent? Is that figure going up, or down?

The figure is hard to estimate, but it sure isn't high. Things that dissolve in straight water are hard to work with, y'know - they tend not to extract so well into ethyl acetate or dichloromethane, and they don't run so great on silica when you try to clean them up. That's worth another blog post in itself - the way that our standard chemistry techniques tend to push us away from a lot of polar molecules that might be just what we need for med-chem.

5. What, off the top of your head, would you say in retrospect is the most time-wasting chemistry you've ever ended up doing?

Tough competition. I'm tempted to say vacuum pyrolysis of corn starch to make levoglucosan, but I needed that for my dissertation, so it can't be called useless.

The real winner, in retrospect, has to be a series of reactions I did in my first couple of months in my grad school group, when I was still taking classes and working in the lab part time. I was presented with a route to a tetrahydropyran compound that we needed, a four-or-five stepper that involved an aluminum alkyne opening an epoxide, a Lindlar hydrogenation, a ring closure. . .I can still draw the damn thing on the board, now that I think about it, and it's been twenty-five years ago this spring. Being a first-year grad student, I hopped to it - and hopped right into the mud, since the route bogged down (and how) at the ring closure stage). I kept at it for a while, and then one evening I decided to look up my target compound in Chemical Abstracts.

That wasn't so easy in those stone ax and bearskin days - command-line access to CAS via a rockin' 1200 baud modem and a terminal was still a few months away. I paged through the five-year indices, and found. . .my compound. In a Tetrahedron paper. Two steps, from stuff you could buy from Aldrich, and you form the ring in the first step through a Prins reaction. I was shocked. Surely this couldn't be a known compound. Surely someone must have looked the structure up before coming up with that route I'd been given.

Surely not. And thus did my lab education begin. So you know, when I think about it, even though those first couple of months were a waste of chemicals and effort, perhaps they weren't as much a waste of time as I thought. . .

Comments (19) + TrackBacks (0) | Category: Graduate School | Life in the Drug Labs

June 9, 2009

Instant Med-Chem Wisdom

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Posted by Derek

I didn't note it here when it came out last year, but I wanted to recommend this paper to all the readers who are medicinal chemists. It's an effort by M. Paul Gleeson of GSK to generalize some rules from huge piles of oral dosing data in the company's files. It's all boiled down to a set of charts, for different classes of compounds (neutral, acidic, basic, and zwitterionic), and you can see the effects of changing molecular weight and/or polarity on things like bioavailibility, potential for hERG problems, clearance, etc.

There are no major surprises in the charts. But it's very useful to have all these "rules of thumb" in one spot, and to have them backed up by plenty of data. For experienced medicinal chemists, it's a distillation of everything that we should have been learning. And for those starting out, it's a way to get a fast understanding of what matters when you're making new structures. Check it out!

Update: for a much more sceptical take, see here.

Comments (4) + TrackBacks (0) | Category: Life in the Drug Labs | Pharmacokinetics

May 29, 2009

Ever Have One of Those Days?

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Posted by Derek

I've been evaluating an interesting and useful piece of equipment the last few days, and getting a lot of things done with it. At about 8:20 this morning, though, I marched into the lab and proceeded to clog, mis-plumb, and generally absurdify the thing, and I've spent the rest of the day trying to get back to the way things were at 8:15. You know, before I laid my magic hands on the apparatus and gave it the healing touch. Honestly, I couldn't have done a more complete job if I'd been wearing a rainbow wig and honking a horn.

At the moment, all seems to be working, but I've labored under that illusion several times today. If this doesn't do the trick, I'm going to bring in a troupe of Pomeranians and train them to jump over the thing. Sheesh.

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Wait For It. . .Wait For It. . .

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Posted by Derek

Here's something that I'll bet every bench chemist has experienced: thinking that you've quenched some nasty reagent (it has to be gone by now!) only to find that it's very much still with you. These guests that won't leave can be smelly, corrosive, or downright dangerous when they finally yawn, stretch, and decide that it's time to move off the couch.

Alkylaluminum species, in my experience, take their time for longer than you'd think possible, and then depart in a tearing hurry. I used to use several diethylaluminum-X things (cyanide, alkynes, and so on), and was taken by surprise early on by their lackadaisical response to methanol or water at the end of the reaction. "Surely there's some excess aluminum junk in there", I remember thinking the first time this happened, "but there's nothing happening. Maybe I should just squirt in some more." That last phrase has been the prelude to many exciting chemistry moments, and so it was here. Not long after I acted on that impulse, the reagent caught on the fact that it had lots of methanol surrounding it ("Hey, I react with this stuff, don't I?"), and another geyser was born.

Perhaps the king of the "I thought it was hydrolyzed" bunch is phosphorus oxychloride. That stuff takes forever to get around to reacting with water, although on the face of it, you'd imagine it fizzing and sputtering as soon as it got within range. But no, many chemists who've used this reagent have returned to their fume hoods to find the contents of their sep funnels or waste jars gradually coming back from the dead. Milkshake can tell you all about it at Org Prep Daily, and so can many others: never take this one for granted.

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May 27, 2009

Surfin' On The Surface

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Posted by Derek

There are a lot of ways to think about the chemical reagents that we have stirring around in our flasks. But one of the basic ones, and one of the most useful, divides them into classes according to whether they’re in solution or not.

When things are in solution, they may act funny, but at least everything’s starting out on the same footing. If all the components are dissolved (and if everything’s stirring the way it should), then they all have the chance to find each other and do their respective things. But if some reagent is still a solid in there (powder, chips, what have you), that takes you into the nonintuitive world of surface chemistry.

This actually happens quite a bit. Plenty of standard organic reactions involve insoluble things where the chemistry takes place on the surface. There’s formation of a Grignard reagent from magnesium turnings, deprotonation with powdered sodium hydride, hydrogenation over palladium-on-charcoal – these are all classics. And I'm not even mentioning the surface-driven industrial scale catalyst systems today, which is unfair of me, since the economies of the entire industrialized world depend on them. But in all cases, the real details at the molecular level of these reactions are not easy to work out.

People are still arguing, for example, over just how catalytic hydrogenation works on the metal surface, although the general details of the mechanism are known. That one’s complicated by not just being the plain metal, but a weirdo solution of hydrogen in the metal lattice. There’s no dispute, though, that the reaction is taking place on the surface of the metal, and that the higher the surface area the better off you are.

That’s one big variable right there: surface area. Finely divided substances are very different players in these systems, and many chemists find (early in their lab careers) that they’ve unwittingly bought front-row seats for a demonstration of just how different they can be. Finely divided powders have a lot of surface area in them, and if that’s a rate-limiting factor, you can find yourself with something that’s easily a hundred times more reactive just by picking up a different bottle of what appears (at first glance) to be the same substance. I once saw someone substitute lithium powder for lithium sand in a prep without thinking about this issue, and not so much later, I got to see the same guy clean the inside of his fume hood out with a scrub brush.

But there’s more than just surface area affecting some of these reactions. Grignard formation, for example, seems to take place (at least initially) in fresh breaks or cracks on the magnesium surface. That exposes metal that hasn’t had a chance to become coated with anything (like a layer of magnesium hydroxide), and (zooming in) it also may reveal individual reactive magnesium atoms, left out on the edge and insufficiently surrounded by their teammates. Once these react and fly off into solution, the ones around them become exposed, and so on, and the oxidized layers become undermined and flake off. The standard Grignard-initiation tricks are all designed to speed this process along. A drop of iodine will react quickly with any magnesium points or edges, exposing still more fresh rough surface, as will reaching down under the solution and breaking the turnings with a spatula (or, alternately, grinding them with a heavy stir bar).

These days, what’s really complicating things is the ability to generate (and characterize) nano-sized particles. At some point, these things can stop behaving like tiny bits of the bulk substance (which can be enough of a difference in itself, as mentioned above), and start acting like completely new beasts. And the really nano-sized stuff has a better chance of actually being in solution – but that brings on various headache-inducing thoughts about what “being in solution” means on this scale. If you have clumps of (say) palladium a few dozen atoms wide, which manage to be solvated enough to float around, is that a heterogeneous reaction or a homogeneous one? At that size, is that a "surface", or not (and is the reaction really taking place on it?) What if the nanoparticles are immobilized on a solid support - do they stay and react there, or is the reaction driven by the few that escape? (That effect has been noted in the Heck reaction, among others).

We need to understand these things better than we do - there are surely a lot of very useful things that could be done if we had better control over catalysis and surface chemistry. It's going to keep a lot of people occupied for a very long time.

Comments (5) + TrackBacks (0) | Category: Inorganic Chemistry | Life in the Drug Labs

April 3, 2009

The Mechanical Chemist?

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Posted by Derek

We use a lot of automated equipment in the drug discovery business. There’s an awful lot of grunt work involved, and in many cases a robot arm is better suited to the task – transferring solutions, especially repetitive transfers of large numbers of samples, is the classic example. High-throughput screening would just not be possible if you had to do it all by hand; my fingers hurt just imagining all the pipetting that would involve.

But I wouldn’t say that the process of medicinal chemistry is at all automated. That’s very much human-driven, and a lot of the compounds on most med-chem projects are made by hand, one at a time. Sure, there are parallel synthesis techniques, plates and resins and multichannel liquid handlers that will let you set up a whole array of reactions at once. But you do that, typically, only after you’ve found a hot compound, and that’s often done the old-fashioned way. (And, of course, there are a lot of reactions that just don’t lend themselves to efficient parallel synthesis).

But I remember the first time I saw an automated synthetic apparatus, back at an ACS meeting in the mid-1980s. There was a video in the presentation (a real rarity back then), and it showed this Zymark arm being run to set up an array of reactions, assay each of them after an overnight run, and report on the one that performed the best. “Holy cow”, I thought, “someone’s invented the mechanical grad student”. Being a grad student at the time, I wasn’t so sure what I thought about that.

This all comes to mind after reading a report over at Wired about a robotic system that has been claimed to have made a discovery without much human input at all. “Adam”, built at Aberystwyth University in Wales, seems to have been set up to look for similarities in yeast genes whose function hadn’t yet been assigned, and then (using a database of possible techniques) set up experiments to test the hypotheses thus generated. The system was also equipped to be able to follow up on its results, and eventually uncovered a new three-gene pathway, which findings were confirmed by hand.

And Ross King, leading the project at Aberystwyth, is apparently extending the idea to drug discovery. Using a system that (inevitably) will be called “Eve”, he plans to:

. . .autonomously design and screen drugs against malaria and schistosomiasis.

"Most drug discovery is already automated," says King, "but there's no intelligence — just brute force." King says Eve will use artificial intelligence to select which compounds to run, rather than just following a list.

Well, I won't take the intelligence comment personally; I know what the guy is trying to say. I’ll be very interested to see how this is going to be implemented, and how it will work out. (I'll get an e-mail off to Prof. King asking for some details). My first thought was that Eve will be slightly ahead of a couple of the less competent people I’ve seen over the course of my career. And if I can say that with a straight face (and now that I think about it, I believe that I can), then there may well be a place for this sort of thing. I’ve long held that jobs which can be done by machines really should be done by machines.

But how is this going to work? The first way I can see running a computational algorithm to design drugs would be some sort of QSAR, and we were just talking about that here the other day – most unfavorably. I can imagine, though, coding in a lot of received wisdom of drug discovery into an expert system – Topliss tree for aryl substituents, switch thiophene for phenyl, move nitrogens around the rings, add a para-fluoro, check both enantiomers, put in a morpholine for solubility, mess with the basicity of your amine nitrogens, no napthyls if you can help it, watch your logD - my med-chem readers will know just the sorts of things I mean.

Now, automating that, along with feedback from the primary and secondary assays, solubility, PK, metabolite ID and so on. . .mix it in with literature-searching capability for similar compounds, some sort of reaction feasibility scoring function, ability to order reagents from the stockroom, analyze the LC/MS and NMR traces versus predictions, weight the next round of analogs according to what the major unmet project goals are. . .well, we're getting to the mechanical medicinal chemist, sure enough. Now, not all of these things are doable right now. In fact. some of them are rather a long way off. But some of them could be done now, and the others, well, they're certainly not impossible.

I'm not planning on being replace any time soon. But the folks cranking out the parallel libraries, the methyl-ethyl-butyl-futile stuff, they might need to look over their shoulders a bit sooner. That's outsourcing if you like - from the US to China and India, and from there to the robots. . .

Comments (28) + TrackBacks (0) | Category: Drug Development | Drug Industry History | General Scientific News | Life in the Drug Labs

March 16, 2009

The Equipment Graveyard

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Posted by Derek

The comment that showed up recently about unearthing an "original Cable and Wireless dephilostagenator" in a lab reminded me of the huge lab moving job I was in on some years ago. We were packing up the entire company's research site and moving it to another spot in New Jersey (Bloomfield to Kenilworth), and this was supposedly the biggest moving job in the US that year. I do know that the Garden State Parkway was used for the parade of 18-wheel trucks at like 3 AM several times, by special arrangement with the state. (You normally can't take trucks on the thing; that's for the Jersey Turnpike, which doesn't go anywhere real close to Kenilworth).

At any rate, as we started clearing things out, there were several layers of equipment. First were the things that we'd either ordered or had used fairly recently - fine. Behind that, or in the less traveled cabinets, were things that we recognized, but (in many cases) didn't even know that we had. Finally, we began to unearth things that we hardly even knew the names of. I remember finding a dropping mercury electrode apparatus down our way; it's still the only one I've ever seen. It had that solid, black-enameled 1952 look to it, with the name of the company written in silver script lettering on the side, "Dyno-Electromat" or something of the sort. It reminded me somehow of those solid old electromechanical adding machines.

That one was only going to find a home in a museum or in a hazardous waste collection dumpster, and you can guess which alternative won out. But when a site shuts down or moves, there are generally large piles of perfectly usable equipment left sitting around, and it finds its way out into the market one way or another. Courtesy of another commentator, here are some folks from Yale digging through stuff that I might have leaned up against at some point. . .

Comments (13) + TrackBacks (0) | Category: Drug Industry History | Life in the Drug Labs

March 5, 2009

Your Temperamental Diva Reactions

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Posted by Derek

Since I was talking the other day about getting published procedures to work (or not!), I thought I should mention that most chemists have, at one time or another, had reactions of their own that not even they can get to work right every time. Most chemical reactions are reasonably robust, within limits (see here for a proposal to establish some!) But every so often, you come across one that has a narrow tolerance, sometimes for things that you can’t even put your finger on.

I’ve seen this happen particularly in low-temperature carbanion reactions. Some of these anions don’t particularly want to form in the first place, and they can be quite sensitive to concentration, the presence of different amounts of salts and counterions, variations in temperature, and so on. The rates and efficiencies of cooling and stirring can affect some of these factors, as can the age and handling of the reagents, and the rates at which they’re added into the reaction mixture. If you’ve got a system that just barely works, a lot of things can push it over the edge.

My personal experience with this first came in grad school, when I had a cyanocuprate reagent opening an epoxide. As I mentioned on the blog a few years ago, I tried that system out, after several other reagents had given not-so-great yields, and it worked really well. So I tried it again – same results! I scaled it up (at the time, “scaled it up” meant running it on about a gram), and it worked again. Problem solved! Little did I realize that the reaction would never work again. It failed the next time, and the next, and the next. I tried everything I could think of. I made everything cleaner, I made everything fresh: no product. I made everything sloppy, with no particular care, the way I’d done it in the beginning. No product. Nothing ever worked. I never did sort out what was going wrong; it was easier, in the end, to find another reaction.

Scaling up such a reaction is especially difficult – even relatively laid-back reactions have to be looked at closely when moved up to larger scales, much less a jumpy, skittish one that gets the vapours and passes out at the first sign of trouble. It’s the job of the process chemists to avoid such narrow-window chemistry whenever possible. The idea process reaction is one that provides the same yield, with the same purity profile, under a wide range of conditions: foolproof, in other words. Naturally, nothing is really foolproof (fools are too tricky), but you do what you can.

Comments (30) + TrackBacks (0) | Category: Life in the Drug Labs

March 3, 2009

How Good (or Bad?) Are Patent Procedures, Anyway?

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Posted by Derek

All the comments on the Lundbeck / Dr. Reddy's imbroglio got me to thinking: how good are patent procedures, anyway? I said in that earlier post that I didn't think that they were that much different from procedures in the open literature, but I'd like to throw the issue open for comment.

You might think that patent procedures would be better, actually. There are potential legal implications to bad patent writeups that don't apply to lousy procedures published in a journal. You're supposed to teach how to make the new chemical matter (or how to do the new process) that you're claiming, and if your patent's details really are insufficient to fulfill that requirement, you have a problem. Patents have been invalidated over such disputes. If you thought your invention worth the trouble of patenting, you'd presumably be motivated to provide sufficient detail to make sure the patent is granted, and that it holds up if challenged.

That said, not all that many patents get seriously challenged over such issues. It takes lot of time and a lot of money, and the number of cases where it's worth the trouble are limited. And a patent has to be pretty lousy (or pretty deceptive) to truly fail to teach what its procedures outline. I guess what I'm asking about is the wide middle ground - the various procedures that aren't necessarily make-or-break for the validity of the patent, but are in there as parts of synthetic schemes. What's your success rate following these? And is it better or worse than your success rate trying to reproduce things out of, say, The Journal of Organic Chemistry?

Comments (21) + TrackBacks (0) | Category: Life in the Drug Labs | Patents and IP

March 2, 2009

Hot Chemistry, Low Tech to High

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Posted by Derek

Time for some lab talk. There are usually a number of different ways to attack a given problem in organic chemistry. You go with what you know, or what looks most likely to work, or what you actually have the equipment (or funds) to realize. This range of choices goes all the way down to what you’d think would be pretty trivial questions, such as: how do I heat up my reaction?

The standard way to do this is to take the usual flask you’d run the thing in at room temperature and dunk it into something hot. That can be an oil bath with a heating coil in it (good temperature control, but messy), a solid heating mantle of ceramic or metal (clean, but doesn’t change temperature so readily), a woven glass heating mantle, a sand bath on a hot plate, what have you.

Then you can go a bit higher-tech, and heat up your reaction with microwaves. I talked about this here a few years ago (and I note that somehow that stretch of blog time has never been archived on this site; I'll have to work that in some time). The early days of the technology featured (first) kitchen models hauled directly into the lab, then carousel devices built to go inside their cooking spaces. But over the years things have settled down to custom-built chemistry microwave setups, walk-up instruments that let you drop a sample tube in, set the temperature and time that you want, and walk away to pick things up later. Microwave heating has become a preferred way to run a lot of palladium-catalyzed reactions.

Does the microwave do anything special other than heat things up, though? That’s been an arguing point for several years. Various “microwave effects” have been proposed, with mechanisms ranging from the unlikely to the pretty believable. In that last category is the thought that when you’re using powdered metal catalysts, that since these absorb microwaves strongly they give some sort of local micro-heating effect that drives the reactions forward.

Could be – but apparently isn’t. A recent paper from Oliver Kappe's lab in Graz, Austria looks at Heck reactions done that way. Kappe is a recognized pioneer and expert in microwave synthesis (see his latest book, linked below), and if you're interested in the field he's well worth reading. In this case, careful experimentation established that the microwave reactions work well because of their heating profile: they get up to temperature very quickly, which seems to be beneficial. But they found no evidence of a specific microwave effect when they ran the reactions under similar heat gradients but with different energy sources.

They also tried this reaction via yet another heating technique, flow chemistry, which I last spoke about here. That turned out to be pretty interesting, too. They were pumping their two starting materials hot over a cartridge of supported palladium-on-carbon catalyst, but found a couple of odd effects. For one thing, the first flow runs tended to give a lot of side reactions, which was surprising considering how clean the conventional runs were. Looking over the system carefully, the team found that the two reactants were separating from each other as they went down the catalyst tube. They couldn’t couple as efficiently because they were pulling away from each other – the alkene coupling partner came out first, while the aryl halide dragged behind, presumably slowed down by interactions with the powdered carbon support.

The other unexpected effect was that even after partially fixing that problem, after a dozen runs or so the reactions weren't working so well. Then the earlier fractions collected and left to sit turned out to be depositing shiny mirrors of palladium metal on the insides of the glass tubes, and all became clear. The Heck reaction was leaching the palladium metal off the solid support! This had been a mechanistic proposal before, but the flow apparatus provides some real evidence to back it up. When you do this in batch mode, via microwave or whatever, the palladium species get a chance to re-absorb onto the carbon as the reaction cools down, and you're none the wiser, but the flow system just washes 'em on through.

What finally did the trick was to add very small amount of the palladium to the starting system, pump that through a hot tube reactor, and use another scavenger column to clean out the metal. You can get away with that in a Heck reaction, since they can run using ridiculously low catalyst loads. I have to say, I hadn't thought so much about this possibility; that's somewhere in between my Type I and Type II flow reactions in my own scheme.

I mentioned that Kappe has a new book, titled Practical Microwave Synthesis for Organic Chemists: Strategies, Instruments, and Protocols. I haven't seen it personally, but if you're interested in microwave work, it looks worthwhile.

Comments (22) + TrackBacks (0) | Category: Life in the Drug Labs

February 25, 2009

Inspiration Is Where You Find It

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Posted by Derek

Have you ever worked for a company with its own corporate anthem? It would probably have to be a fairly large outfit; I don’t think a smaller shop would be able to afford such a thing, even if they somehow decided that they needed one. (Here’s some advice: if your small or medium-sized company rolls out its own song, strongly consider hitting the exits if you can. That’s the sort of mindless expenditure that only a behemoth can get away with).

I’ve encountered one of these, in one of my former positions. We were having some big site-wide meeting, and one of the honchos introduced the video clip. There are whole agencies who do these things – they write the songs, hire people to sing them, produce the video, and so on, and the product of one of these bizarre production companies was what we got to see.

And what a sight it was. A perfectly calibrated multiethnic assembly began to belt out our new company song with verve and enthusiasm. There were plenty of solo shots and different camera angles. It was all about dreams and teams, visions and decisions, exceeding and succeeding. The singers grinned, looked confidently up into the future, and joined hands as they got to the chorus. I watched all this with mounting dismay and horror, wanting to clap my hands over my ears, both to shut out the music and to keep my soul from trying to flee my body via my Eustachian tubes.

I don’t think that this was the reaction the song was meant to elicit, but I didn’t seem to be alone. As I left the auditorium with some of my fellow chemists, we speculated on whose idea this anthem might have been, how much it had cost, on whether the firm that produced it was from North Korea or not, and wondered how the experience of listening to it might have affected our lifespan and fertility. One of my group said that there surely must have been better songs available, and suggested that he personally would have been much more motivated by AC/DC’s “Highway to Hell”.

I had to agree; that would have done it for me, too. I started imagining a re-take of the video: the same blue backdrop, one of our executives striding out, giving the camera a manly smile, and saying: “Yes, here at _____ Pharmaceuticals, we truly are on a Highway To Hell. Won’t you join us?” The same happy singers would come streaming out from both sides, swinging into the chorus. . .oh, that would have been much better. And overall, rather more accurate than all that “driven by our vision” stuff, too, now that I think about it.

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February 24, 2009

Structure-Activity: Lather, Rinse, and Repeat

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Posted by Derek

Medicinal chemists spend a lot of their time exploring and trying to make sense of structure-activity relationships (SARs). We vary our molecules in all kinds of ways, have the biologists run them through the assays, and then sit down to make sense of the results.

And then, like as not, we get up again after a few minutes, shaking our heads. Has anyone out there ever worked on a project where the entire SAR made sense? I’ve always considered it a triumph if even a reasonable majority of the compounds fit into an interpretable pattern. SAR development is a perfect example of things not quite working out the way that they do in textbooks.

The most common surprise when you get your results back, if that phrase “common surprise” makes any sense, is to find that you’ve pushed some trend a bit too far. Methyl was pretty good, ethyl was better, but anything larger drops dead. I don’t count that sort of thing – those are boundary conditions, for the most part, and one of the things you do in a med-chem program is establish the limits under which you can work. But there are still a number of cases where what you thought was a wall turns out to have a secret passage or two hidden in it. You can’t put any para-substituents on that ring, sure. . .unless you have a basic amine over on the other end of the molecule, and then you suddenly can.

I’d say that a lot of these get missed, because after a project’s been running a while, various SAR dogmas get propagated. There are features of the structure space that “everybody knows”, and that few people want to spend their time violating. But it’s worth devoting a small (but real) amount of effort to going back and checking some of these after the lead molecule has evolved a bit, since you can get surprised.

Some projects I’ve worked on have so many conditional clauses of this sort built into their SAR that you wonder whether there are any boundaries at all. This works, unless you have this, but if you have that over there it can be OK, although there is that other compound which didn’t. . .making sense of this stuff can just be impossible. The opposite situation, the fabled Perfectly Additive SAR, is something I’ve never encountered in person, although I’ve heard tales after the fact. That’s the closest we come to the textbooks, where you can mix and match groups and substituents any way you like, predicting as you go from the previous trends just how they’ll come out. I have to think that any time you can do this, that it has to be taking place in a fairly narrow structure space – surely we can always break any trend like this with a little imagination.

Another well-known bit of craziness is the Only Thing That Works There. You’ll have whole series of compounds that have to have a a methyl group at some position, or they’re all dead. Nothing smaller, nothing larger, nothing with a different electronic flavor: it’s methyl or death. (Or fluoro, or a thiazole, or what have you – I’ve probably seen this with methyl more than with other groups, but it can happen all over the place). A sharp SAR is certainly nothing to fear; it’s probably telling you that you really are making good close contacts with the protein target somewhere. But it can be unnerving, and sometimes there’s not a lot of room left on the ledge when you have more than one constraint like this.

Why does all this go on? Multiple binding modes, you have to think. Proteins are flexible beasts, and they've got lots of ways to react to ligands. And it's important never to forget that we can't predict their responses, at least not yet and not very well. And of course, in all this discussion, we've just been considering one target protein. When you think about the other things your molecule might be hitting in cells or in a whole animal, and that the SAR relationships for those off-target things are just as fluid and complicated as for your target, well. . .you can see why medicinal chemistry is not going away anytime soon. Or shouldn't, anyway.

Comments (40) + TrackBacks (0) | Category: Drug Assays | In Silico | Life in the Drug Labs

February 23, 2009

The Limits of Free Scientist Chow?

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Posted by Derek

This piece over at Science magazine's "The Gonzo Scientist", brought back some memories. John Bohannon, in the midst of an investigation of truffles, tried an experiment on some party guests: rank a series of five patés according to taste. There were three authentic ones, two fake ones (liverwurst and whipped Spam), and. . .dog food.

He did tell people that dog food was one of the choices. Interestingly, although it ranked last in the taste test, people were no better than chance at identifying it as such. Perhaps they expected it to taste better than it did? But the reason this made me smile was thinking about the usual behavior of scientists and engineers down by the coffee machine. You know what I'm talking about - put anything down there, and people will eat it. It's a standard way of clearing out dessert-like things from home that you don't want around the place; take it to work and it'll disappear.

Well, I saw that put to the test once at a former company of mine. One of the freer spirits down the hall put out a bowl of chocolate-flavored hamster treats and sat back to watch the results. Unlike the dog-food experiment, he did not inform his subjects - but in his defense, he told me that he'd tried one himself, and that although they were somewhat gritty, he'd had worse.

Results? The hamster treats disappeared, of course. I'm just glad he didn't press on with this line of research - and as for me, I made sure never to eat anything left by the coffee machine at that end of the hallway. . .

Comments (18) + TrackBacks (0) | Category: Life in the Drug Labs

February 18, 2009

Supplies of Suppliers

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Posted by Derek

When I joined the Wonder Drug Factory in late 1997, you still had to buy chemicals by writing down the name and catalog number on a form (and press hard; it was one of those multicolor triplicates). I thought that was pretty primitive then, since at my previous company we’d already gone to electronic ordering (clunky, especially in retrospect, but a lot better than anything involving blue, white, and yellow forms). But to find out where to buy the chemicals you wanted – now that was a challenge.

ChemSources was the usual solution. That was (is, I guess) a large volume containing compounds indexed by name and formula, with the suppliers listed for each. There was a red one for domestic suppliers, and a similar-sized blue book for international ones. And although it came out regularly, it was perforce always out of date. How could it not be? The suppliers changed their catalogs constantly. For that matter, the list of suppliers changed constantly. It wasn’t unusual to look up a compound, find its only commercial source was some little outfit you’d never heard of, and find on tracking them down that they’d gone out of business the previous year.

No one does it that way any more, of course, and good riddance. ChemSources appears to still be in business, and you can even get their bound volumes for your shelves. But why would you do such a thing? Even they offer online searching - well, for a subscription fee. But why would you do that? There are free sources for basically the same information. If you just want data on some compound and where it might turn up, ChemSpider is a good place to look. And if you want supplier information, eMolecules looks like the place to go. Their model is "basic search for free", and if you want pricing, export of data, or integration with your in-house databases, you can sign up for their "plus" service and pay fees.

And that's pretty reasonable, because I get a lot of use out of the free service, myself. I can see prices in my company's in-house ordering software. But I'm not one of the most price-conscious chemical consumers out there, since I'm mostly ordering small quantities of a lot of different things. As long as someone isn't egregiously ripping me off, I'm fine (and that's what our Purchasing department is there to check on, anyway, and don't they just love me over there). One of the things that I enjoy about eMolecules, though, is that they help me figure out what a lot of these little bar-coded vials are. There are a lot of suppliers that will send you ten milligrams of stuff with no real label on the vial, just an eight-digit number or the like, which isn't much help. If you don't label them right then - which often involves loading a CD that they shipped with the vials - you can be puzzled in a few weeks or months when you need the stuff again.

But the eMolecules folks have all these people in their files - Life, ChemDiv, Asinex, Specs, ChemBridge, and the other members of the catalog-number-only club. The search isn't perfect (for one thing, they're missing a fair bit of the corresponding CAS numbers to search by), but it's a lot better than anything else I've come across for free.

Comments (11) + TrackBacks (0) | Category: Life in the Drug Labs

February 6, 2009

Prep TLC: The Good Old Days Live On

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Posted by Derek

I did something in the lab the other day that I hadn’t done in several years: run some preparative TLC plates. I had some small reactions that needed to be cleaned up, and the HPLC systems were all in use, so I thought “Why not?” (I wrote here about the decline of analytical TLC in general in some labs, and I think it's fair to say that the larger-scale prep version has seen an even steeper drop in use over the years).

Prep TLC, for those of you not in the business, is a pretty simple technique. You take a square glass plate that’s been coated with a dry layer of ground silica, a white slurry that for this application is about the grittiness of flour or ground sugar. You then take your mixture of gunk, dissolve it up in a small volume of solvent, and deposit it in a line across the bottom of the plate, an inch or so up from one side and parallel to it. Then you take a large glass container and add some solvent to the bottom of it, and put your plate in so that the streaked line of material is near the bottom. Here's one running.

The solvent soaks into the layer of silica, and after it gets up an inch or so it hits your line of stuff. As it continues to move up, soaking further and further up the glass plate, the different components of the mixture will be carried along at different rates. The compounds that stick to silica gel (for one reason or another) will lag behind, while the ones that don’t will move out into the lead. After an hour or so, the solvent line will be up near the top of the plate, and your mixture will now be spread out across it into a series of bands. (The TLC page at Wikipedia has some useful images of this). Up at the top, running with the solvent, will the the nonpolar stuff that didn’t have anything to slow it down. Right down near the bottom, not far up from your original streak, will be the most polar stuff, especially any basic amines – silica gel is mildly acidic, so the amines will stick to it very tightly indeed. And in between will be the other components, divided out according to how they balanced out the pull of the silica gel support with the attraction of the solvent moving them along. Sometimes you can see them as colored bands on the silica plate, but more often you shine a UV light on the whole plate to see them. The silica we use has an ingredient that makes it fluoresce green under ultraviolet, and our compounds usually show up as dark blue or purple bands against the green. It’s a color combination known to every working synthetic organic chemist.

You can see that picking different solvents for this process can change things a great deal. A weak solvent (like hexane) will allow almost everything to stick to the silica. (A compound has to be mighty greasy to be swept along by just hexane; I doubt if there’s a drug in the business that you’d be able to clean up that way). A standard mix is some proportion of ethyl acetate mixed with hexane. You can go up to straight ethyl acetate, or even further by mixing in methanol or the like. And if you’re desperate, you can go to most any solvent mixture you like – three-solvent brews, toluene, acetonitrile, acetone, whatever works.

So how do you get the things off? By the lowest-tech method you can imagine. You mark the position of the band (or bands) you want, and then take a metal spatula and scrape the silica there off the plate. You them dump that into a flask and stir it with a strong solvent, then filter off the silica and wash it some more to rinse your compound out.

This used to be much more of an everyday technique, but automated column chromatography (same principle, pumped through a tube) has taken over. But prep TLC still has its appeal. Done with skill, it can provide very clean compounds, with quite good recovery. In fact, its low cost and power have made it a favorite technique at places like WuXi, the outsourcing powerhouse in China. I've had several first-hand descriptions of their prep TLC room, with rows of plates being run, marked, and scraped in assembly-line fashion. It's the sort of thing you'd only do in a cheap-labor market, because of the unavoidable hand work involved, but it is effective.

I don't know where WuXi gets its plates, but if you make your own, it's an even cheaper technique (discounting labor costs, naturally). You take up the silica gel powder in water, make a thick, well-mixed slurry out of it, and spread it across a square of glass, shaking and tapping it to get the air bubbles out. Back when I was doing summer undergraduate work, I poured a number of these things, although it's certainly nothing I've had experience with since the first Reagan administration. For all I know, that's how WuXi does it now. Perhaps they've found a low-cost supplier of their own, but the idea of a cheap supplier for a Chinese outsourcing company is an interesting one all by itself. . .

Comments (32) + TrackBacks (0) | Category: Life in the Drug Labs | Pharma 101

February 4, 2009

Fancy Building, Fancy Science?

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Posted by Derek

I see that there’s a new biochemistry building at Oxford, written up here in Nature. It was designed by a London architectural firm, Hawkins\Brown (love that backslash, guys, so very modern of you), and according to the article, the design:

”. . .ensures that the 300 researchers working there communicate as much as possible. The traditional layout is reversed: here, labs are on the outside, divided by clear glass walls from the write-up areas, which are open to a vast, five-storey atrium. Everyone is visible. Open staircases clad in warm wood fly across the atrium at odd angles, and each floor hosts a cluster of inviting squashy leather chairs and coffee tables, giving the impression of an upmarket hotel.”

You can judge for yourself here. But as I was reading that, I kept wondering, where have I heard descriptions like this before? Oh yeah, the last time I moved into a new building. Actually, every single time I’ve moved into one, come to think of it. I was part of a gigantic corporate move in 1992 into what was billed as a “high-interaction facility”, which was nothing of the sort. And then at the Wonder Drug Factory, one of the new lab buildings had the whole research area behind a large glass wall; it was the first thing you saw when you came into the place. Unfortunately, since it was full of snazzy equipment, it became part of the standard tour for visitors (the combichem labs were largely abandoned by then), and the people working there sometimes felt like zoo animals. And my current building has the labs all around the outside walls, and a huge atrium in the middle of the building (to what purpose, no one is sure; it’s completely empty).

Most of the Nature article, though, is taken up with the artworks that were commissioned for the new building. I can’t pronounce on these without seeing them all, although the hanging birds display reminds me of a display I saw hanging in a shopping mall in St. Louis in the late 1980s. I do get a bit worried when I hear some artwork described as “rais(ing) questions about how we organize and view the world around us”, since that’s the worst kind of boilerplate artspeak. (Find a large abstract installation you can’t use it on). Another statement about how “if you have a greater degree of visual literacy, you reflect more on both the way you represent things, and also the way that may limit the way you think about them”, falls into the same vaguely depressing category.

“Time will tell if money spent on art gives a significant return in scientific discovery”, is how the article ends up. But how will we know? Set up a control building with no artwork at all, or one furnished only with the Pre-Raphelites? (Full disclosure – I’d rather work in that last one). My guess is that the people who work there everyday will gradually stop seeing the artworks at all; their biggest effect will be on visitors, for what that’s worth.

And as for laboratory building design in general, my suspicion is that there aren’t that many useful general design schemes. Once you’ve fallen into one of those slots, what will matter most for productivity will be the boring details about the size of the benches and hoods, the ease of using shelves and cabinets, the number and location of electrical outlets and sinks, and so on. As for interaction between the scientists, I agree that it does a lot of good: but how to force it? There seems to me to be a tradeoff between convenience and interaction – the most interactive buildings I’ve worked in were the ones that forced me, though a limited number of doors and stairs, to walk down long corridors past a lot of open (and rather cramped) offices and labs. Spread things out, put in a lot of access points, and people just won’t see each other as much.

So here’s the question: I’m sure that many of them can hurt it, but has anyone worked in a building that seemed to help discovery? Examples welcome, and feel free to link to pictures.

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January 23, 2009

The Real Hazards of the Lab

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Posted by Derek

A run of bad accident news today, and all of the same kind. The Chemistry Blog has the story of a fatality in the labs at UCLA. The short and painful details are: inexperienced student, t-butyllithium, flammable clothing, and panic (as in not running toward the safety shower).

This is very sad to hear about, and as with so many lab accidents, one of the saddest parts is how easily it could have been prevented. t-BuLi is, of course, a well-known fire starter, and the student did know about that problem. But one of the keys to working with dangerous substances is to think through what you’ll do if something goes wrong. For a pyrophoric compound, that means knowing where the nearest fire extinguisher and safety shower are. It’s very easy to panic when something goes wrong, but if you’ve rehearsed what to do beforehand, you have a much better chance of doing the right thing in tough circumstances.

I pass this along to the students who read this site, and I’m sure the other experienced lab workers here will agree: always think “OK, what’s the worst thing that can go wrong with this reaction?”, and think about what you’ll do if that happens. Fire? Explosion? Sudden leak of nasty toxic stuff? Think it over. Anyone working in a laboratory should always know where the nearest fire extinguisher is. That is, the nearest appropriate one – if you’ve got a separate Class D model for metal fires, or even just a sand bucket, then when you need it you’re really going to need it. And everyone should know where the nearest safety shower is, because no one ever just sort of needs to use one of those. I’ve had to run and pull one once in my career, and let me tell you, it was a damned good thing that I knew where to go when the chips were down.

The other news I have was communicated to me privately, so I won’t go into details other than to say that it appears to be another fatality, this time involving inhalation exposure to trimethylsilyl diazomethane. The problem with these sorts of reagents is that you might think that they’d cause breathing trouble immediately, but you’d be wrong. Diazomethane, phosgene, methyl bromide and others can actually take hours to kill a person, and for a good part of that time, the only symptoms might be a slight cough. But serious lung damage can be coming on slowly during that period, and by the time it’s clear that there’s a problem it’s usually too late to do very much about it. Unfortunately, in some cases, it’s too late right from the start, but that takes quite a bit of exposure, and indicates a serious mistake somewhere along the line.

Anyone who works with such volatile and damaging reagents needs to be completely aware of what they’re doing, and to only handle them under good ventilation. I’ve used such things many, many times in my career, without incident, and so have most working organic chemists. But we should never lose respect for what we’re holding in our hands.

I’m not trying to scare beginning chemists out of doing lab work. It has it hazards, but so does driving to work in the morning or cutting up food for dinner. (When I was in graduate school, my mother once expressed her worries about my lab work, but I told her that the most dangerous thing I did was to drive 650 miles back home on holidays). But every well-appointed chemistry lab is full of death in screw-capped bottles, and that bears thinking about. Random, unforeseeable accidents are, fortunately, very rare. But that means that the others didn’t have to happen, and that’s painful to contemplate.

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January 13, 2009

Lack of Experience, You Know

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Posted by Derek

OK, solid chemistry around here today. It looks as if I'll be running a ring-closing metathesis reaction soon. Nobel Prize in 2005, all over the chemistry journals for years. . .and I've never had occasion to use one until now. And when I think about it, there are quite a few other reactions in that category for me.

For example, I'm not at all sure that I've ever done a directed ortho-metalation. I've come close a few times, and I couldn't absolutely swear that I've never done the reaction, but none come to mind. No Fischer indole synthesis for me, because I've always been able to buy the indoles I need, and the same thing applies (fortunately) to the widely disliked Skraup cyclization for quinolines. I've never done an Eschweiler-Clarke reaction, although there have been several times I've needed to form methyl amines, and it probably would have been a good idea.

I've never done any of those multicomponent condensation reactions (Ugi, Passerini, etc.), partly because I've never done much combinatorial chemistry. And I've never done a Rosenmund reduction, but jeez, in this day and age, who has? No Julia olefination, no Fries rearranagements, no Kolbe-Schmitts (or Kolbe anything, come to think of it). And no Paterno-Buchi reactions, because I haven't really done any photochemistry for about twenty years.

I suppose the biggest gaps in my record are the RCM (soon to be filled) and the directed metalation (unless I can think of one that I've blocked from my memory somehow). Most of the other big ones I've done at one point or another, albeit perhaps only once or twice: the last time I ran a Wurtz coupling, on purpose, anyway, was twice in the summer of 1983. I have run a lot of the obscurities as well, of course (Shapiro elimination, anyone?) And I have a lot of fondness for some lesser-known reactions, such as the Prins cyclization, which got me out of a tight spot in my first year of grad school (I've been grateful ever since).

So here's my chem-geek question for the laboratory-bound part of my readership: what famous reactions have you never done? Have you been avoiding it for some reason, or have you just never needed the thing (and wondered why it's so darn famous)? Confess below!

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January 9, 2009

Poor Equipment Revisited

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Posted by Derek

A colleague came by a while ago and said "You know, the comments to that last post of yours are in danger of turning into Monty Python's Four Yorkshiremen sketch". At the moment, things are running about 50/50 between the "lack of equipment teaches you skills" and "lack of equipment wastes your time" camps. . .

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The Perils of Poor Equipment

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Posted by Derek

The late Peter Medawar once wrote about resources and funding in research, and pointed out something that he thought did a lot more harm than good: various romantic anecdotes of people making do with ancient equipment, of great discoveries made with castoffs and antiques. While he didn’t deny that these were possible, and admitted that you had to do the best with what you had, he held that (1) this sort of thing was getting harder every year as science advanced, and (2) while it was possible to do good work under these conditions, it surely wasn’t desirable.

His most interesting point was that lack of equipment ends up affecting the way that you think about your research. It’s not like people with insufficient resources sit around all day thinking of experiments that they can’t run and can’t analyze. If you know, in the back of your mind and in your heart, that there’s no way to do certain experiments, then you won’t even think about them. Your brain learns to censor out such things. This limits your ability to work out the consequences of your hypotheses, and could cause you to miss something important.

Imagine, say, that you’re working on some idea that requires you to find very small amounts of different compounds in a final mixture. A good LC/MS machine would seem to be the solution for that, but what if you don’t have access to one? You can spend a lot of time thinking about a workaround, which is mental effort that could (ideally) be better applied elsewhere. And if you had the LC/MS at your disposal, you might be led to start thinking about the fragmentation behavior of your compounds or the like, which could lead you to some new ideas or insights – ones that you wouldn’t have if you’d had to immediately cross off the whole area.

If you’re in a resource-limited situation, then, you’ll probably try to carefully pick out problems that can actually be well addressed with what you have. That’s a good strategy, but it’s not always a possible one. Huge areas of research can be marked off-limits by the lack of key pieces of equipment, and by the time you’ve worked out what’s possible, there may not be anything interesting or important left inside your fence. Medawar’s point was that being stuck inside such a perimeter would not only hurt the way that you did your work, but could eventually do damage to the way that you thought.

It occurs to me that this is similar to George Orwell's claim in "Politics and the English Language" that long exposure to cheap, misleading political rhetoric could damage a person's ability to think clearly. "But if thought corrupts language, language can also corrupt thought". There may be other connections between Orwell's points and scientific thinking. . .definitely a subject for a future post.

In fairness, I should mention that the flip side of this situation isn’t necessarily the best situation, either. Having everything you need at your disposal can make some researchers very productive – and can make others lazy. Everyone has stories of beautifully appointed labs that never seem to turn out anything interesting. There’s danger in that direction, too, but it’s of a different kind. . .

Comments (35) + TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs | Who Discovers and Why

November 13, 2008

The Yield Monster - And Its Friend, The Model Monster

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Posted by Derek

Organic chemisty can be a real high-wire act. If you’re taking a compound along over a multistep sequence, everything has to work, at least to some extent: a twelve-step route to a compound whose last step can’t be made to work isn’t a route to the compound at all. To get the overall yield you multiply all the individual ones, and a zero will naturally take care of everything that came before it.

Even very respectable yields will creep up on you if you have the misfortune to be doing a long enough synthesis. It’s just math – if you have an average 90% yield, which shouldn’t usually be cause for distress, that means that you’re only going to get about 35% of what you theoretically could have after ten steps (0.9 to the tenth). An average 95% yield will run that up to 60% over the same sequence, and there you have one of the biggest reason for the importance of process chemistry groups. Their whole reason to live is to change those numbers, to make sure that they stay that way every time, and without having to do anything crazier than necessary along the way.

When you’re involved in something like this and you know you’re going to be approaching a tricky step, the natural temptation is to try it out on something else first. Model systems, though, can be the road to heartbreak. In the end, there are no perfect models, of anything. If you’re lucky, the conditions you’ve worked out by using your more-easily-available model compound will translate to your precious one. But as was explained to me years ago in grad school, the problem is that if you run your model and it works, you go on to the real system. And if you run your model and it doesn’t work, well. . .you might just go on to the real system anyway, because you’re not sure if your model is a fair one or not. So what’s the point?

This gets to be a real problem in some labs. While ten steps is medium to long for a commercial drug synthesis, it’s just the warmup for a lot of academic ones. Making natural products by total synthesis can take you on up into the twenty- and thirty-step levels, and some go beyond that, most horribly for everyone concerned. In such cases, you’d much rather have several segments of the big honking molecule built separately and then hooked together, rather than run everything in a row.

But what if you spend all that time on the segments, but you can’t put the things together? The most famous example of that I know happened in Nicolaou’s synthesis of Brevetoxin B. The initial disconnection of this terrible molecule into two nearly-as-awful pieces turned out to have been a mistake. Despite repeated attempts, no way could be found to couple the two laboriously prepared pieces to make the whole molecule, and untold man-hours of grad-student and post-doc slave labor had to be ditched for a new approach. If you want to see the approach that worked, here’s a PDF of a talk about it.

But if you go linear, you’re taking the same risk, and the math will absolutely eat you alive. A 90% average yield will ensure that you throw away 95% of your material if you keep going for 28 steps. And keeping a 90% average over twenty-eight steps is just not possible with real-world chemistry, either – and yes, I’ve seen those papers where they do, but I don’t believe them. Do you? Make it 25 steps of average 90%, and three 60% losers, and now you’re down between one and two percent of your material left. Which is no way to live.

I note that the above summary of the Brevetoxin synthesis counts 123 synthetic steps. It calculates an average yield of 91%. A 2004 synthesis from Japan comes to 90 steps with an average yield of 93%.

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November 5, 2008

We Now Return to Our Regularly Scheduled Program

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Posted by Derek

About a year ago I wrote a post on flow chemistry. That, broadly speaking, is the practice of doing reactions by pumping them through some sort of reaction zone, instead of putting everything into a flask and letting it rip.

There are refinements. In batch mode, you can of course add reagents in sequence, or trickle them in by slow addition. And there are several variations to flow chemistry - in my mind, I have three categories. Type I flow reaction, in my numbering, are the ones that don't depend on any reagents in the tubes themselves. Everything you need is in solution, and you're just using temperature and/or pressure to make them do what you want. Nucleophilic displacements and cycloadditions are in this category: mix up your starting materials, pump 'em down the hollow tube, and get your product out the other end. Ideally.

Type II flow reactions, then, are the ones that need some sort of solid-supported catalyst. Palladium couplings (or other metal-catalyzed processes) are a perfect example of this, as is the H-Cube hydrogenator. Now you have some solid matrix inside your tubing, and you're pumping material over that. Heat and pressure are still very much a part of things, but the catalyst is, too - and the advantage here is that it doesn't end up in your reaction mixture. Starting materials should go in, and product should come out, and you should be able to use the catalyst again. Ideally.

And Type III flow reactions, in my scheme, are the ones that need full equivalents (or more) of solid supported reagent. I think that the companies getting into flow apparatus should keep these in mind. That's because you're going to use these things up, eventually, and the companies involved will be able to sell you more. ("Give 'em the razor and sell 'em the blades", as King Gillette said). All sorts of chemistry might fall into this category - reductive aminations are the first thing that come to mind from a med-chem perspective. All sorts of reactions with nasty workups are candidates for this sort of approach.

But there's a catch, the dirty secret of flow chemistry from my experience so far: you know how we medicinal chemists sometimes have trouble making soluble compounds? Well, brace yourselves when you go with the flow reactors, because you're going to be clogging things up left and right. Any flow apparatus that does not take this into account should be regarded with suspicion: "easy to clean out" is a very desirable quality. Things have to be run more dilute than you think they do, and in stronger solvents. That can mean trouble on the back end, with more (and more difficult) solvents to get rid of in the isolation.

If anyone out there is also involved in the flow world and can talk about it, I'd be glad to hear some experiences. For bench-scale medicinal chemistry, the field is still in its early days, and there are lot of things that haven't been tried yet.

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October 28, 2008

Out the Door and Down the Stairs

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Posted by Derek

I’ve noticed over the years that my patience in seminars and talks has been eroding. This started in graduate school – I certainly sat through my share of lousy talks back then, but I was starting to skip out on the occasional one, after a certain level of grimness was reached.

For example, I remember walking down the hall with a new post-doc, when the building’s speakers came to life. “May I have your attention, please. . . “ We stopped to listen. “There will be a seminar in the main auditorium in ten minutes, entitled “Raman Spectroscopy of Synthetic Asphalt Roofing Materials” (I swear that this is a real title, or something very close; it was appalling). The new guy asked, in a slightly worried tone “Do you guys in the group usually go to these things?”

And at that point, one of my fellow group members came lurching out into the hallway, pantomiming elaborate choking gestures as he pointed desperately at the speaker up on the wall, slumping against the wall as the horror of the seminar’s title overcame him completely. We watched him slide to the floor, still gesturing at the intercom, and I said calmly: “No, we skip a few of them now and then”.

Well, over the years I’ve continued to skip a few of them now and then, and my threshold has been steadily creeping up. I realize that many of the topics that keep me glued to my seat are, by any objective standard, rather dry. Give a detailed talk about enantioselective hydrogenation, the thermodynamics of multivalent binding, or even the latest thinking about the patent office’s requirements for obviousness rejections, and I’ll be right there, practically munching popcorn. To me, those things are interesting. But plenty of things aren’t.

It’s to the point now where there are single phrases that give me that “late for the door” feeling. After that hits, it’s a major effort for me to stay in my seat. So, speakers, if you see me out in the audience and think that the ambience would be improved without me, it isn’t hard. Just spend a few minutes going on about “cross-functional goal setting” or the wonders of ISO nine-thousand-whatever. I’ll spray gravel on my way out. One day I’ll probably end up dangling from a bunch of knotted tablecloths, having rappelled down the side of my building from an upper-floor conference room. “Vision statement”, I’ll gasp to the passers-by as I drop to the sidewalk in relief. “They invited me to work on a new vision statement. . .”

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October 20, 2008

Fearful Symmetry?

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Posted by Derek

It’s worth examining your own scientific prejudices and biases from time to time, to see if they’re still valid. Of course, that begins with the difficult task of figuring out what they are – it’s hard to think of these things when you need them. So I try to make note of my presuppositions when I find myself acting by them, flagging them for later review.

One of these that’s come up recently is the bias that I (and many other medicinal chemists) have against symmetric compounds. (By that I mean palindromic compounds with a mirror-plane right down the middle of their structures). We tend not to make such compounds; we downgrade screening hits with that look to them, and if we start to work on one the first things we do is to desymmetrize it and see if it gets any better. Why?

I think that one reason must be that there aren’t many truly symmetric binding sites out there. Proteins, while they can have large-scale symmetric structures, are usually pretty twisty and heterogeneous on the scale of a drug-sized molecule. Even in the cases of real protein symmetry (a dimer of two identical subunits, say), your compound would have to be fitting into some very select spaces to be feeling that symmetrical environment perfectly.

So a symmetric drug molecule feels wrong, somehow unoptimized. But there’s no reason that its two seemingly identical ends have to be doing the same thing on each side. They could easily be binding to completely different residues, or in different ways – it’s worth remembering that the symmetric structure we draw on the board may not have much in common with the molecule’s real 3-D conformation: a few zigs and zags in the rotatable bonds, and things aren’t as balanced as they looked.

Perhaps we shouldn’t be so hard on these structures. I’ve crossed several of them off my lists over the years, but I think from now on I’ll give them more of a chance. Anyone with me?

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October 13, 2008

Old School - Really Old

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Posted by Derek

We try to be delicate when we synthesize our molecules – really, we do. Delicate reactions often have better yields and fewer side products. Exotic catalysts in perfectly tuned metal coupling reactions – these things are wonderful when they work, because you go from pure starting material to darn near pure product.

But life in the drug labs is not always thus. We also have to turn back the clock, and break out reactions that our grandfathers would have recognized – dark, fuming things that will eat a hole in your lab coat. Nitration is one of these – good old nitric acid is still very much around for that reaction, often in vile mixtures with sulfuric and the like. It’s cheap, and it often works, so you can’t get away from it. And if 1:1 nitric/sulfuric won’t perforate your clothing, you must have put on armor instead of Armani.

Chlorosulfonic acid is another such reagent. It’s nasty by anyone’s standards, but it’ll stick a chlorosulfonyl group onto an activated aromatic ring in one step, which is nothing to take lightly. You don’t want to pour that into water to work it up, not unless you want to see it splatter all over your hood. Nope, you’ll need a trip to the ice machine – slow drizzling over crushed ice is the traditional workup, for good reason.

That’s a good acid for another brute-force reaction that we still have with us: the Friedel-Crafts. Fancier ways exist to acylate an aromatic ring – those metal-catalyzed ones, for example, often in the presence of carbon monoxide. But who wants to use CO if you don’t have to? And you need a leaving group where the acyl group is going to go. The Friedel-Crafts will just come in and jam one in on an unsubstituted carbon, if the electronics of the ring are right. And all you need to do is treat your molecule with some hammer-of-the-gods reagent like chlorosulfonic acid, polyphosphoric acid (which looks and acts like honey from Hell), or straight aluminum chloride powder. That last one is at least a solid, albeit a corrosive one, but you pay the toll during the workup. That’s when it hydrolyzes to piles of white aluminum oxide junk, often turning your reaction into a thick mess.

So no, it’s not all twenty-first chemistry, all the time. World War I-era chemistry is still very much with us at times. Actually, I sort of like it that way. When I have to break out the polyphosphoric acid, the powdered iron, or the elemental bromine, I feel as if I’m keeping faith with my predecessors. They wouldn’t know what to make of the LC/mass spec machine, but they’d grin when they saw me trying to work up my aluminum chloride reactions.

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September 29, 2008

Why Don't You Just. . .

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Posted by Derek

For the most part, the biologists on a drug discovery project expect us in the med-chem labs to be able to make pretty much anything we need to make. Actually, I don’t have to go that far – the other chemists more or less expect that, too. Chemistry’s a big field, with a lot of reactions and techniques, and if you want some particular structure badly enough, there are usually ways to get to it.

But not always, and not always by routes that you’re willing to put up with. That’s especially true early in a project when you need some robust chemistry to turn out a lot of diverse analogs quickly, so you can have some idea of which parts of the molecule are most important. Synthetic trouble at this stage is frustrating for everyone involved.

I was on a project a few years ago that ran into this exact problem. Compounding the pain was the way the lead compound looked when it was up on a screen during a meeting: small, perfectly reasonable, easy to deal with. Hah! It was a werewolf, that thing. None of the ideas that we had ever worked out the first time, and many of them never worked out the last time, either. Meeting after meeting would take the same format when there were outside managers or other chemists present: “But why don’t you just. . .” “We did. It doesn’t work.” “But then you should try. . .” “We know. We tried that. It doesn’t work.” “Well, OK, but then you could always come around and. . .” “We could. If it worked. But it doesn’t.”

New chemists would be added on to the program to try to get things moving, and they’d always come in rolling up their sleeves, muttering “Do I have to do everything myself around here. . .” How do I know? Because I was one of them. Within a month or two, though, I was in the same shape as everyone else on the project, looking at a bunch of NMRs and mass spec traces and trying to figure out what went wrong. Meanwhile, helpful folks would wander past the whiteboard and ask me how come we hadn’t tried the reaction that had just failed for the eleventh time. Eventually we learned to offer the more persistent questioners a supply of our starting material so they could solve the problem themselves and be heroic, but nothing ever came of that.

The project managed to stagger to a clinical candidate, but ran into mechanistic problems in the more advanced animal models. (That was really the hot fudge topping on the whole sundae – this was one of those therapeutic areas whose definitive animal models were too complex and costly to run until you were absolutely sure you had The Compound). I haven’t run into one quite like this since, and with any luck, I never will.

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September 17, 2008

Sugars: Still Crazy After All These Years

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Posted by Derek

I did carbohydrate chemistry for my PhD - well, I used carbohydrates as starting materials to make other molecules, but I did my share of pure carbohydrate stuff along the way. And although that was over twenty years ago, the stuff I did is still considered by most people to be a sort of esoteric thing, an odd specialty that not many people have experience with. Time has clearly not mainstreamed sugar chemistry.

It's not like people don't use the things, often for just the reasons that I used to (as versatile chiral starting materials). But the reputation of the compounds lingers. I think it's because of all the odd little reactions that sugars do. There's a certain amount of knowledge that has to be learned - all that stuff with the anomeric center, for starters, and all the name reactions that only occur in sugars, like the Ferrier rearrangement.

Then there are the protecting groups. With all those hydroxys hanging around, a lot of them are going to have to be tied up for extended periods while your work gets done. But every hydroxy group on a sugar ring has a slightly different personality - they acylate and deacylate in a particular order, for one thing, which varies from one sugar system to another. And there are the acetals and ketals to tie up two hydroxyls at once - very useful, but there are a lot of different combinations that can form under different conditions and with different carbonyl reactants.

The closest analog to the field that I can think of is steroid chemistry. In its day, that was a hugely popular and important field, with all sorts of ins and outs - tricky transformations that you learned from the old hands. But these days, hardly anyone cares - pure steroid chemistry is a backwater, and many of the esoteric reactions are largely forgotten. Sugar chemistry has escaped that fate - it's still relevant - but hasn't escaped the atmosphere of an eccentric club.

My own sugar knowledge, while still sound, is not exactly up to date. I know that the field has moved on over the years, but I've had only sporadic need to keep up, since carbohydrates don't appear in many drug structures. I've been able to work in some of them once in a while, but I've never worked on a project where my sugar experience has been front and center.

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August 25, 2008

How Not To Do It: Water Aspirators

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Posted by Derek

You need access to vacuum if you’re going to work at the bench in chemistry. In fact, you need more than one kind. Reasonably hard vacuum (well, by our standards, which is laughable by the standards of the physicists) is down in the single Torr or below – that is, less than about 1% of normal air pressure. We use that for pulling out residues of water or organic solvents from our compounds. You can’t usually see it happening from the solid ones, but the syrupy liquids will foam up or blow a long series of thick bubbles when the vacuum is applied. The foam can be an irritating problem at times; some things will fill your flask with sticky bubbles and go right on up into the vacuum line if you’re not watching them.

The lesser vacuum lines are used for bulk evaporation of solvent (on your rotavap) and for filtering things off. We do an awful lot of both of those, too, and a full vacuum-pump pull is too vigorous for them in most cases. Evaporating down reactions is a constant task in an organic chemistry lab; I’d rather not think about how much of it I’ve done over the years. As for filtration, there are many cases where a solid product can be filtered out of the bulk liquid (which is good) or where some undesired solid by-product has to be filtered out before you can go on (not as good).

The low-tech way to get the sort of pull-it-though vacuum you need for these things is a water aspirator. You don’t see these as much any more, and you don’t see them at all in industry, since they necessarily pull solvent vapors into the water stream. But they work. An aspirator is basically a narrowing tube that hooks up to a hard-spraying water tap and has a sidearm fitting. The accelerating blast of water pulls the air in the tube along with it as it goes, creating a useful vacuum. If you wanted to make one rather more environmentally friendly, you’d keep a well-stocked dry ice condenser in line with it to trap out the solvent vapors before they go down the drain (which is what your rota-vap should have on it, anyway), but even with that, you’re always going to be turning the water flow into a waste stream. As I say, you don’t see them as much these days.

But we used them back when I was in grad school, that’s for sure, mostly for the rotavaps. If you wanted to keep things from splashing around back in your hood, you attached some rubber tubing to the other end of the thing and ran it further down the drain a bit.

Well, one day, one of the guys in the lab next door to me was shocked to see water blasting around in his hood. It was a real fountain, just geysering out full blast from what must have been a cracked water line or something in the back. He ran over and immediately shut off every tap – but to no avail. Roaring, showering water everywhere. Getting a look at the source, he realized, to his consternation, that the water was coming up out of the drain in the back of his hood. I remember standing there with him, staring at this in disbelief. It looked like a special effect. How on earth could you get water blasting up out of a drain pipe?

Suddenly it hit me. I ran around to the other side of the lab, where a new Japanese post-doc had taken up residence. “Masa”, I asked him, “Did you just put that rota-vap in your hood today?” “Yes, yes, just started it today”. There was a water aspirator flooshing away back in the back of his hood. “Did you put some rubber tubing on that thing?” “Tubing? Oh, yes” “How much?!” “Whoaaa. . .” He spread his arms to indicate the mighty extent of the rubber tubing he’d added.

Mighty, indeed. He’d run the stuff down his drain, through a horizontal pipe and right through a T joint, and back up out of the drain of the other guy’s hood, which backed on to his. So when he turned his water on full throttle, he immediately started irrigating his labmate’s space. We finally go thing turned off, and trimmed back the rubber tubing to a more reasonable length (like, not seven feet), and order was restored. For a while.

Note: if you want to see How Not To Do It to a really expensive vacuum rig, try here.

Comments (25) + TrackBacks (0) | Category: Graduate School | How Not to Do It | Life in the Drug Labs

August 19, 2008

Fighting Boredom, Profitably

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Posted by Derek

I wanted to recommend this post by Milkshake over at Org Prep Daily (and not just because he liked the recent column I wrote for Chemistry World). I was writing about the limited number of reactions that some med-chem labs get locked into, and the effect of this both on the compounds that get made, and on the motivation of the chemists. Milkshake has a good set of recommendations on how to avoid the boredom trap, and I recommend checking them out. He ends with the following:

You should care about the chemistry methodology and do things not just to crank out the final compounds to fill up the testing queue. Your boss (has) perhaps lost all his chemistry interest already and maybe he is unnerved about the project progress and pushes people hard - but while you try not to get fired you don’t necessarily want to think like your boss (and end up wretched). If you continue to look at your research project with curiosity and do things also for the sake of your chemistry interest you are likely to be more original because thinking about the methodology will suggest new directions in your medchem project. You may get accused of playing with chemistry and going off-tangent but you will likely remain more content and productive. . .

And this is all true. Most projects need some oddball compounds thrown into them, to keep things interesting (and honest), and it’s the people who are keeping up with the literature who will probably make them. I went through a period some years ago when I didn’t stay current with the journals very well, and if I’d let that continue to slide, it would have had a bad effect. (RSS was one of the things that saved me!)

But there’s another very good reason to stay sharp and run the unusual reactions, though: the boring reactions are increasingly going to be shipped to someone else, someone who probably works in a very different time zone. Yep, this is my “give ‘em something they can’t get in Shanghai” talk again. The outsourcing shops are there to pound out molecules as quickly as possible, and they’re going to use well-established chemistry as much as they can. Now, that’s the same pressure that operates in most med-chem projects, but I strongly recommend differentiating yourself if possible.

Be the person who runs the new stuff, who reads the literature and adopts things quickly, and who makes compounds that aren’t like all the stuff that’s already in the screening deck. You don’t have to go completely crazy, you know. There are plenty of good, reasonable structures that no one else is making at your company – have no doubt – and if you’re the person who makes them and who introduces new chemistry into the department, you have something with which to justify your salary (or a higher one!) On the other hand, if you’re the person who cranks out the sulfonamide libraries, well. . .they can get that cheaper somewhere else, you know.

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July 28, 2008

Questions You Don't Necessarily Want the Answers To . . .

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Posted by Derek

1. “Hey, who dropped that condenser out on the floor in front of my hood? That looks just like the one I had on my reaction flask. . .”

2. “How come the toxicology people haven’t called me about our lead compound yet? Two-week tox finished a while ago, and usually they’re a lot faster than this. . . “

3. “Is there any active aluminum compound left in this reaction or what? I keep dripping methanol into it to quench it, and nothing’s going on at all so far. . .”

4. “Who’s going to scale up our candidate compound, anyway? We need 300 grams of the stuff, and the scale-up group is booked solid. . .”

5. “So, is this the high-pressure hydrogen line or the low-pressure one that I’m opening?”

6. “I wonder what the error bars are on that behavioral assay. . .”

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July 21, 2008

Backtracking, Necessary and Unnecessary

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Posted by Derek

One of the things that no one realizes about research (until they’ve done some) is how much time can be spent going back over things. Right now I’m fighting some experiments that should be working, have worked in the past, but have (for some reason) decided not to work at the moment. Irritating stuff. There’s a reason buried in there somewhere, and when I find it things will be that much more robust in the future, but I’d hoped that they were that solid already.

And across the hall, a check is going on of some screening hits. When you get a pile of fresh high-throughput screening data, including some fine-looking starting compounds for a new project, what do you do with it? Well, if you have some experience, the first thing you do is order up fresh samples of all the things you could possibly be interested in, and check every single one of them to make sure that they actually are what they say on the label. Don’t start any major efforts until this is finished.

In fact, you should order up solid samples from the archives along with some of the DMSO stock solution that they used in the screening assay. They might not be the same, not any more. False negatives and false positives are waiting in your data set, depend on it: compounds that should have hit, but didn’t because they decomposed in solution, and compounds that (sad to say) did hit only because they decomposed in solution. You’ll probably never know about the first group, and you can waste large amounts of time on the second unless you check them now.

Getting a project going, then, can seem like trying to get a dozen nine-year-olds into a van for a long trip. Someone’s always popping out again, having forgotten something, which reminds someone else, and your scheduled departure time arrives with everyone running in circles around the driveway.

But nine-year olds can eventually be corralled, as can the variables in most scientific projects. But not always. Where you don’t want to be is the situation people had with the early vacuum-tube computers. Vacuum tubes have not-insignificant failure rates. So if you have, say, twenty thousand of the little gizmos in your ENIAC or whatever, doing the math on mean-time-between-failures shows you that the thing can run for maybe forty-five minutes before blowing a tube (unless you take heroic measures). And the more vacuum tubes you have, the worse the problem gets: make your computer big enough, and it’ll blow right after you throw the switch, every time.

So that’s the other thing you have to watch when troubleshooting: try to make sure that your problems aren’t built into the very structure of what you’re trying to do. In med-chem projects, look out for statements like “we have all the activity we need, now we just need to get past the blood-brain barrier”. Sometimes there’s a way out of those tight spots, but too often the properties that (for example) could get your compound into the brain are just flat incompatible with the ones that gave you that activity in your assay. You’d have been better off approaching that combination the other way around, and better off realizing that months ago. . .

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July 18, 2008

Lowe's Law of Diurnal Distribution

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Posted by Derek

Here’s an appropriate topic for a Friday, although at first many of you may think I’ve lost my mind. What would happen if you combed the full text of the experimental sections of the chemistry journals, looking for how long people ran their reactions?

I’m pretty sure that I know what you’d see: there would be a lot of scatter in the short time periods, with some peaks at the various half-hour and hour marks just for convenience. But as you went out into the multiple-hour procedures, I feel sure that you’d see pronounced spikes in the data at around sixteen to twenty hours and again at around 72 hours.

Some readers have doubtless started nodding their heads, having done the math. Those times correspond to "overnight" and "over the weekend", and I'm willing to bet that they're over-represented (and how) in the data set. I'll go on to predict scarce examples in, say, the 14-hour or 38-hour ranges - there's not much way to run a reaction for those intervals and not be in the lab too early in the morning or too late at night.

A second-order prediction is that when such reactions are found, that their origins will skew heavily toward academia rather than industry. And I'm also willing to bet that patent procedures will tend to follow the working-day timelines more than the general literature, for the same reasons. My last higher-order prediction is that the reaction times would not, in fact, obey Benford's Law, as many other data sets of this kind do.

As far as I know, no one's ever done this sort of analysis, but I suppose it would be possible, especially for someone at Chemical Abstracts or at one of the scientific publishers. If someone wants to try it, please let me know what comes out. And if the results follow my predictions, please feel free to refer to the title of this post or something similar. I won't object.

Comments (31) + TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs | The Scientific Literature

July 9, 2008

How's The New Boss Doing?

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Posted by Derek

Here’s a question that came up in a discussion at work the other day: when a new head of research comes in, how long should you give them before judging how they’re doing?

That’s a tough one to answer, I think, because there are a lot of variables. First is the size of the outfit, coupled with the scope of the position. A really big organization is a very, very hard thing to change, no matter how powerful the new person might be. I’m not at all sure how possible it is to change a company’s culture, but I’m pretty sure that it requires major shock therapy to do it. (If any of you have read C. N. Parkinson on what he calls “injelititis”, you’ll know the sort of thing I have in mind).

And different levels of authority affect processes with different timelines. A head of chemistry will be able to show results in less time than a head of research, who will need less time than a head of total R&D, because that person has to wait for the clinical results. As I’ve mentioned before, that seems to me to be one of the biggest challenges in this industry – the way that big changes can take years to work their way through to the results stage. It’s hard to steer intelligently if the front tires respond ten miles after you cut the wheel over hard.

You also have to ask what the new person is being asked to do. Steer the course on something that already seems to be working? Or shake the place up and make things happen (for once)? Expand the workforce, contract it, spend money or save it, stick with the existing therapeutic areas or branch into new ones? The job descriptions on these things are pretty wide-ranging, so the evaluations have to be, too. Without a clear idea of what the new boss is trying to do, it’s impossible to say how well it’s being done. You could wind up giving bozos credit for something that had nothing to do with them, or blame excellent managers for things that were completely out of their abilities to control. (I know, I know, that kind of thing happens all the time, but you don’t have to add to it if you can help it).

So, how long for an evaluation, then? One to three years for head of chemistry, five or six for head of research, up to ten for head of R&D (if they last that long?) I'd be interested in hearing other estimates. . .

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July 3, 2008

I Can Has Ugly Molecules?

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Posted by Derek

A colleague and I were talking the other day about some of the molecules that turn up when you dig through a company's internal database. This was a favorite sport of mine during slow afternoons at the Wonder Drug Factory - I would put in a query for bizarre or unlikely chemical groups and see what fell out. I was rarely disappointed - eventually I assembled a folder of the most hideous examples, which never failed to astound.

The compound collection at my current employer isn't nearly so weird, fortunately. But every drug company has large lists of compounds that aren't so attractive as leads, because they were made in the last stages of previous projects. This is a well-known problem, often referred to as a gap between "drug-likeness" and "lead-likeness". For the most part, the compounds you start a project with don't get smaller - they get bigger, as people hang more things off of them to get more potency, selectivity, or what have you. So you're better off starting as small as you feasibly can, giving you room for this to occur without taking you off into the territory of too-huge-to-ever-work. (That's one of the fundamental ideas behind the vogue for fragment-based drug discovery, for example).

"Too-huge-to-work" is a real category, as my industry readers will gladly verify. I think that the "Rule of Five" cutoffs have been sometimes applied a little too mindlessly, but there's no getting around the fact that if your latest molecule weighs 750 and has thirteen nitrogen atoms in it, the odds of it being a drug are rather slim. As my colleague put it, when you make something like that and send it in for testing, what you're saying is "I know that almost every molecule that looks like this fails. But I'm different. I feel lucky". And that's no way to run a research program. Given finite time and finite money, you're better off prospecting in chemical areas with better chances.

So what to do? We kicked around the idea of setting up some filters in the compound registration system itself - if someone tries to send in some horrible battle cruiser of a molecule, the system would make a puking noise or something and refuse to register the compound at all. There would have to be be some sort of override (perhaps for a higher-level manager to authorize) for those times when you actually have evidence that the ugly molecule works, but maybe the "You Lose: Make Something Else" screen would focus attention on the properties of what's being made. Of course, if anyone ever implemented this, the arguing would begin about where to draw the line (maybe there'd be a yellow "warning zone" in between), but I think that everyone agrees that at some point a line should be drawn.

So, for my readers around the industry - do you have such a cutoff? Can you register any crazy compound that crosses your bench, or does your company's software fight back? If so, what's the feedback - beep, e-mail warning, electric shock? Inquiring minds want to know.

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June 4, 2008

Tote That Barge, Lift That Bale

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Posted by Derek

I was talking with a colleague recently about the different cultures that have grown up in different drug companies where lab associates are concerned. For those outside the industry, those are non-PhD-holding scientists, who (for the most part) do not move into managerial positions. There's room for a whole separate blog post on the people who (for one reason or another) never got the PhD degree but are the equal or superior of anyone who has, but for now I'm talking about the rest of the associate population.

As people get more experienced, they become more valuable, or at least they should. An experienced chemistry lab associate is one of the most readily employable people in the industry, under normal conditions. A company may or may not feel a need for another twenty-year middle manager type, but there's always a need for hands at the bench to make compounds, and good associates are the people who make the most. And with some time in the industry, they have a far better understanding of the real world of drug discovery than any PhD coming in fresh out of their post-doc.

Or at least they should. There are, though, some companies that treat their associates more like draft animals, putting them in the position I held in the summer of 1979 when I worked for in a greeting card factory before going to college. I was a "materials transport handler", which meant "See that big pile of stuff here? Haul it over there." It's the only time I've done manual labor for money for more than an afternoon, when I think about it. But I'm told that there are shops in this industry that tell their associates exactly what to do at every turn, up to the point (so I hear) of having them take spectral data and turn it over to their supervisors rather than interpret it themselves.

That's something you associate with the old-style German and Swiss labs, where there's a clear heirarchic division between the PhD holders in their offices and the "laboranten" out in front of the hood. Even there, I don't think this is quite as rigid as it used to be, so the thought of this here in the US is quite odd. But it does seem to go on, so I'm asking the readership: what's the status of the usual lab associate where you work?

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June 3, 2008

Oops

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Posted by Derek

We recently encountered a problem that’s (unfortunately) a rather common one. An enzyme assay turned up an interesting hit compound, with some characteristics that we were hoping to see for leads against our target. A re-test showed that yes, the activity appeared to be real, which was interesting, since this hit was a welcome surprise from a class of compounds that we weren’t expecting much from.

It was a comparatively old compound in the files, and all we could find out was that it had been purchased rather than made in house. Looking around, it seemed that there were very few literature references to things of this type, and only one commercial source: the Sigma-Aldrich Library of Rare chemicals, known as SALOR. That, though, was a potential warning flag.

Those compounds come from an effort started by Aldrich’s Alfred Bader many years ago, who started trolling around various academic labs looking for unusual compounds that no one wanted to keep around any more. Over time the company has accumulated a horde of oddities that are often found nowhere else, but there are several catches. For one, these things are usually available only in small quantities, tens of milligrams for the most part. That’s plenty for the screening files, but you’re not going to make a bunch of analogs starting from what comes out of a SALOR vial. Another catch is that the compounds are sold, very explicitly, as is: the university sources tell Aldrich what’s on the label, so that’s what they sell you and caveat emptor all the way, dude.

So often as not, you get what we got, a nice-looking white powder which, on closer analysis, turned out to only have a vague relationship to the structure on its label. We knew that we were in trouble as soon as the first NMR came out: way too much stuff in one region, nowhere near enough in some others. Mass spec confirmed that this thing weighed more than twice as much as what it was supposed to. We’ve since pretty much nailed down what the stuff really is, and our interest in it has decreased as each of the veils has been removed from the real structure.

We’re correcting the data in our own screening files, of course. And yes, we’re going to tell the folks at Aldrich to change their label, too, assuming they have any of this stuff left. At least the next person will know what they’re getting. For once. But there are more of these things waiting out there – in every large compound collection, in every catalog, in every collection of data are mistakes. Watch for them.

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May 30, 2008

Ah, Glassware

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Posted by Derek

Well, while the mail continues to come in about my post yesterday, I’m going to pull back from the global perspective and zoom back into the glassware drawers of my lab bench today. A while back I wrote about the different sizes of ground glass joints that organic chemists typically use. People from outside the field are sometimes struck by the fact that we don’t have to do as much glassblowing and the like as they might have thought. Decades ago there was a lot more, but for a long time now we’ve been able to build up all sorts of apparatus (apparati?) by connecting standardized glass fittings together.

This has all sorts of advantages, letting us assemble odd custom configurations pretty easily, and change them without too much work. The downside is that the ground glass joints aren’t by themselves vacuum tight – not by the standards of inorganic chemists, for sure – and need to be anointed with thick, nasty vacuum grease before they can be trusted to that level. And if you don’t grease them for normal work, which we tend not to because the grease gets into your compounds, then the joints tend to freeze if left too long or too tight.

There are all sorts of voodoo tricks for unsticking them. I pride myself on being able to do it, but (objectively) I don’t think my success rate is all that greater than the norm. For the record, my technique is to put a few drops of silicon bath oil up around the edge of the stuck connection and let it soak in for a few hours. Then I rapidly heat the outside joint, grab it with a towel, and do the usual pulling and tapping while hoping for the best. There are better ways, but they're typically found only in a glassblowing shop.

When I last wrote about this fascinating subject (hey, chemists like their glassware), I mentioned that I’d gotten in the habit of using 29/42 size joints. (That’s a measure of size: the first number is a diameter, and the second is the length or taper). That’s a larger one than is common in American labs; you see it more in Germany, among other places. I’m so used to it now that the standard 24/40 glass joints you see all over the place look narrow and shrunken to me – will I really be able to get my product out of that?

The standard small size these days is 14/20 – that’s the size of all our 5, 10, and 25 milliter flasks. (You can get 100 mL flasks (or larger) with that size joint, too, but they start to look disproportionate and weird, and there’s no real reason for large flasks to have such a small neck). In between that and good ol’ 24/40, though is the 19/22 size, which I really should look at again. It would be the wide-mouth counterpart to 14/20, in the same way that 29/42 is to 24/40. I’d probably like it.

But I’ve hardly seen a flask of that size since I was an undergraduate, and that whole range of glassware immediately recalls sophomore organic chemistry labs. I wondered why that was, but now I have the story thanks to reader Norm Neill of glassmaker NDS Technologies, who saw its birth at Kontes:

"The 19/22 Glassware kit was developed jointly by Eric Nyberg from Kontes Glass and Dr Howard Martin from Lake Forest College in the late 1950's. . .they wanted to scale down the size of the glassware from the traditional 24/40 glassware to something smaller so it could be issued as a complete kit to a student and locked in his lab drawer. . .The next size down from 24/40 is 19/38 but the joint length was too long to allow us to scale down the kit (and) fit into a standard lab bench drawer. The 19/22 medium length joint was the best trade off at the time. . .The packaging of the kit was so popular that during the early 1960's production had to be allocated. The overwhelming success of the 19/22 glassware started the development of an extensive line of 14/20 glassware under the Bantamware® brand."

It's my impression that the 14/20 glassware has been taking over the student market in recent years as well, what with the move to smaller and smaller amounts of solvents and reagents. That makes me wonder if 19/22 glass has a future, which means that I'll probably find some lunatic reason to switch my small-scale stuff to it really soon, giving me the most oddball glass collection in the place. . .

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May 20, 2008

The Miracle Solvent

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Posted by Derek

For those who were wondering, my copper reactions the other day worked out just fine. They started out a beautiful blue (copper iodide and an amino acid in straight DMSO – if that’s not blue it’s maybe going to be green, and if it’s not either one you’ve done something wrong). Of course, the color doesn’t stay. The copper ends up as part of a purple-brown sludge that has to be filtered out of the mix, which is the main downside of those Ullman reactions, no matter how people try to scrub them up for polite company.

And DMSO is the other downside, because you have to wash that stuff out with a lot of water. That’s one of the lab solvents that everyone has heard of, even if they slept through high school chemistry. But it’s not one that we use for reactions very much, because it’s something of a pain. It dissolves most everything, which is a good quality, but along with that one comes the ability to contaminate most everything. If your product is pretty greasy and nonpolar, you can partition the reaction between water and some more organic solvent (ether’s what I used this time), and wash it around a lot. But if your product is really polar, you could be in for a long afternoon.

That mighty solvation is something you need to look out for if you spill the stuff on yourself, of course. DMSO is famous for skin penetration (no, I have no idea if it does anything for arthritis). And while many of my compounds are not very physiologically active, I’d rather not dose myself with them to check those numbers. At the extreme end of the scale, a solution of cyanide in DMSO is potentially very dangerous stuff indeed. I’ve done cyanide reactions like that, many times, but always while paying attention to the task at hand.

Where DMSO really gets used is in the compound repository. That dissolves-everything property is handy when you have a few hundred thousand compounds to handle. The standard method for some years has been to keep compounds in the freezer in some defined concentration in DMSO – the solvent freezes easily, down around where water does (Not so! Actually, I've seen in freeze in a chilly lab a couple of times, now that I'm reminded of that in the comments to this post. Pure DMSO solidifies around 17 to 19 C, which is about 64 F C - a bit lower with those screening compounds dissolved in it, though).

But there are problems. For one thing, DMSO isn’t inert. That’s another reason it doesn’t get as much use as a lab solvent; there are many reaction conditions during which it wouldn’t be able to resist joining the party. You can oxidize things by leaving them in DMSO open to air, which isn’t what you want to do to the compound screening collection, so the folks there do as much handling under nitrogen as they can. Compounds sitting carelessly in DMSO tend to turn yellow, which is on the way to red, which is on the way to brown, and there are no pure brown wonder drugs.

Another difficulty is that love for water. Open DMSO containers will pull water in right out of the air, and a few careless freeze/thaw cycles with a screening plate will not only blow your carefully worked out concentrations, it may well also start crashing your compounds out of solution. The less polar ones will start decided that pure DMSO is one thing, but 50/50 DMSO/water is quite another. So not only do you want to work under nitrogen, if you can, but dry nitrogen, and you want to make sure that those plates are sealed up well while they’re in the freezer. (As an alternative, you can go ahead and put water in from the start, taking the consequences). All of these concerns begin to wear down the advantages of DMSO as a universal solvent, but not quite enough to keep people from using it.

And what about the compounds that don’t dissolve in the stuff? Well, it’s a pretty safe bet that a small molecule that can’t go into DMSO is going to have a mighty hard time becoming a drug, and it’s a very unattractive lead to start from, too. That’s the sort of molecule that would tend to just go right through the digestive tract without even noticing that there are things trying to get it into solution. And as for something given i.v., well, if you can’t get it to go into straight DMSO, what are the chances you’re going to get it into some kind of saline injection solution? Or the chances that it won’t crash out in the vein for an instant embolism? No, the zone of non-DMSO-soluble small organics is not a good place to hunt. We’ll leave proteins out of it, but if anyone knows of a small molecule drug that can’t go into DMSO, I’d like to hear about it. Taxol, maybe?

Comments (16) + TrackBacks (0) | Category: Drug Assays | Life in the Drug Labs

May 15, 2008

Copper: A Gentleman's Disagreement

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Posted by Derek

I was running a copper-catalyzed coupling reaction the other day when my summer intern asked me how it worked. I showed her the mechanism that the authors of the paper had proposed, but pointed out that it was mostly hand-waving. The general features are probably more or less right: the copper iodide presumably does form some kind of soluble complex with the amino acid that’s needed in the reaction mix, and that may well form some sort of complex with the aryl halide, which opens up the ring to nucleophilic substitution, etc. If this were an exam, I’d give full points for that one.

But a lot of these couplings are, as I pointed out to her, very hazily worked out. The Ullman reaction, in various forms, has been with us for many decades, and there are more variations on it than you can count. If it always worked reasonably well, or if people had any strong ideas about how it did so, the literature on it wouldn’t be in the shaggy shape it is. Copper chemistry in particular has been (simultaneously) a very useful area for people to discover new reactions, and a horrible trackless swamp for people trying to explain how they work.

All you have to do is look at the vicious exchanges between Bruce Lipschutz and Steve Bertz during the 1990s about whether such as thing as a “higher-order cuprate” exists. I have absolutely no intention of reconstructing this argument; I would have to be paid at a spectacular hourly rate to even attempt it. It's enough to say that the arguments raged, in an increasingly personal manner, about what state the copper metal was in, what ligands coordinated to it, and what the active form of these reagents might be (as opposed to what the bulk of the mixture was at any given time). It culminated in what must be one of the most direct titles for a scientific paper I've ever seen: It's on lithium! An answer to the recent communication which asked the question: 'if the cyano ligand is not on copper, then where is it?'. That's in Chemical Communications 7, 815 (1996), if you're interested (here's the PDF for subscribers). Bertz continued to shell Lipshutz's position past the time when any fire was being returned, as far as I can tell, and continues to work in the area. Lipshutz, for his part, hasn't published on the higher-order cuprates in some time (being no doubt heartily sick of the whole topic), but has kept up a steady stream of work on new reactions involving copper, nickel, and other metals.

So if well-qualified researchers, brimming with grad students, postdocs, and grant money, can argue for years about copper mechanisms, I'm going to stay out of it. As time goes on, I'm increasingly indifferent to reaction mechanisms, anyway. I want to get product out the other end of the reaction. And while there are times when knowing the mechanism can help reach that goal, those times do not occur as frequently as you might hope.

Comments (16) + TrackBacks (0) | Category: Chemical News | Inorganic Chemistry | Life in the Drug Labs

May 14, 2008

Summer Student Time

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Posted by Derek

I have a summer intern this year, and she has (so far) not caused anything to burst into flames. That’s the first thing you ask of a summer student, and the fact that she’s gotten several reactions to work is just a welcome extra. A summer with no laboratory bonfires will be a successful summer, as far as I’m concerned.

That’s because I’ve experienced the alternative, as I’ve detailed here before. If most of the lab fire stories you hear start out with the phrase “We had this solvent still. . .”, the rest of them all seem to begin with “We had this summer undergrad student. . .” (You can imagine the flame-filled end to any story that starts out with a summer student distilling some solvent – that Venn diagram leaves you with no way out at all).

No, after watching an undergrad next door to me kick a four-liter jug of pyridine all over the floor, causing a shimmering wave of unspeakable pyridine vapors to almost knock me off my feet. . .and after watching another one walk away for two hours after setting up a reduced-pressure DMSO still, which inadvertently turned into a high-pressure apparatus and blew DMSO and calcium hydride all over the inside of a hood. . .and after watching them charcoal reactions by plugging heating apparatus straight into the wall outlet instead of into the Variac. . .and, well, you get the idea.

I should add that I was no great shakes as a summer undergrad myself. I did a summer after my sophomore year with Tom Goodwin, but didn't get a great deal accomplished (through no fault of his!) Then after my junior year, I worked with Dale Boger, back when he was at the University of Kansas, but I mostly (and rather slowly) found a list of conditions that don't work for inverse electron demand Diels-Alder reactions. But although I spilled some generous amounts of solvent, I didn't set anything on fire.

No, we're going to have a calmer and more productive summer around here. I have my student working on a problem I've had a longstanding interest in, one that needs some variables chased down and figured out. With any luck, enough data will be generated to make for an interesting publication late in the year, and everyone will come out ahead.

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May 12, 2008

Explaining It All

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Posted by Derek

One of the reasons I starting this blog was that many people I met were interested in my job. Very few of them had ever talked to someone who discovered new medicines for a living, and a surprising number of them (well, surprising to me) had no idea of where medicines came from in the first place.

Talking to such folks (interested, but with no particular training in science) gave me some good practice in explaining the work. It helps that the kind of work I do is actually fairly easy to explain. There are a lot of details – as with any branch of science, the closer you look, the more you see – but I haven’t run across any key concepts that can’t be communicated in plain language. (It also helps that medicinal chemistry, as it’s actually practiced, uses an embarrassingly small amount of actual mathematics).

The toughest things to deal with are the parts of the field that actually touch on physics and math. My vote for the hardest everyday phenomenon to explain at anything past a superficial level is magnetism. So that means that explaining how an NMR machine works is not trivial. At least, explaining it in a way that a listener has a chance of understanding you isn’t – a while ago, I took up the challenge to try to explain it here in lay terms, and I haven’t done it yet, for good reason.

Explaining statistical significance is doable, but going much past that (principal components, the difference between Bayesian and frequentist approaches) takes some real care. And, of course, when you open the hood on chemical reactivity, the mechanisms of bond-forming and bond-breaking, you quickly find yourself in physics up to your armpits. It’s easier to stipulate, openly or by assumption, that there are such thing as chemical bonds, and that some of them are stronger than others. You don’t want to start answering a question about why one group falls off your drug molecule easier than another one does, only to find yourself fifteen minutes later trying to explain the Pauli exclusion principle. Counterproductive.

But the basics of medicinal chemistry can be sketched out pretty quickly, which makes some of the more curious listeners wonder, after a while, why we aren’t better at it. The best example I can give them is to advance a quick, hand-waving explanation of, for example, how compounds get into cells. Then I point out that that explanation is unnervingly close to the best understanding we have of how compounds get into cells. The same holds for a number of other important processes, way too many of them.

And that's why drug discovery is simultaneously frustrating and fascinating. We know huge numbers of things, great masses of detail that can take years to piece together. And it's not enough. Some of the most important puzzle pieces are still weirdly ill-defined, and there are probably others whose existence we haven't even realized yet. I'd be willing to bet that if you scanned the whole history of pharmaceutical discovery, you'd find people at every point thinking "You know, in any thirty years they should have all this figured out". But the years go by, and they - we - don't. Give it another thirty years, you think?

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May 5, 2008

Naming of Names

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Posted by Derek

We order chemicals from all sorts of suppliers – big, reputable outfits like Sigma-Aldrich-Fluka all the way down to places that none of us even have heard of before. In those latter cases, the primary question is always whether or not the reagent will actually show up, and the secondary one is how long it’ll take. There are some of those small suppliers who pad their catalog with things that aren’t exactly available, not yet – but hey, they will be if someone orders them. They’ll just tell you it’s back-ordered, and tell someone in the lab to get cracking.

And when you get your compound in, they arrive in various forms. Glass or plastic bottles are the norm, naturally, with the occasional irritating (but presumably necessary) sealed-glass ampoule. But after some time in the lab, you can tell some of the suppliers from across the room. For example, the Japanese company TCI sends a lot of its compounds in normal-looking glass bottles, but these are first put inside capped plastic containers, like larger translucent versions of the ones that 35mm film probably still comes in. And once you taken them out, their glass bottles have these odd plastic labels on them which come up around the screw cap and are perforated around the cap’s border. On the labels, they also have that same thin, fussy, serif font that the Japanese have been using for Roman-style letters for decades (since the war?) and is only in recent years disappearing from their world.

Maybridge, British vendor of all kinds of odd stuff, often sends its compounds in these weird little squat brown-glass bottles with small black caps on them. They must have the world supply of that particular bottle shape tied up, since I’ve never seen one anywhere else. It most resembles the small bottles that solutions for injection are packaged in. So many of the company’s catalog items are in such bottles (or even smaller ones) that it seems wrong somehow when you come across a huge (huge for Maybridge) hundred-gram bottle with their label on it.

Most of the suppliers have neutral-sounding names like those above. They could be chemical companies, vendors of kitchen cabinets, real estate trusts, who knows: Maybridge, Oakwood, Lancaster (now gone, and their blue labels with them). And some of them are unmistakably in the chemical supply business, but rather blandly named (Pharmacore, for example, or Chembridge). Some names are, perhaps, mistakes: the namers of Asinex, for example, seem to have been unaware that the closest Engish word is “asinine”, which means that they have to hope for people to pronounce that “s” as if it were a “z”. (I should mention that both Asinex and Chembridge indulge in one widely hated practice: putting no useful information on their tiny vials other than a catalog number or bar code – Bionet (Key) is a similar offender).

In this dull company, I’m always glad to see the weirdos. I miss the now-purchased-away British supplier called Avocado – green labels, naturally – and always wondered who named them and why. Tyger Scientific makes me wonder if there’s an English major in somewhere at their founding, fond of William Blake. And there’s one company that came into the industry under the glorious name of, I am not making this up, “Butt Park”, and many are the chemists they’ve made stand puzzled in front of the supply cabinet. (I'd provide a link, but I can't find a direct one, and Googling it can be a real minefield).

I refuse to consider that name a mistake. That's a feature, not a bug, and I wish that there were more competition in the category. I would proudly and purposely send business to, say, Batshit Chemical Supply, Inc., even if they back-ordered me every single time.

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April 15, 2008

Walk Around Some

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Posted by Derek

Not many chemists come into the drug industry knowing very much about biology. I certainly didn’t, not on the level that was needed. It’s not surprising, but it’s also not as much of a handicap as you’d think, at least not at first.

That’s because the first job of a new hire in the med-chem department is to crank out compounds, and that goes for both the PhD and Master’s levels. (Those roles diverge as time goes on, though). But with a few obvious rules in hand (no hot reactive functional groups, no huge greasy monster molecules, etc.), a person can contribute reasonable-looking compounds pretty quickly. No biological knowledge needed.

But if you’re going to be more valuable than a new hire (and as time goes on, you’d better be), then you have to start picking up some more of the broader science of drug discovery. That turns out to involve a lot more than chemistry, which is one of the things that chemists have to get adjusted to. If you’re going to move up to the point of being considered to lead a new project, you’re going to have to show that you can converse with the folks who know protein expression, assay development, molecular biology, PK, toxicology, and so on. You’re not going to be expected to come in and solve their problems (although if you do manage to solve one once in a while, it’ll do both you and them some good). But you are expected to understand what they’re talking about.

So that’s a piece of advice I can give to new chemistry hires in this business: get ready to learn everyone else’s business, too. Listen up when the people from the other departments talk about what they’re up to, and especially when they complain about their problems. Try to understand why they’re complaining, and ask them (especially one on one) about what they usually try when this sort of thing happens. The occasional paranoid might think at first that you’re compiling info in order to mess with them later, but you shouldn’t be the sort of person around whom that suspicion credibly lingers. In general, if the people in those other groups are any good at all, they’ll be glad to tell you what’s going on, and you’ll pick up a lot of practical knowledge.

The consequences of not doing this sort of thing become more severe as time goes on. At one of my former companies, we once brought in a job candidate from BNP (Big Name Pharmaceuticals). He’d been around seven or eight years, enough time to be considered fairly experienced. But people at that level vary a lot, and he was (as it turned out) on the low end. When we’d ask him about, for example, any formulation problems he’d had to deal with on his project compounds, he told us that well, he didn’t usually go to those meetings, his boss did. And when we asked him about how he got along with the PK group – well, they were over in another building, and he hardly ever saw them. And so on, and so on.

He was well along to being crippled by the way things were done at BNP. Actually, it may have been more the way he was doing things. From talking with other people from that shop over the years, it’s clear that it didn’t have to be that way – if you made the effort, you could go to those meetings, and if you took the time, you could go over to those other buildings and show your face. But you didn’t have to, and this guy (since he didn’t have to) didn’t bother to. And by keeping to his burrow, he hadn’t learned nearly as much as he could have. We didn’t make him an offer. So talk to people, talk to people outside your field. If you’re any good at all, they’ll learn something from you, too.

Comments (14) + TrackBacks (0) | Category: How To Get a Pharma Job | Life in the Drug Labs

April 14, 2008

A Meditation on Solvents

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Posted by Derek

Hexane (or its cheaper, less well-defined cousin, petroleum ether) is the proto-solvent. Light and thin, it’s the weakest at actually dissolving anything, so it’s the background to most stronger mixtures in a purification. Like most other solvents, though, it’ll strip the oils right off your skin, leaving you spiderwebbed with white lines across your fingers and in need of some lotion. Its smell isn’t pleasant, but it doesn’t really stink, either. A nonchemist would easily place it in the oil / kerosene / gasoline end of things, which is exactly where it belongs.

When I first encountered ethyl acetate back in college, little did I realize that I was picking up the scent of the rest of my life. I've been in the lab ever since, and so has it. Pleasant, unspecifically fruity, vaguely bubblegum-like, the smell of that solvent is a daily companion to almost every synthetic organic chemist in the world. Mixed with hexane in different proportions according to your needs, it runs the majority of chromatographies in the world. Squirt bottles of it sit around on benches. By now, it’s an old, old friend, and the smell of it says that I’m actually getting something done.

Ether (the real ether, diethyl ether) seems like it’s close to not being there at all. No long for this world, it’s supremely light, and evaporates so quickly, that it just barely holds on to the liquid state. It has a slightly dangerous overtone to it, since it can ignite so easily and forms explosive peroxides if it’s left sitting around. The somewhat smothering smell can’t quite be described, but is instantly recognizable. Its oxygen atom gives it more dissolving power, so ether/hexane mixtures are good for delicate separations, although often impractical on a larger scale. To me, ether is sort of a lighter, stronger hexane, in the relationship that titanium has to steel.

Methanol, on the other hand, has no smell – no smell whatsoever to me, at any rate, despite what that Wikipedia link says, although I think I can tell it from air. Pure lab ethanol smells great, but methanol is a blank to me. It’s the most watery of the common solvents – it’s lighter, but that OH group gives it some surface tension, which (along with its bizarre weight) is one of water’s defining characteristics. You notice the difference, compared to thin, slippery hexane or ether – methanol is a solvent with some body to it. It’s powerful stuff in chromatography, too – one per cent added to a weaker solvent will totally change things.

Do you call it dichloromethane or methylene chloride? The latter probably gets more use, and rolls off the tongue a bit more easily. This stuff is like the demon form of hexane – it has no oxygen atoms like ether or ethyl acetate, but is a pretty strong solvent, in what always seems a mysterious way. With another immediately recognizable but hard to describe smell, its odor is the prototype of “chlorinated”. But the thing that stands out the most is its weight. This is the only common solvent that’s heavier than water, and you can build up your arms doing curls with jugs of the stuff. We don’t use its even denser cousin chloroform all that much; it would be even better bodybuilding material.

Acetone is one of the solvents familiar both in and out of the lab: nail polish remover, without the added scents. You hardly ever run an actual reaction in the stuff, though, and when you do it feels a bit odd. That’s because acetone has become the default flask-rinsing solvent of the chemistry world. I’m not sure when that was settled, but it was decades ago: a perfectly respectable solvent, stuck in the role of janitor to all that brown, red, and yellow stuff stuck to the inside of a million round-bottom flasks.

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April 9, 2008

Another Pop Quiz!

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Posted by Derek

Time for another quick quiz on whether you have what it takes to be a big-time medicinal chemist. Prepare for some not-so-welcome old friends to visit you yet again:

1. Your two main assays refuse to act as if they’re part of the same project. Most of your potent compounds in the first enzyme assay don’t do much against the cells, and the best cellular compounds are no great shakes in the enzyme assay. There’s a narrow zone of overlap, but it doesn’t look big or robust enough to base the whole project on. Do you pursue the cellular activity, on the theory that that’s the effect you’re looking for, or pursue the enzyme activity (on the grounds that it’s the right target, and you just have to get the things into the cells), or consider revamping the assays completely, or what?

2. In the next case, your disconnect doesn’t occur until you get to metabolism and PK. When you run your compound across liver enzymes, they grind it into dust. But you did that after you dosed the animals, you buckaroo, and not only did the compound seem to work OK, but its blood levels weren’t bad, either. So how come it looks as if it should be disappearing? The most destructive of the enzymes, by the way, was the human one. Are you worried about that, or not?

3. The project you’re on has a compound profile as a goal – so much potency, at least so much selectivity, and the like. As time goes on, there’s one selectivity assay in particular that you just can’t seem to shake. The only time you see a decent separation between your activity and the one you don’t want is in a compound series that you don’t like – they’re big and greasy, and although they look very active in the enzyme assay, they never perform as well as they should in the animals. But it’s starting to seem as if you have a choice: good properties or selectivity, but not both at the same time. What to do?

4. OK, let’s back up some. You’re working on a project that hasn’t really made it to the medicinal chemistry stage. The screening folks have run the target, and forwarded you their data. Nothing shows up really potent, but there are some 500-nanomolar things scattered around. And “scattered” is the word, all right. You probably have two dozen near-singletons in that range – nothing seems to show much of a robust effect across a given class of compounds. But this is a target that everyone wants to start a program on - it's hot, it's happening. How do you proceed?

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March 26, 2008

The Lucky Bonus Pack

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Posted by Derek

I ran a reaction the other day which gave me two very similar products. That's not so uncommon, but this one really shouldn't have been able to do that. (For the chemists in the audience, these two so similar, in fact, that the usual LC/MS conditions only showed one peak. NMR tells you different, though, and a painstaking multiple-elution TLC in some nonstandard solvent mixtures resolves the two spots).

I thought about the problem a bit, and decided that the first thing to do was to check my starting material. And there they were: two very similar starting materials, together in the same jar. Mind you, there's only one structure on the label. No wonder the stuff was so sticky. I'd received the Special Extended Edition without knowing it - odds are, the supply company sent it to me without knowing it, either, although that'll change when they get my e-mail. One of the components, anyway, seems to be the right stuff, so I suppose it could be worse.

This happens more often than it should, often enough that every working chemist has a similar story or two. And it doesn't correlate that well with the size or renown of the company you're ordering from, since everyone sources material from all over the place. Little mom-and-pop operations have sent me plenty of fluffy, flawless stuff, while Aldrich has on occasion mailed me goo. (On another occasion they mailed me a perfectly empty sealed ampoule with a label on it, but since the label didn't read "Air", I thought I had reason to complain). That doesn't mean that reputations don't vary. Even though they're now part of the same company as Aldrich and Sigma, those Swiss fanatics at Fluka do this sort of thing to you comparatively less often than their cohorts.

Not all the unopened slime you encounter is necessarily the fault of the company that shipped it. Some things just aren't stable, or at least aren't so stable in the back of an unventilated truck or sitting out in the sun on a loading dock. And the longer it is after an order's been received, the more the problem is likely to be with the receiver. A look at the condition of the vials in a drug company's compound repository will convince anyone that the kinds of molecules we like may not have indefinite shelf lives.

In this case, it's going to be easier to clean up the starting material and run the reaction again than it would be to clean up my dueling products. Easier yet would be to get a bottle of the right stuff from the supplier, but this one isn't exactly a high-volume compound, and I suspect that it's all the same nasty batch on their shelves. Worth a try, though. And thus does science stagger on.

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February 15, 2008

Putting Out the Inevitable Fires

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Posted by Derek

Lab fires don’t happen as often as you might think, at least to hear the way organic chemists talk. We all have alarming stories of alarming reactions (often set up by some rather alarming labmates), but these things are harvested over a fairly broad range of experience. It’s a familiar enough topic that I can remember someone sitting down at lunch while we were swapping lab stories and saying “Oh, this conversation. . .”

But happen they do, and it’s always worth taking a couple of minutes to think about what you do in such a situation. That depends on the fire, of course. For starters, a small one burning out of the neck of a flask can be put out quickly just by slapping a beaker over the top of it. Never neglect that possibility, because it’s fast, effective, and (truth be told) if no one saw you do it, no one necessarily has to know that your (minor!) fire even happened.

Larger ones aren’t going to be so easy, but there are some potential ways out of those, too. My wife had a labmate in her molecular biology department who was always setting off blazes with the ethanol she used to wipe things down with. (This person neglected to turn off the Fisher burner used for sterilizing wire loops, etc., before she started sloshing the alcohol around). A fire like that will just burn itself out if you close the hood sash and let it rip for a few seconds, as long as you’re sure that there’s no fuel source (like the wash bottle of ethanol you might have chucked in there in a moment of panic, for example).

Most chemistry hoods, though, have all too many sources of fuel in them, so you probably won’t be able to put out a blaze through benign neglect. If it comes to a fire extinguisher, make sure you already know where the nearest one is, for starters. You'd be surprised how hard it is to find one of the darn things when you really need it. And once you've found it, make sure that you know which kind you’re using. The carbon dioxide ones don’t make the horrible mess that the dry-chem ones do, which is one thing in their favor, although I think in general they’re a bit less effective. You can tell the difference immediately – the carbon dioxide ones have the big nozzle on them, while dry-chem is a short, plain hose. My lab is outfitted with the latter, which makes me wish more than ever that we never have to use them.

And if you happen to have halon extinguishers (are those still around?), make a note of that, because the technique you may have learned for using the other ones won’t work. Instead of coming in and aiming at the base of the fire, with halon you have to stand further back and let the stuff shower down on it. A colleague of mine once blew the contents of a flaming oil bath all over the lab because he hadn’t been trained in that distinction.

The safety people always tell you that if you’ve used up one extinguisher and the fire still isn’t out, to head for the door rather than reach for a second one. That’s probably good advice (although I’ve seen it disregarded), and I’d advise you to take it. Actually, I’d advise you never to have that decision to make at all, but that’s not always up to you. You may be doing nothing but adding sodium sulfate to a bunch of dichloromethane today, but who knows? The guys next door might be gearing up for Trimethylaluminum Fiesta Days. You never can tell.

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February 13, 2008

One Time Only. Or Maybe Just a Few.

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Posted by Derek

I’m going to be working up an Arbuzov reaction this morning, which is an odd thing for me to say. That’s because to the best of my recollection, which is pretty good, I’ve only run any of those during one period in my lab career. That was back in grad school, along about 1985, I’d say. I hope this one proves more useful than that one did – I was trying to make some dimethyl diazomethylphosphonate, and the prep was a relentless barrage of No Fun. (The first part of the sequence was identical to this).

I keep a list in my head of songs that I’ve only heard one time (no, I don’t appear to be normal, thanks for asking), and perhaps it’s time for me to assemble a list of reactions that I’ve only run once. That’s a tougher one, because if a reaction fails, you may well run the thing again. Still, I’ve only done one hydrogenation at 2000 psi with rhodium on alumina (July 3, 1984, and it looked like used lawnmower oil afterwards, I should add), and I’ve only used samarium iodide one time (and it didn’t work). But for a longer list I might have to settle for some things that I ran for a brief period and never have since.

The Claisen rearrangement would fall into that class, for sure. A feature of my early grad school work, I’ve never had the need to run one since. I can't think of the reaction without smelling ethyl vinyl ether in my memory, which is not a feature, in case you're wondering. I did a lot of carbohydrate reactions back then that I haven’t had the need to return to, either – Ferrier rearrangements being just one of them. And, like many other chemists, I had a brief photochemistry period, in my case during my post-doc, and have never run one of those again, either. Others that enjoyed their day in the sun and have never been seen again in my hood are the Prins reaction, nitrone cycloaddition (not since I was an undergrad in 1983), Lindlar hydrogenation, and the Henry reaction.

The thing is, any of these could make a comeback at any time. They’re still all perfectly reasonable reactions, and depending on what comes out of the next high-throughput screen or literature search, I might be setting one up next week. You never know. But there are some reactions that I think I’ve said goodbye to forever. In some cases, that’s because better alternatives are now available - I mentioned here that I haven’t used PCC for oxidations in years, and I think that one’s been pretty much superseded.

Others are history because I either very much doubt I’ll have the need for them, or because I just flat out Don’ Wanna. For example, I made Dess-Martin periodinane three times on a hundred-gram scale, during a period in the early 1990s when it wasn’t commercially available, and I plan, with any luck, never to do that again. The prep has been improved since those days, but that explosive intermediate was never something I enjoyed seeing. I don’t think I’ll be synthesizing fluorosulfonic acid starting from hydrofluoric acid any time soon, either. I did that one as an undergrad, too, if you can believe that – this guy must have had confidence in me, which I’m not at all sure was warranted by the evidence at hand. Nor do I foresee any need to make Fremy’s Salt from scratch again. (You can see someone else do it here, though - the internet amazes me sometimes). And if I never do another reaction that requires half a mole of phosgene, that’ll be fine with me, too.

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February 7, 2008

Write It Down, Write it Down

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Posted by Derek

A couple of years ago, I wrote about electronic lab notebooks, and pointed out how much better they've made my record-keeping. My new job also uses an electronic platform, to my relief, and if anything it's better implemented than the one I was using before. It's clear to me, that software lab notebooks are the only way to go. Drawing the structures, setting up duplicate or related experiments, attaching all the data files from LC/MS and NMR, the ease of retrieval for patent filing purposes, the ability to search structures across a whole organization's experience - there's no substitute. (One thing they don't handle well, though is TLC data, which I was just talking about - anyone have a solution for that?) But that aside, going back to paper would be agonizing; a directive to use hardbound notebooks would induce terror and dismay.

Still, both of the electronic notebooks I've used are in-house jobs. I've had some mail wondering if I have any recommendations among the commercially available software, and that's a question I can't help out with at all. So I thought I'd throw this one out to the readership: what's worked for you? And how much did it cost? Is there anything open-source that'll do the job? (I've heard of Wetlab and OS-ELN, but know nothing more about them).

And here's another question, which is more of a poll. Are you using paper or pixels for your notebook? If you answer in the comments, which I'm glad to report seem to be working again, mention what kind of work you do and if it's in an academic or industrial setting. I'm curious to see if the expected correlations show up. . .

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February 6, 2008

Dig the New Breed

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Posted by Derek

You know you’re getting older when techniques that you used to use constantly are in danger of becoming lost arts. The one that I’m thinking about today is thin-layer chromatography, or TLC. This is a classic lab method, taught to generations of undergraduates and used by untold hordes of working organic chemists. And it’s slowly on the way out.

Before we go into what’s killing it, a brief bit of background for the non-chemists in the crowd. To do a TLC, you take a plate of glass (or something else stiff, like thick aluminum foil) that’s been coated with a thin layer of some finely ground solid. The usual choice is silica gel, which is basically very pure, very finely ground sand. In its powdered state, it resembles a slightly grittier form of corn starch. In the old days, you’d spread this stuff out on the plates yourself, but it’s been twenty years since I saw anyone do that. During my whole career, you’ve been able to buy them premade, in all sorts of variations.

Then you take a drop of your mixture and put it on the silica layer, down near the bottom of the plate. Once it dries, you stand the thing up in a beaker or jar that has some solvent in the bottom - the idea is to wet the plate at the bottom, but not so far up that it rinses off your spot. As the silica gel layer wets, the solvent creeps up the plate. And (as in all the other forms of chromatography), the various compounds in your mixture will travel faster or slower, depending on their interactions with the silica versus with the solvent. A strong polar solvent (methanol) will tend to whip everything up with the solvent front, and a wimpy one (hexane) will tend to leave everything back at the start. Adjusting the solvent mixture can give you a spread of spots up and down the plate once you've let it run for a bit, and you can see those with a UV lamp, or by dipping the plate in some reagent that will generate colored material from your compounds. Excellent pictures of the process can be found here.

TLC is cheap, fast, convenient, and can be run in untold different variations. So what's killing it? Something even faster, more convenient, and more powerful: liquid chromatography/mass spectrometry. That was just barely possible when I was in grad school, and was expensive and tricky when I was in my early years in the industry. But now the machines, while still not cheap, are everywhere, and they're used in walkup mode. Just enter your data - or link it over from your electronic lab notebook - put your sample vial in the rack, and go away. What you get back is a better separation than TLC can give you, and every peak/spot now can be checked for the masses of the compounds in it. You can ask all the possible questions, such as "which peak has the mass I'm looking for?", or "What the heck is the main mass in that peak, anyway?". The mass spec gives you more information than you can deal with, and it's all stored digitally for your later perusal and second thoughts.

This trend has been coming on for years now, but it's reached a very noticeable point. Even a comparatively old-school guy like me hardly runs TLC plates any more. Once in a while, I'll need to, but mostly, it's just "throw it on the LC/MS". And I get the impression that people coming through grad school now are losing the finer points of TLC completely. And why not? They've never had to worry about them at all. . .

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February 1, 2008

A Few Questions For My Fellow Pharma Chemists

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Posted by Derek

1. You’ve got a compound repository, right? Lots of vials, robot retrieval systems if you’ve got the cash, all that stuff? What fraction of those vials are full of sticky stuff that are colored warning shades of dark orange, red, or soy-sauce brown? And of those, what fraction has had colorfulness overtake it while in your repository racks, as opposed to the stuff that arrived looking that way? Bonus question: are you aware of any cranberry-red wonder drugs, and have you ever heard of anyone formulating a big manufacturing batch for Phase III while checking to make sure it’s the right shade of brown?

2. You’ve got some molecular modelers, right? And you ask them to try to dock some of your compound ideas into your favorite binding sites? OK, first question: how many times have any of them come back to you saying that they can’t fit something in? If the answer is “never”, you have a problem with your modelers. Second question: if you do get told that your compound doesn’t seem to dock, do you keep going down the hall until you find someone who can jam your idea into the model? In that case, the problem is closer to home.

3. You’ve got biologists on your project, right? In vitro assay people, then the in vivo group, ready to test whatever makes it that far? So, how much compound do they ask for? And how much of that do they plan to actually use? When they ask, how much compound do you tell them you have on hand (or can make)? And what fraction of what you really have or can make is that, exactly? Depending on the ratio between these various answers, you can either have no problems or you can be living with quite a few different ones simultaneously.

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January 25, 2008

Extractions: A Way of Life

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Posted by Derek

Over at Org Prep Daily, Milkshake did an excellent post earlier this month on extraction techniques. It’s well worth looking over, even for experienced lab crew. Solvent extractions are a way of life for organic chemists, a fact that has not changed since the beginning days of the science, because (for one) we still do the bulk of our reactions in one sort of solvent or another, and (two) because the bulk of our reactions need to have garbage removed from them, and this is the first line of cleanup. (Here it is in real life - scroll down).

For those readers who aren’t chemists, three paragraphs of explanation: extraction works on the “like dissolves like” principle. A look at a bottle of oil-and-vinegar based salad dressing that’s been sitting for a while will show the familiar layers, with the oil on top and the aqueous layer below. If you were to take samples out of each and analyze them, you’d find that they contain rather different parts of the dressing mixture. The oil layer will have the compounds that can’t dissolve in water very well – organic pigments like carotenes or lycopenes, for example. They’re better off in with the oil molecules; they don’t have any polar molecular features strong enough to horn in on the hydrogen bonds that water uses to stick to itself.

Down in the water layer, on the other hand, is all the stuff that has such polarity. All the amino acids and most proteins will be there, as will the sugars and other soluble carbohydrates. These compounds have a lot of groups (hydroxyls, amines, carboxylic acids) that can interact strongly with the small, polar water molecules. Since there’s a lot of vinegar in there, too, acid-base chemistry will be a factor. The compounds with strongly basic groups (fishy amines and the like) will be protonated by that acetic acid, and the resulting salt is a natural for the water layer. A few base-containing things that might otherwise be just as happy in the oil layer will be pulled in by this effect.

So if you have a messy mixture of stuff, you can separate the greasy components from the polar ones by shaking up the lot in a mixture of water and some solvent that’ll form a separate layer. Sometimes you’ll want one layer, sometimes the other, depending on what your product is like, but most of the time organic chemists are throwing out the water layer and keeping the other one. There are other tricks – for example, if your compound’s acidic or basic, you can adjust the aqueous layer the other way to hold it as a salt, wash out all the other goo with solvent, and then change the acidity so that your compound will now go into a fresh solvent wash. In all these cases, you drain off the appropriate layers with one of these.

I would not like to hazard a guess at how many extractions I’ve done. Shaking a sep funnel is such a basic act of organic chemistry – every time you mix something up and wait for the layers to separate, you’re participating in a rite that goes back to the days when labs were only illuminated by sunlight or fire. It’s one of the few things that a scientist from the 1850s would immediately recognize if teleported in front of my fume hood, that’s for sure (the fume hood itself would be a revelation, for starters).

I have to say, though, that Milkshake’s nom de blog is an unfortunate one for the topic, since one of the worst things that can happen to you during an extraction is a thick emulsion. That’s when the layers don’t want to separate – millions of tiny droplets of each component decide, for various irritating reasons, that they’re happy where they are, thanks, and don’t pair off with their former comrades. The result is a thick, opaque mess, so the name for the most intractable emulsions is, naturally, “milkshake”.

One of the things he mentions as seldom seen these days is actually one of my favorite pieces of lab apparatus: the liquid-liquid continuous extractor. Sad to say, I don’t have one these days, but I could find or buy one if the need arose. There’s something appealing about setting up a continuous, automatic purification. Being able to see the results over time (the solvent pot in these things gets uglier) makes you feel as if you’re getting something done even if all you’re doing is standing there watching the extractor. A fine apparatus it is, and worth a post of its own some day. . .

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January 24, 2008

Cheap Happiness

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Posted by Derek

There are some well-known expensive ways to make scientists happy: buy them lots of equipment and put it in fancy new buildings, pay them lots of money to work there. Come to think of it, that works on just about anyone. But there are some cheap ways to make them happy, too, and companies are really hurting themselves if they don’t pick up on them.

Recognizing what the people in the lab do doesn’t cost very much. Odds are excellent (odds are downright overwhelming) that the people downstream in regulatory affairs and marketing have no idea of who the people were that came up with the latest drug they’re trying to get over the top. Some of them, in a large company, may have only a rough idea of where it came from at all.

Let ‘em know, but do it the right way. Company newsletters get thrown away, mass e-mail get deleted. No, next time there’s a department-wide meeting over there, give ten minutes or so to bring up some of the people who discovered and worked on the current hot compound. If one of them is up for it, have them say a few words. Seeing the hordes of people working on their compound will cheer up the scientists, and seeing where the compounds came from will be a new experience for marketing. Human contact is good; it’s harder to let people down after you’ve met them and seen them.

You can run this in a negative sense, too, naturally, if you’re so inclined. Get one of the higher-ups in the company to mispronounce the name of a discovery project or two during a big speech, and watch what happens. I’ve seen it myself – it works like bug spray on morale, and one of the reasons is that everyone knows that it’s such an easy mistake to avoid.

Not being a hard case about time is another one. You’d think that this would cost money, as people abuse your generous spirit, but for the most part, it’s the opposite. I knew a lab at a former company where the lab head immediately swiveled to look at the wall clock whenever an associate arrived in the morning, or left in the afternoon. This person couldn’t seem to help it. They had to check to make sure they were getting their full day’s work out of the underlings. Morning, evening, check that clock. What did this buy them? A lab full of people who made sure to never set anything up that would take them one minute past Official Quitting Time, and who made the absolute most out of any sanctioned opportunity to not be in the lab with their boss. Not the outcome you want. The same goes, on a larger scale, for vacation days. Slip people a day here and there when they need it, and they’ll work when they’re there.

Keeping people informed isn’t that expensive either. I’ve worked in places where, once a compound went off to the clinic, it vanished off the edge of the earth as far as the people in the discovery labs could see. There was one time when a drug that had been years in development was canned, and chemists who had spent many of those years only heard about it by third-hand rumor. That’s just not right, and it sure didn’t improve anyone’s mood. Losing a drug from the clinic is never a happy occasion, for sure, but you don’t want to add to the pain. . .

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December 21, 2007

Winterize Your Ideas

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Posted by Derek

It’s time, across most of the drug industry, for people to prepare their labs for a few days off. Some companies officially close between Christmas and New Year’s. At the others, you’ll find about 20% occupancy, and those people will likely as not be taking advantage of the time to shovel stuff out of their offices. Not much drug discovery lab work gets done in the last week of December, I can tell you.

I’ve written before about how I used to leave my lab space in what I thought was good shape, only to come back after the break and find that I’d labeled flasks with helpful legends such as “Large Batch” or “2nd Run”. And every January, there I’d be, looking at some tan-colored stuff and thinking “Hmm. Second run of what, exactly?” I could usually work it out, but a couple of times over the years I’ve had to run NMR or mass spectra just to figure out what I was getting at.

So, make sure your stuff is labeled with something more intelligent, is my advice. And even more importantly, make notes to remember lines of research, and plans of what to do. It’s easy to lost the thread after being off for a while. This isn’t always bad – one of the good things about a break is that you lose the threads of a few things that are well lost. But it’s a good idea to write down what’s in progress, what you plan to do about it, and what you’re going to try to do next.

I’m convinced that a lot of good ideas get lost. They're not followed up on, they're forgotten, or they're buried under later duties. I've been trying to keep that from happening, which is one reason I was asking about literature and note-organizing software a while ago (more on that in January). One of my tasks today is making sure that all the current thoughts I have are battened down for the season. As usual, it'll probably turn out that some of the things I'm doing now would be well replaced by some of the things I've just been thinking about.

Comments (9) + TrackBacks (0) | Category: Life in the Drug Labs | Who Discovers and Why

December 19, 2007

Scrape Off Some Attitude

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Posted by Derek

There is a pecking order in chemistry. That’s because there’s one everywhere. If it’s a human endeavor, staffed by humans, you’re going to have hierarchies, real and perceived - who you did a post-doc with, what huge company you're a big wheel in. But that doesn’t mean that we have to bow down to them, and it doesn’t excuse this sort of thing, from The Chem Blog:

” Waaaaaayyy back at the ACS in San Fran at the poster session, we were walking around and introduced ourselves to this guy standing in front of his poster. Now… old boy (a graduate student) engaged us in some dialog about his poster and we were getting along famously, my friend asking most of the intelligent questions (I was still recovering from giving blood a few hours before and drinking multiple beers immediately after.) As conversations normally flow, he asked us where we were from. I told him my fine institution and my buddy told him his. I assume he wasn’t put off my by school, but the look on his face when my buddy told him where he was from was at first a “are you serious” chuckle, which melted into one of those “do they have a department” and finally to a resound(ing), “I’m done with you.”

I stood there and watched it the whole time. So, my buddy being naive to the ways of the world, kept asking questions but the answers weren’t forthcoming any more. In fact, in the midst of a question my buddy was asking, the guy actually walked away from his poster and started talking to his friends. . .”

Read the rest of the post for the rest of the story, which goes off in a different (and still interesting) direction. But as for this behavior, there’s just no call for it. As far as I’m concerned, if a person is asking intelligent questions, they’ve already provided all the credentials they need to show. Likewise, I reserve the right to discriminate against time-wasting bozos (just as I reserve the right to define that class, although I’ll bet that most of my picks would easily pass a show of hands). But if you’re presenting a poster, you have, whether you realize it or not, entered into an agreement to take on the broad unwashed masses.

Tactfully dealing with the clueless is a learned skill, but no such skill seems to have been called on here. This is tactfully dealing with the intelligent and informed, and if you can’t do that, you have some serious problems. It takes an awful lot of red-hot results to make up for a really obnoxious attitude, and a degree from Big Name U is only partially going to offset one as thick as this. Now, it's true that there are certainly some pretty abrasive folks from BNU, but the ones with the proven big-time track records can at least get away with it. Too many other morons take the shortcut, deciding that the nasty attitude is some sort of essential first step – in some cases, deciding that it and the Big Name is all they need.

Out here in the real world, where Poster Boy has yet to tread, it becomes clear that the wonderfulness of a marquee school background eventually goes stale. There are places in the drug industry where working for particular academic bosses will give you a leg up – for a while. It’s a real advantage to be able to get in the door that way, no doubt, but once you’re through the door you generally have to produce something. (And it’s good to keep in mind that even these advantages don’t necessarily last forever. A rollicking management purge can destabilize an old-boy network very quickly).

No, doing lots of work and doing it really well is a better long-term strategy. (Another part of that strategy is to make sure that people know who’s doing it, but that's a topic for another day). And having a personality that makes people grit their teeth and wait for you to leave is not such a good long-term plan. I wish Poster Boy well, but I hope that he has a lot to talk about. This isn't one of those businesses where you can get by on looks.

Comments (38) + TrackBacks (0) | Category: Academia (vs. Industry) | Graduate School | Life in the Drug Labs

December 13, 2007

Underperforming Triple Bonds

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Posted by Derek

I've written before about some elements and functional groups that don’t exist, but which I want anyway. Today I write in praise of triple bonds, and with the forlorn hope that they could do more. The thing about triple bonds is that they’re straight, the steel spacer bars of the chemist’s building set. Every type of bond has its characteristic angle, and for this one it’s 180 degrees. There’s nothing else like it.

Let’s take on the CN case first. I need something like a nitrile that’s not metabolically labile. There’s nothing like CN – it’s polarized because of the nitrogen, and the triple bond just sort of pokes that charge out there. No other functional group is an exact mimic. But the weakness of the triple bond is that it’s a bit precarious, energetically. Piling up those bonds buys you less and less stability as you go, so there’s quite a bit of energy to be sprung. (That’s why the simplest CC alkyne, acetylene, is such an energetic fuel). In the case of the nitrile, it can be torn up by the liver. Although it sometimes escapes, it’s always under suspicion.

And there’s another problem: its electron-withdrawing means that if you put it on an alkyl carbon it generally makes any hydrogens next to it too labile, so most of the ones you do see are on aromatic rings. And there’s another minor problem with the alkyl cases: if you put a CN anywhere that it can act as a leaving group, you run the risk of giving off the nitrile’s evil twin, negatively charged cyanide ion. Yep, a rock-solid, nonreactive nitrile group would be a big hit. Note to self: get cracking on that one.

While I’m at it, I want to tighten up those alkynes. C-C triple bonds show up sometimes in drugs, but they’re show up a lot more if we weren’t worried about them getting metabolized. You can get some interesting molecular shapes by putting in an alkyne, but the liver loves to oxidize them, especially if they're sitting out there on the end of the molecule. With one stroke of an enzyme it can turn a small, all-carbon terminal alkyne into a nice, soluble carboxylic acid that’ll probably send the whole structure sluicing right out the kidneys. The liver lives for that stuff, and it drives us medicinal chemists crazy.

If I’m going to be in triple-bond wishing mode, I might as well go all the way: I mean, C-C and C-N are basically the only stable triple bonds that we can use. How fair is that? The other possibilities (with oxygen, sulfur, and so on) are all charged up and reactive, and can hardly even be bottled up or even observed, much less dosed as a drug. (Well, there’s carbon monoxide, the simplest CO case, but although it appears to be a neurotransmitter, most weirdly, it has some problems as a drug candidate). A whole new world of new molecules would open up to us – new shapes, new polarity, stuff that no drug target has ever tried to deal with before – if it weren’t for the laws of physics. Note to self: tell someone else to get cracking on that.

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December 3, 2007

The Big and the Little

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Posted by Derek

I was talking about vacuum distillation and recrystallization the other day, and several people pointed out in the comments that large-scale chemistry still relies on these techniques. That’s absolutely right, especially recrystallization. It’s all a question of scale.

These two are bulk techniques – they work out fine on reasonable amounts, but they’re very difficult to run on a microscale with conventional techniques. Distilling a kilo of something is just about as much work as distilling ten grams of it – but distilling ten milligrams, now that’s something I wouldn’t want to be in charge of. Going the other way, distilling ten kilos starts to take you into a another different world, and one of the main reasons operates across the entire scale: surface to volume ratio.

In a distillation from a really large flask, you have to find efficient ways to heat the thing, because just sticking it into a really, really big heating mantle or oil bath gets to be problematic. The surface area of the flask is going up as a square, and that’s what you’re depending on to transfer to heat to the inner volume. But that volume’s going up as a cube. In a 100-mL flask, no part of the contents is more than two or three centimeters from the wall, whereas in a 100-liter system the commute from the edge has grown to something pretty substantial.

Your heating problem is also a mixing problem, since those technologies don’t scale smoothly, either. In a 100-mL flask you can drop a good-sized magnetic stir bar in and whip the solution around smartly with the spinning magnet of a regular stir plate. A proportional stir bar for a 100-liter flask would be a real brick, liable to crash right through the walls of the flask, and you’d need some sort of diesel-powered stirring plate to spin the thing. Needless to say, there are plenty of heating, mixing, jkl and distilling methods for the industrial scale – the existence of gas stations is a testimony to that – but they don’t look much like what people like me use to make twenty milligrams of a test compound.

So much for the big stuff, now take it down to the ten-mg scale. The area-to-volume problem is now reversed. You can’t buy a proportionally sized distillation head, because you’d need a deranged artist of a glassblower to make one. Your tiny volume of solution will just spread out and coat the insides of the smallest distillation rig available. You’re working far within the error and loss of a normal distillation, and your sample will disappear into this gap and never be seen again. I can imagine some sort of microscale rig made out of glass capillaries, although I’ve certainly never seen such a thing. (Surface tension would surely start to become an issue with its operation). Microfluidics is a hot research area, but as far as I know they’ve yet to move on to distillation. I hope someone gives it a shot.

Now consider chromatography. Ten milligrams is plenty of material to work with on an HPLC system. (And if you’re just interested in analysis, and not isolating preparative amounts at the end, ten milligrams becomes a mountainous heap). But running an HPLC on 100 grams is pretty much out of the question. Running even a normal column on that scale isn’t much fun, and when you head up to ten kilos it becomes a major undertaking that you’d do all kinds of things to avoid. (Like, say, spending a week or two trying out recrystallization conditions). The amount of solvent become really substantial, as does the expense and trouble of handling it. It’s not that chromatography doesn’t get done on large scale, it’s just that it gets done only after better alternatives have been completely ruled out.

Recrystallization goes up and down the scale a bit better than these other two techniques. It’s tricky to do on a small scale, but if you have a good solvent combination to form the right kind of crystals you can recrystallize a ten milligram sample if you absolutely have to. One problem with trying to use the technique on that scale is that it generally takes a lot of messing around with the conditions to get a good system, and if you only have ten mgs you probably can’t get away with that. I’d much rather run that sample down an HPLC, though, believe me.

Crystals are much more fun when you’re making a few grams, where you don’t have to worry about every single bit stuck to the sides of the glassware. And the folks working on larger scale just love recrystallization more than anything. It’s true that you have to heat things up at the start, but the heating doesn’t have to be done as critically as in an actual reaction, since you’re generally just trying to get things to dissolve. And once everything has cooled back down and the new crystals have fallen out of solution, it’s just a filtration and wash, and that’s something that can be done well even on a gigantic scale.

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November 26, 2007

Still and All

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Posted by Derek

I did something today that I haven’t done in several years: a vacuum distillation. That used to be a larger part of every chemist’s life, but advances in chromatography have eaten into a lot of the older techniques for purifying compounds. Recrystallization is another obvious example of a lost art, one that I’ve steadily heard characterized as such for the last twenty years. Well back before my time, people purified their liquids through distillation and their solids by recrystallizing them, and that was that.

Both of those can still be the best way to go, depending on your compounds. When you come across these methods in the older literature, you always have to ask yourself if you should stick with them, or if a chromatography would do the job more easily. Today, though, it was a modern procedure I was following, so distillation it was.

still%20head.jpgFor the non-chemists in the audience, here's how you do it. You rig a glass apparatus onto the top of your round-bottom flask of gunk - there's one at the left. This "still head" has a short neck coming up, a bend that accommodates a thermometer, then a cold-water circulating condenser built in right before a tube to deliver the drops of distilled product. Along that region there's another fitting to hook the vacuum pump up.

Pulling a vacuum on the system lowers the boiling point of the liquids inside it - one of the reasons you have to adjust recipes at high altitude, actually. (If you lower the pressure enough, you can get water to boil at room temperature). Without that lowering, many compounds would have to be heated up so much to distill them that they'd start to decompose. Heating things to that point isn't much fun, in any case. Far better to pump things down and take them over at a more reasonable temperature.

The usual technique is to pump things down first, just to get any bumping and bubbling out of the way as leftover low-boiling solvents and dissolved gases clear out. Then you gradually increase the temperature on the distillation pot until things start to boil. You can see the condensation form on the inside of the still head as things get going, then drops start to condense and drip off the end of the thermometer back into the pot. A bit more heating and things make it over to the condenser, roll down the collection tube, and into the receiver flask.

cow.jpg
Of course, you may have more than one thing in that pot. The stuff that's boiling out will eventually all come over, and as you heat things up some more the next higher-boiling component will then start to boil and the process repeats. That's why they make adapters that can fit several receiver flasks - these things will turn to accomodate different fractions, one after the other. The common lab name for these is a "cow" (Germans call them "spiders").

When you're finished, you generally have one or more flasks full of clear liquid on the far end of things, and the distillation pot generally looks just awful. All the high-boiling impurities have concentrated, and the resulting mix has been thoroughly cooked. It's a dramatic illustration of what you've accomplished - dark brown sludge separated out from pure product. Distillation makes you feel as if you've earned your lunch break.

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November 25, 2007

You Do The Easy Stuff; I'll Do the Easier

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Posted by Derek

A reader from inside the industry writes:

How is 'what's made' influenced by the synthetic knowledge of the individual med chemist? I would guess that with all the pressure on targets that you've written about, there must be some level of sub-conscious selection based on ease of synthesis, so the difficult structures either never get made or get made later. . .(but) difficulty is a subjective term. The better the chemist the more molecules fall into the easy category. . .

. . .One thing I've noticed is the explosion in bi-aryls since the Suzuki and related chemistry came along. Is this due to a sudden realsiation that bi-aryls could be good molecules or is it due to the fact that Suzuki chemistry is easy?

I've wondered about this one myself, as have many other chemists I've known. It's true that as synthetic chemists we tend to go for the low-hanging fruit; I don't think that anyone could deny it. And that's largely due to pressure to produce results, although I wouldn't rule out laziness, either (never rule out laziness).

But you can often get pretty interesting things to happen by doing simple reactions and small changes. Think about the number of times you've seen activities totally altered by one methyl group, or the metabolic problems that have been fixed by adding a para-fluoro. We don't feel as much need to move into new territory as we might.

As for variation between individual chemists, that's why you want to hire a set of people with diverse backgrounds. (And no, I don't mean HR-style diversity, I mean chemical and scientific diversity). The literature is big enough and varied enough so that people can have a lot of experience and still not overlap with their colleagues much in their favorite reactions and structures. People will still go for the easy stuff, but with any luck there will be enough different definitions of "easy stuff" to keep people from piling up too much.

But I think that this factor isn't quite as big as it used to be, what with the advent of modern literature searching. People can pull out all sorts of reactions from the literature and give 'em a try - it's hard to remember that it used to be quite a bit harder to do that. So what do my industrial readers think - do we just make the easy stuff? If we do, is that a problem? How much is "easy" a function of who's doing the chemistry? And has that changed over time?

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November 15, 2007

Maybe Not Improved, But Definitely New

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Posted by Derek

My lab and I have plans to start experimenting with several compound classes that we’ve never handled before. In fact, for some of these, no one’s handled them before. Some of these are not only novel as in patentable, for which fairly small changes can suffice, but novel as in what-the-heck-is-that. I couldn’t be happier.

Honestly, I have no idea of what I’d do with a job where I knew what was going to happen next. Years of science have ruined me for a lot of other occupations. I was putting some of these up on the board the other day, and mentioning what I’d like to try. “Do you know if you can do that?” someone asked, and I answered that no, I didn’t, and as far as I could tell, no one else did, either. I can draw out a bunch of reasonable-looking reactions, but the structures themselves may well have other ideas.

The first time I realized that I was in new territory, although to a much lesser degree, was back in my first year of graduate school. My first few reactions generated things that were already known in the group, naturally, and then I made some model systems that were already known in the literature. But pretty soon I remember making a compound that I realized just flat-out wasn’t in Chemical Abstracts, because no one had ever had the need to make it before. (As far as I know, no one’s had any need to make the stuff again, either – if someone has, I hope they got more use out of it than I did!) But there it was, in a flask: something that had never existed before.

My list of such compounds is now rather lengthy. In the drug industry, naturally, we spend just about all our time making compounds that haven’t existed before. (If they’ve been exemplified somewhere, you can forget about a patent on the chemical matter itself). Our livelihoods depend on cranking out thousands upon thousands of compounds that no one else has made. I haven’t seen the figures, but I’d guess that a large fraction of the new small organic molecules that get registered every year in Chemical Abstracts are from pharma. Those patents with the three-hundred-page experimental sections do start to add up.

This latest stuff, though, goes a few steps beyond that, to whole compound classes that no one’s touched yet. I may well find that there’s a whole set of very solid reasons why these things haven’t appeared in the literature – perhaps these reasonable reactions of mine have been tried in recent years, but found only to produce more of that gooey dark stuff in the bottom of the flask. We shall see. I’ve certainly made my share of that material.

But I doubt that all of them are in that category. So with any luck, soon I’ll be making something no one’s ever made, and finding things out about it that no one’s ever discovered. And as I said, I couldn’t be happier about that.

Comments (9) + TrackBacks (0) | Category: Life in the Drug Labs | Who Discovers and Why

November 14, 2007

How You Doin'? How's Everybody Doin'?

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Posted by Derek

At many companies, this is performance review season. As I’ve written about before, this is a particularly hard thing to do right in a research organization. It’s so hard, actually, that never once have I heard of one where the scientists were satisfied with how people were being rated. I think it’s probably impossible for any organization, if you want to know the truth. It’s like trying to design a perfect voting system. No matter what happens, some people are going to feel, perhaps even with justification, as if they’ve been had.

But evaluating scientists is especially thankless. If you have a lot of really good ones, it’s a little like filling out yearly reports on poets. Hmmm. . . Mr. Larkin. I see you haven’t published anything so far this year, and still no collection since The Whitsun Weddings. . .wasn’t that on your goals statement for this period? I don’t really see how we can give you an “exceeds” rating given all that. And Mr. Lowell, it’s true that you produced a great number of sonnets during this review period, but I can’t help but believe that these were less of an effort than some of the work you’ve done for us before, and they certainly had less of an impact on our operations. No, I think that “meets expectations” is probably the correct category this year. . .And as for you, Mr. Housman, we need to ask ourselves just how long it has been since A Shropshire Lad. . .

Rating research productivity sends you into the same thickets. If someone hammered out a long list of analogs, but used pretty much the same chemistry to make each of them, how do you rate that compared to someone who had to hand-forge everything (and produced a correspondingly smaller pile)? How much should number of compounds count for, anyway – how about impact? What if the big bunch of compounds didn’t do much for the project, but one of the tough ones opened up a whole new area? (Or what if it was the reverse?) But isn’t that partly luck – what if the one that hit was totally unexpected, even by the person who made it? What if it became a great compound for reasons totally out of their hands?

And then you get to the people who aren’t necessarily cranking out analogs, the lab heads and such. They’re supposed to be leading projects, managing direct reports, coming up with ideas. How’d they do? How can you tell? Can you reliably distinguish a project that got lucky, or had a better starting point, from a well-managed one that has nonetheless been wandering around in the wilderness? Put your best people on, say, a protein-DNA interaction target, and pretty soon they won’t look so good, either.

No, even with the best rating system in the world, it would be hard to fill out the reports on drug discovery projects. And you can take it as given that no one is using the best rating system in the world. (Some may in fact be experimenting with the worst). The yearly frequency of ratings is one problem – anything tied to the calendar is a potential problem, since the compounds, the cells, and the rats never know what month it is. This has been a problem for a long, long time. I once quoted from Rayleigh’s biography of physicist J. J. Thomson. You wouldn’t want to run a whole department on the following system, but you don’t want to ignore the man’s point, either:

"If you pay a man a salary for doing research, he and you will want to have something to point to at the end of the year to show that the money has not been wasted. In promising work of the highest class, however, results do not come in this regular fashion., in fact years may pass without any tangible results being obtained, and the position of the paid worker would be very embarrassing and he would naturally take to work on a lower, or at any rate, different plane where he could be sure of getting year by year tangible results which would justify his salary. The position is this: you want this kind of research, but if you pay a man to do it, it will drive him to research of a different kind. The only thing to do is to pay him for doing something else and give him enough leisure to do research for the love of it."

And the insistence of many HR departments that the ratings fall on a normal distribution is another problem. Sure, if you hired a few thousand random people and turned them loose on the work, you could expect some sort of bell curve, assuming that you’ve solved that problem of fairly evaluating them. But you didn’t hire your people at random, did you? Everyone’s supposed to be at some level of competence right from the start. Some of those performance distribution curves are reflecting the randomness of research or the defects in rating it, rather than any underlying truths about performance.

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November 12, 2007

Here Be Chiral Dragons, With Fluorinated Fangs

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Posted by Derek

There’s a saying that you see attributed to all sorts of old humorists, which goes something like “It’s not the things you don’t know that get you, it’s the things you know that just aren’t so”. (I always put it down to Kin Hubbard, but the best case can probably be made for Josh Billings). What you can’t argue about is the truth of the thing, and that truth gets demonstrated at all phases of a drug discovery project.

You see it all the time in the med-chem labs, that’s for sure. After a project has been going a while, a lot of people have had a crack at the SAR, and have made a lot of different compounds. Everyone has put their own facorite groups on, and things have been tried out on all the reasonably accessible parts of the structure. That’s when the myth-making starts – I’ve never been on a project where it didn’t.

“Trifluoromethyl in the 4-position’s a killer – I wouldn’t put anything electron-withdrawing there if I were you”. “You need the R stereochemistry at the benzylic site; those always work better than the S”. “Somebody tried to make the meta-substituted compound – it never worked.” “All the methyl compounds get cleared faster than the fluoros”. This sort of things will sound very familiar indeed to my drug-discovery readers. Anyone who joins a project that’s been going for a few months or more will get all the folk wisdom of this sort that they can stand.

But how much of it is real? In my experience, about half, and sometimes less. Many of these rules of thumb are born from only one or two examples, often as not from the earlier days of the project when other parts of the structure were different. It’s a rare project where you can mix and match with impunity, which means that these rules often outlive their validity. You really have to go back and check up on these things. And sometimes, disturbingly, there’s no foundation at all. This is a real danger in a long-running project with a lot of manpower changes and a long list of compounds. Once in a while you see everyone convinced of something that has no empirical support at all – it’s just something that “everyone knows”. Making compounds to put such superstitions to the test should be actively encouraged.

But depending on the culture of your company, or just your project team, that’s not always easy. Some project leaders ask for (or at least tolerate) a certain percentage of let’s-find-out compounds, which I think is healthy. But in other shops you have to brave well-meant ridicule or outright hostility when you send in analogs that challenge the accepted wisdom. As usual, it’s a question of the odds. If you make nothing but contrarian compounds, you’ll have a lower hit rate than the folks who are following up on the current leads. But if all you do is follow up on the current leads, never looking back or to either side, you’ll miss out on a lot of potentially useful things. Moderation in all things, the man said.

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October 25, 2007

Looking Backwards

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Posted by Derek

A colleague reminded me the other day of a project that he and I had worked on back at the Wonder Drug Factory seven years ago. "Seven years ago", I thought. . .I was the project leader on that one, trying to keep things alive as weird toxicology kept torpedoing everything. In the end, we held it together long enough to get four compounds into two-week tox testing, whereupon every one of them wiped out for yet another set of ugly reasons. Ah, yes. No one's going to have to work on that stuff again, that's for sure.

Hmm, I thought. What was I doing seven years before that? Well, I was back at my first drug industry job in New Jersey. The company had just moved into a new building the year before, and the old site was on its way to becoming a Home Depot. I was spending my days cranking out molecules hand over fist. Boy, did I run a lot of reductive aminations. It's safe to say that during those years I ran the majority of all the reductive aminations that I'll ever run in my life, unless something rather unforeseen crops up. We made thousands of compounds on that project, and I remember pointing out in a talk that nobody makes that many compounds if they really understand what they're doing. This was not a popular line of reasoning, but it's hard to refute, unless saying how much you don't like something counts as a refutation.

And seven years before that? Still in the lab. I was midway through grad school, wrestling with the middle of what turned into twenty-seven linear steps by the time I pulled the plug. (At this point, I began to reflect that I've been doing chemistry for quite some time now). In 1986 I didn't know that I wasn't going to end up finishing the molecule, and I was still hauling buckets of intermediates up the mountainside, only to find them alwyas mysteriously lighter and smaller by the time I got to the top. My response, naturally enough, was to start with larger buckets - what else was there to do?

And seven years before that? That finally takes me over the chemistry horizon, back to my senior year of high school in Arkansas, and to what might as well be a different planet entirely. Although I was interested in chemistry - as I was in most all the sciences, something I've never lost - I'd never heard of a Grignard reagent, and I didn't know what a nucleophile was. Counting up, I see that some time next year will mark the point at which I will have spent a slim majority of my lifetime doing organic chemistry, which is an odd thought. And it makes me wonder what I'll be up to seven years from now. . .

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October 4, 2007

No Problem At All

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Posted by Derek

I was listening to a seminar speaker today, who as an aside mentioned forming an ester as “about the easiest reaction that you can do”. He had a point. If you have a free carboxylic acid, combining it with an alcohol and some acid will generally give you some amount of the ester, and most of the time it’s a high-yielding reaction. But there are problems if the acid is next to a chiral center, or if there are other functional groups that don’t like being cooked with acid catalyst. So while this one is easy, I’m not ready to give it the title. (The speaker had had trouble with it himself).

But if it’s not the winner, what is? Displacement of a leaving group with a powerful nucleophile (fluoride, azide, cyanide) is usually pretty foolproof, but we’ve all dealt with structures that are too hindered to do it well (or decide to eliminate and form an alkene instead when forced). Reduction of an aldehyde to an alcohol is also hard to mess us – good old sodium borohydride – but chiral centers next to aldehydes are untrustworthy in the extreme. You may get your alcohol, only to find that the dying aldehyde left you a scrambled stereocenter in its will.

How about forming an oxime from the aldehyde instead? I haven’t had to do that nearly as much as the other reactions mentioned, but every time it seemed like (as an old labmate of mine put it) “a reaction that my grandmother could do”. And if you want to cheat a bit, and start from a really reactive system, then it’s hard to beat formation of an amide from an acid chloride, which is why you see so many amides. But my pick for a reaction that can’t fail is another one from the leg-up category: the formation of a urea from an isocyanate. It has to be an awfully hindered or non-nucleophilic amine for that not to work, or a really weird isocyanate. Anyone have an easier reaction than that?

The problem with talking about these things, though, is that when they fail you, you feel like a complete dodo. I once had a primary alcohol that I just could not put a TBDMS protecting group on, and I still remember the looks of pity in the eyes of my co-workers when I would complain about it. When something like that turns on you, you find yourself wondering if maybe you should have gone to truck-driving school instead, like Mom always wanted.

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September 20, 2007

Go With The Er, Flow?

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Posted by Derek

When I was talking about Steve Ley of Cambridge the other week, one of his research areas that I mentioned liking was his work on flow chemistry. This is the benchtop application of a type of reaction that’s been done more often on large industrial scales.

Most of the work that medicinal chemists like me do is batch by batch. We weigh and syringe things into flasks, cool, heat, and stir them, and then pour the resulting stuff out of the flask and clean it up. There are all sorts of techniques that have come along to speed these steps up or to allow you to do more of them simultaneously, but all of them are still in “batch mode”.

Flow chemistry is a bit different. The starting materials flow through an apparatus that (one way or another) causes them to react, and then out the other side. The business section of the machine can be a part that heats up the solutions as they go by, or puts them under high pressure, or forces them over a solid support that contains some catalyst. That last category is especially useful, since the number of metal-catalyzed reactions is increasing with no end in sight.

If the reaction isn’t done, you can send the mixture back through for another pass. If the reaction’s complete, you can (ideally) take the resulting solution on to the next step without necessarily having to clean it up – after all, the catalyst is staying behind on the solid support. If you treat it right, the catalyst should be reusable for quite a while as well.

One of the more widely adopted flow reactors so far has been the “H-cube”. Its makers chose a reaction (hydrogenation) which is very useful, but one that a lot of chemists don’t like to run. The opportunity to easily try out catalysts and conditions that aren’t normally run has been another selling point. Now the company has come out with their X-cube, which is a more general flow reactor.

My question is: has anyone out there used this beast or its competition? I’ve had a little (generally positive) experience with the H-Cube, but none with any other flow reactor. There are a lot of homebrew setups out there, but the commercial space has been filling up recently, too.

Of course, as everyone knows, neat-looking equipment can end up gathering dust. For these flow gizmos to be useful, they’ll have to do things that aren’t easy to do in a flask, and do the flask reactions in a more convenient manner. The flow reactor people aren’t competing with each other as much as they’re competing with a drawer full of round-bottom flasks. I’d be interested to hear from anyone who’s put that comparison to a real-world test. . .

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September 13, 2007

Don't Step Over It, Even If It's Right in Front of You

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Posted by Derek

There are many mistakes you can make in medicinal chemistry. Hah, I got that sentence typed out with a straight face; I wasn’t sure if I could do it or not. Mistakes! We’re up to our clavicles in them. Successful R&D is the triumph of those who manage to bungle things the least, and that doesn’t go just for the drug industry. Talk to engineers, talk to software developers. You’ll get the same perspective, accompanied by much eye-rolling and waving of arms.

And getting used to this, as I’ve noted here and there, is a psychological adjustment that a working scientist has to make. Setting your standards to a no-false-starts no-blind-alleys standard guarantees your failure, or at least ensures that you’ll be driven out of the field before have time for any success. Every working chemist knows what it’s like to put a slide of reactions together for a presentation, only to realize that they’ve just summed up months of effort in what could (theoretically, ideally) have been a few day’s work.

In med-chem, I can think of many examples where I’ve worked on a project only to recommend a compound at the end that was embarrassingly close to the starting point. Twice in a row we ended up with a compound that had one methyl group added to it compared to one of the starting compounds – mind you, those methyl groups really pulled their weight. They made a big difference in the final properties of the molecule, but we’d spent a lot of time exploring bigger changes and other regions of the molecule, none of which worked out well.

Philip Larkin, a favorite poet of mine, said that he learned from Thomas Hardy's work not to be afraid of the obvious. Like a lot of good advice, though, that’s hard to take. Researchers with an optimistic bent will wander off to new parts of the lead molecule, looking for the greener grass that they’re sure is out there. And the pessimistic ones won’t do the stuff right in front of them, either, for fear of how it’ll look. Sometimes the simple stuff gets overlooked, for no other reason that it's simple. Should that count against it?

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September 11, 2007

Fresh Air, Or What Passes For It

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Posted by Derek

For my scientifically employed readers, here’s something my labs don’t have, and I'll bet yours don't either: windows that open. I’ve only been in a couple of chemistry labs that did.

My undergraduate chemistry building (since renovated) had had its windows concreted over in the 1960s. That was bearable most of the time, but the summer I did undergraduate work there, the air conditioned kacked out on us a few times. This was troublesome. You don’t want to be on the fourth floor of a building with no windows in Arkansas in the summertime. Ether in that era was still sold in the round metal cans with the soft alloy caps that you sliced off, and then put a plastic snap-cap over. I remember the poonk-poonk sound of those ether caps blowing off as the temperature rose, which we took as a good substitute for a quitting-time whistle.

My graduate work was windowless as well. It was done in a building where all the lab space was on the inside, so you had to leave the bench and head down the hallway if you wanted to find one of the narrow little window slits at all. It was easy to lose track of time in there, which was probably a design feature (just as in a casino’s gambling floor).

But when I went to Germany to do my post-doc, I had several adjustments to make, among them a lab whose windows not only opened, but needed to be. Like many German buildings, this one wasn’t air-conditioned, so in the summertime you needed to get a breeze going. It was a real novelty to see the wind ruffling the pages of my lab notebook, that’s for sure. I always wondered about how this affected the air balance of the fume hoods, but since they didn’t work that well to start with, it may not have been a concern.

And since then, I’ve yet to see an industrial lab with operable windows, other than my very first one. And even those were almost never used. For one thing, the building had air conditioning, since New Jersey is definitely more tropical than Central Europe. But another reason was that our lab faced directly out onto a major highway, so the only thing you’d get by opening the windows would be exhaust fumes, traffic noise, and (in the summertime) the occasional curse and honk of a horn. I did see my labmate make use of his window at one point, though, after he’d spilled some ethanethiol on his shirt. He tried hanging it out the window to air out. This was unsuccessful, of course, but it says a lot about ethanethiol that it makes you consider hanging your laundry out over the Garden State Parkway to freshen it up.

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September 6, 2007

Aromatherapy

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Posted by Derek

I was talking about reactive compounds the other day, but I should note that some of the reactive ones can still linger around in a peculiar manner. Acid chlorides are a good example, from both carboxylic and sulfonic acids. They’re reactive, all right – just pitch one into a bunch of amine and find out. So you’d think that if you spilled some, that their admittedly nasty aromas would be a problem that solves itself, right? They won’t last long outside the bottle; they’ll react with water and such in the air and stop stinking the place up – right?

Wrong. Some of these guys can hang around for abominable lengths of time if you don’t actively clean them up. The problem is, I think, that while they do react with water, it’s only a fast reaction under stirring conditions. In the bulk phase, the liquid acid chlorides tend to be rather thick and oily. My guess is that the outer layer does react with water (at its own pace), but that diffusion is slowly bringing more unchanged acid chloride to the surface. Where it reeks.

The sulfonyl chlorides tend to be solids, which makes the problem that much worse. The crystals don’t do the stainless-steel thing and form a reacted skin around them that seals up the inside. No, for all I can tell, tosyl chloride (the prototype sulfonyl chloride, found in organic labs around the world) will stink indefinitely. I’ve no idea of what its nose-wrinkling, headache-inducing half-life is, just that it’s very long indeed.

At least its hydrolysis product, toluenesulfonic acid, doesn’t smell. It won’t improve whatever its standing on, true, but at least you won’t know it’s there from across the room. But those oily liquid carboxylic acid chlorides stink horribly as their free acids, too, so over time, if you’re so inclined, you can note the changeover from the musty, acrid smell of the chloride to the rancid, goaty stench of the parent acid. The midpoint of the process is a treat.

So, you lazy chemists, break down and clean the stuff up. It’s not going to get any better unless you put some energy into the system (in the form of hands, elbows, and paper towels). All of our problems should clean up so well.

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August 31, 2007

Here It Goes

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Posted by Derek

Stability is a relative concept in chemistry. In the lab, we tend to use the term a bit loosely, and we mix up with “reactivity”. But those are two axes of an x-y graph, and there are chemicals in all four quadrants. Stable and non-reactive? Sure, for whatever value of “non-reactive” you choose. Stable and reactive: how about acid chlorides? You can keep many of them happily for years away from water, amines, etc., but open the flask and they’ll be ready to party. Unstable and non-reactive? An odd category, but I’d say that something like a polyazide or polynitro compound would fit. It doesn’t do much with other chemicals; it just falls apart on its own, and how. And unstable and reactive? Oh, yeah, we have those, all right.

In the lab, there’s a large middle ground of things that sort of gradually deteriorate on you, but not so quickly as to be a nuisance. Solutions that used to be clear pick up a yellowish cast, crystals get cloudy. This is the sort of stability that people are used to seeing with newsprint paper and household chemicals like bleach – they’re good for a while, but you can’t expect them to hang around forever. In research, you deal with this by either buying new stuff (the industrial way!) or re-purifying the old bottle by distilling or recrystallizing it (the academic way, by necessity).

After these compounds, though, you come to the ones that can give you trouble. There are a lot of compounds that are only stable on a time scale of days, hours, or minutes, and you’ve got to keep an eye on these guys. Often the rate of decomposition is very dependent on how pure the stuff was at the beginning. Trace amounts of water, oxygen, or other such rare substances can start one of these down the slope.

The dangerous ones are the compounds whose decay begets their own decay. These will run away on you, and if there’s enough compound in the flask where heat transfer is a problem, the process can turn violent. At this point, we’re shading over from “troublesome decomposition” to “explosive hazard”. Things like this are best kept as cold as possible, and in dilute solution. Concentrating them or warming them is a deliberately provocative act for which payment will be due.

Even without explosions, this sort of thing can be alarming. I’ve heard of intermediates that were so lively that initial clearish substances in a round bottom flask turned brown and began to fume as the person walked down the hall holding the stuff. Generally, that only happens once, the first time you make one of these beasts. After that, you take appropriate precautions (like having the next reaction step set up right next to this one, ready to go). Or, of course, you just decide that you can live without that one, and never make the darn stuff again.

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August 12, 2007

These You Shall Have Always With You

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Posted by Derek

1. A testy e-mail from the one of the analytical chemists, saying that the open-access walk-up LC/MS machine was clogged - again - and reminding everyone, in a tone both exasperated and resigned, that the machine is not there for everyone just to come and inject their dark orange cloudy stuff into.

2. Lab bench drawers that have accumulated a low-energy high-entropy slough of weird-sized adapters, unusable syringes, metal fittings to machines that aren't even being used any more, and strangely shaped plastic pieces that look as if they must be the vital inner workings of something - but what?

3. A testy note on the common fridge, stating that anything that's left in there by Friday at 3 PM is going to be thrown out, and reminding the reader that this means you. The note is written in faded black Sharpie marker, and the edges of the paper are frayed.

4. A radio, off in the distance in some other lab, playing AC/DC's "Back in Black". What lab radios played before this was recorded, I'm not sure.

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August 1, 2007

Run! Anthropologists!

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Posted by Derek

You know that I’m on a long airline flight when I start blogging about something I’ve read in an in-flight magazine. I’m somewhere over the Great Plains as I write this, and American Airlines is telling me that drug companies need anthropologists to help them manage their scientists.

If they’d left it at that, I probably would have nodded my head. If you can do field work with savage Amazon tribes, you could probably feel right at home observing some lab corridors I've worked in. But no, since this was (like most airline magazine pieces) geared to the needs of middle managers, we get a brief case history:

A new CEO at Pfizer Pharmaceutical (sic, and boy, that narrows it down, doesn’t it?) wanted company scientists to operate differently, but they balked. Anthropologist Marsha Shenk asked them what they’d define as a more effective operation. The scientists realized that ever since they were grad students, they’d been in business to keep their projects funded for as long as possible – because in science, funding is a status symbol. But in business, it’s more efficient to kill projects that don’t show potential for big financial payoffs. About-face! They moved from judging themselves by how long they could string a project along to how quickly they could quash it.

Well, all right, then! We should be seeing some results from that innovative Pfizer approach real soon now, don’t you think? Honestly, though, this passage makes me want to bury my head in my hands. Where to begin?

Let’s see. . .how about we start by pointing out that grad students generally don’t worry much about keeping their projects funded, once the grant application is approved, which is mostly the boss's problem. Grants are written for entire programs of research, and a large graduate group will have several going on simultaneously. The folks working on one project aren’t competing with the ones working on a different one, since they’re funded through different means.

Now let’s try that “funding is a status symbol” line out. I can see how this was an anthropologist’s work, but we’re not talking about feather headdresses (or fancy cars). Funding is indeed a status symbol for professors, but for their students? Their status tracks with the name of their professor, the department they’re in, the perceived hotness of the project they’re working on, and so on. And what does this have to do with industrial drug discovery? Most lab heads and bench scientists don’t spend much time on budgets for individual projects. The money’s there. The company knows about how many programs it can run, with a reasonable number of people on each one. You're working on one of them, or another one of them, and when you're through you'll work on yet another.

Now, I’m not saying that there’s no competition to keep your program alive. That’s the main way that this whole anthropological excursion makes sense. But project leaders want to keep their teams going because they want to deliver, not just for the sheer sake of keeping things going. (You come across people once in a while who have their priorities confused on this, but that tends to get straightened out after it gets noticed by higher management). There's always a case to keep going. Hope does little more than spring eternal, and I’ve never seen a drug discovery program that didn’t think it could solve its problems if it just had a little more time. That’s the thing that spins projects out – they all have problems, and they’re all trying to solve them.

Ah, now we get to the "big financial payoff" part. So, it’s more efficient to kill the losers off, is it? Who knew? You’d think that companies would think about the financial prospects for a drug before they even started a project. . .and you know, here outside the pages of in-flight magazines, that’s just what they do. The projects that don’t look like they could pay off don’t get started in the first place, so you’re left with a bunch of projects, all of which could be profitable if they’d just work. Now perhaps a team of anthropologists can come in and tell us which ones will.

And as quickly quashing . .well, just as there's always a reason to keep going, there are always plenty of reasons to stop. Every single major drug I've ever heard of has been near death more than once. If you make killing things your priority in drug discovery, you risk killing off everything. Remember, the overwhelming majority of drug projects die at one point or another as it is.

But we’re supposed to think that this strategy hit the Pfizer scientists like a hot sizzling bolt of truth. They fell to their knees, confessed their project management sins, and resolved to lead new lives. Anyone at Pfizer want to bear witness for us unenlightened types?

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July 22, 2007

A Farewell to Tin

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Posted by Derek

I was browsing through the posts at Totally Synthetic, which is now my substitute for looking at total synthesis papers in the primary literature, and came across this question:

"However, this brings me to a point of consideration - why are Stille coupling (reactions) more common in academic publications, and Suzuki more so in an industrial/commercial context?"

(For the non-chemists in the audience, these two reactions are ways to skin what is basically the same cat - forming carbon-carbon bonds on a particular class of starting materials). And this is one of those questions with a one-word answer, and in this case you can pick your word. Either "tin" or "toxic" would work just fine. The Suzuki uses boronic acids or esters, which are generally water-soluble and nonpoisonous. The Stille reaction, although it has a reputation for working on small scale in finicky, highly functionalized molecules, uses organotin compounds. These are highly nasty, and very difficult to completely remove from your final compound. If your final compound is going to be something that people are going to put in their mouths, which is our dearest hope in the drug labs, you're just not going to use tin.

And I don't mean that you'll tend to avoid it, or only use it when other things don't work as well. You just won't touch it. I'm not aware of a single pharmaceutical process which uses an organotin reagent, and I'm not holding my breath for one to appear, either. There are a lot of other reagents in this category: things that you basically have to edit out of your repetoire.

Obvious farewells are made to things like nickel carbonyl, which a lot of people in academia don't want to use, either. But in drug research, a lot of people decide to ditch their old grad-school favorites like HMPA, a solvent that can make some reactions work when little else can. But if your compound can only be made using HMPA, is it going to be a drug? Highly, highly unlikely.

Naturally, one way around this difficulty is to assume that the process chemists are going to fix this little problem later on if your compound goes ahead. But your compound isn't going to go ahead, chief. Something nearly as good as your candidate has surely been made in the course of the project, something that doesn't use HMPA. It'll win. You're honestly better off trying something else in the first place and not wasting your time. And the same, exactly the same, goes for the Stille reaction. Enjoy it in the universities, folks. If you go on to industry, you won't be seeing it again.

Update: Check the comments - there are some well-informed disagreements!

Comments (9) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs

July 18, 2007

Over There, Behind That Stack of Whatchamacallits

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Posted by Derek

Laboratories are not immune to a problem that affects many a kitchen. Surveying the counters and the cabinets, ones eye falls on a space-filling gizmo that hasn't been used in months, and the thought comes up before it can be repressed: "I wish I hadn't bought that thing".

As scientists, we don't have late-night infomercials to blame: the fault is not in our cable packages, but in ourselves. A likely way for white elephant equipment to get in the door is by the efforts of someone who used it somewhere else and just loved it. They agitate for it, they get the authorization to buy it, they order it. . .and, likely as not, only they ever use the thing. No one else likes/feels the need/can be bothered to learn how to use it. The advocate eventually moves on, but their hardware, perforce, stays behind.

These things migrate to unused fume hoods, should any exist, or to bench areas so inconveniently located that no one ever occupies them. This natually helps to ensure that no one uses the apparatus again, since it's now so far off the jungle paths. Should anyone try, they often find that vital pieces and accessories have been shed along the way, along with chunks of the documentation.

Biology labs are particularly laden with these things, in my experience. In chemistry, the combichem craze of the 1990s left a lot of stuff washed up on the beach, as did the proliferation of (semi)automated reaction stations and multiple-simultaneous-reaction gizmos. But none of these items are useless - it's just that some of them aren't quite useful enough for the space they take. By the time some of them get thrown out, you can tell how old they are just by the color of their plastic housings and the fonts used for their brand names.

Comments (27) + TrackBacks (0) | Category: Life in the Drug Labs

July 8, 2007

Starting Up Again

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Posted by Derek

I'm back! This entry comes from temporary quarters in Cambridge, which will be my home for about another six weeks. The second half of that period will find the rest of my family in here with me, but for now it's just me, an internet connection, and some take-out souvlaki.

Going to work tomorrow will be a novel experience, after a solid five-month break. But this isn't the first time I've changed jobs, and like everyone else in the industry, I've seen a lot of turnover around me. Both vantage points have suggested some avoidable mistakes when starting a new position.

First off is badmouthing your old company. It's tempting - I mean, after all, you left the place for a reason, right? And isn't the new place so much better, and shouldn't you make everyone happy by telling them so? Actually, no, you probably shouldn't. There's a real risk of coming across as someone who does nothing but moan, and most labs have enough of those folks around already. Keep in mind that you just started, and that people haven't heard you talk much. You don't want your co-workers to realize that half the things you've said so far are complaints. Hold your fire.

You can screw up in the opposite direction, too, of course. (You always can, a general principle I try never to forget). Talking about how things were so much better back at the old gig won't win you any friends either, obviously. Sure, maybe it was easier to order supplies, or get instrument time, or whatever. But no one cares, and you shouldn't either.

This it-was-better stuff turns, very quickly, into another method of complaining, and we're back to the same place as with the first mistake. My view is that grousing about work conditions is something that should be done only among peers that you've worked with for a good while, people who know you and have seen that you can get the job done. At a new job, you don't have anyone in that category yet, so it's better to keep quiet. And anyway, how silly does it look to start in on how things are done when you haven't done anything yet?

Other mistakes: coming on as if you're the answer to everyone's prayers (because that, of course, makes the inference that everyone was doing it wrong until you showed up - if you really are the answer to said prayers, that'll become apparent on its own pretty soon, wouldn't you think)? And its opposite - starting off so quietly that people start to wonder why you were hired in the first place. It's normal (and a good idea) to shut up and listen for a while at first, but that can be taken too far. Eventually, you'll need to speak up.

Well, I won't be making these particular mistakes, I hope, but that just reserves me the right to make some others. At any rate, it's good to get back to research, and no mistake about that.

Comments (13) + TrackBacks (0) | Category: How To Get a Pharma Job | Life in the Drug Labs

May 16, 2007

Sunbeams, Single Electrons, and You

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Posted by Derek

A comment on the most recent post got me thinking about photochemistry. I've done that, but just for one project, and I'll bet that many other chemists have had the same pattern.

A lot of people who've never done light-powered chemistry find the idea neat - no nasty reagents, no masses of inorganic salts to remove, just shine a light on the flask and you're done. It seems like Chemistry Of The Future - you feel as if you should be wearing some sort of white jumpsuit with padded shoulders if you ever get around to setting some up.

The idea is appealing, but the reality is less so. Photochemistry often isn't as clean as you picture it being - a look at your clear starting solution gradually turning orange and brown under the punishing glare of the UV lamp tips you off about that. Things get hot in those setups, too, which also doesn't fit the sleek, cool, futuristic template. When you take a hot flask of darkened gunk off the lamp, it's hard not to wonder what would have happened if you'd just cooked it in the oil bath the old-fashioned way.

Probably not what happened under illumination, though. Light does do some odd stuff, and there are some neat-looking reactions that can be run that way. The problem is, many of those neat reactions are free-radical mechanisms, and that's what leads to a lot of that colorful crud. There are a lot of concerted mechanisms that can be driven photochemically, and those should (in theory) be cleaner, but in my experience, it can be hard to keep a lot of radical chemistry from going on, and it can swamp the cleaner stuff right out.

Radical reactions were all the trend back when I was in grad school (get off my lawn!), but while they've never disappeared, they've never caught on to become an essential part of every organic chemist's toolkit. There are several well-used reactions that run (or can run) by single-electron processes, but as a class, free radicals still have an exotic, slightly disreputable look to them. People will look at a potential transformation on the board, and say "Hmm, I bet I could do that by a dipolar cycloaddition", or "I'll bet that I'll able to do an olefin metathesis to get that". There are dozens of reaction classes that you reach for without thinking twice: metal-catalyzed coupling, epoxide opening, reductive amination, electrophilic ring substitution. But do you reach for a free-radical closure to a five-membered ring, a well-trodden radical process if ever there was one? Well, I don't, anyway - and I've done the things. Do you?

Comments (9) + TrackBacks (0) | Category: Life in the Drug Labs

May 14, 2007

Safer Every Day!

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Posted by Derek

Perverse incentives can work in any direction you choose. I was talking here the other week about lab safety, and how it's a good thing to know where the fire extinguishers are. But what if you're working in a place where discharging one of those extinguishers sets off an avalanche of paperwork and committee meetings? Do you use the thing, or does the vision of all that wasted time give you pause, while the flames leap around your glassware?

If it's a seriously nasty fire, you're probably going to pull the pin and worry about the consequences later (and for a fire like that, it's good to remember that going for that second extinguisher is usually a bad idea, compared to, say, diving for the stairs). But what if it's just medium bad, and if you're not sure if it's going to get worse? Other things being equal, you should probably do the most effective thing you can to put it out. But other things aren't always equal in industry.

I've worked where the safety culture was limited to occasional warnings not to blow yourself up, and I've worked under intrusive, no-sparrow-shall-fall regimes. Neither of those, as far as I could see, kept me safer than the other. The problem is, if you're going to aggressively document every possible incident and near miss, to be entered into the massive database and discussed in detail at the mandatory regular safety meetings (attendance taken and computed into the year-end bonus formula). . .well, people are going to sit on most of the ones that they think that they can get away with. The harder you work to log every lapse, the more of them you'll miss.

Once people have reached a certain level of competence and experience, lab safety is largely a matter of thinking about what you're doing, realizing what you know and what you don't know, and planning ahead. These are all highly desirable qualities, both in and out of the lab, and they cannot be expressed by decree. No safety committee is going to make people smarter, and no multi-page web form will make them more alert. In this world, actually, the opposite is much more likely. . .

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May 3, 2007

Forewarned is Forearmed

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Posted by Derek

If you work in an organic chemistry lab, odds are excellent that eventually you're going to have to handle some sort of emergency. There are so many energetic materials used, and so many flammable substances around to go up with them, that sooner or later every working chemist has (or is close to) a fire or explosion.

I don't want to sound too alarmist, because most of these are small affairs that go out quickly. Some of them, though, are small affairs that should go out quickly, but get transformed by bad decisions into large, exciting ones. And once in a while you get one that starts off large and just keeps building, and good luck to all concerned. Here's the question, though: how do you behave?

There's no way to know a priori, and there's no way to know about your labmates, either. You can place some bets: a person who's normally level-headed has a better chance of remaining true to type in a sudden emergency (as does a person who's usually jumpy, for that matter), but there are no guarantees. You have to wait until a situation develops to find out. Some folks are going to surprise you, in either a positive or negative way.

The biggest problem many people have is that they freeze up, unable to think of the best course of action. In my experience, doing nothing in a lab crisis is a much likelier problem than doing something immediate, forceful, and wrong. (Immediate action is usually a sign that the person involved has thought about their options in advance). It always pays, when setting up some chemistry that might turn lively, to picture yourself bolting for the nearest fire extinguisher. That'll at least fix its location in your mind, not to mention concentrating your attention a bit on what you're doing. If a fire extinguisher isn't the answer to your potential problem (which it is, in many cases), then by all means imagine doing whatever else you'll need to do if things go wild - heaving in buckets of sand or handfuls of ice, shutting off valves, what have you.

The problem with freezing up (or with its equivalent, running around in circles), is that not only are you not doing anything about the problem at hand, you're probably interfering with the efforts of anyone who is. You'd be surprised at how many times you have to push someone aside to get a clear shot with an extinguisher, for instance. Doing something is the first choice, but getting out of the way for someone else to do something is not to be disparaged.

In some twenty-five years in academic and industrial labs, I've probably been in the vicinity for about six incidents which were serious trouble, either real or potential, and several others that could have turned that way, but didn't. It's been a while since the last one, though, and that's how I like it. But once I get back into the lab, you can be sure that I'll be checking to see where the fire extinguisher is, because you never know.

Comments (18) + TrackBacks (0) | Category: Life in the Drug Labs

April 17, 2007

The Doctorate and Its Discontents

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Posted by Derek

The doctorate-or-not discussion is roaring along in the comments to the last post, and they're well worth reading. I have a few more thoughts on the subject myself, but I'm going to turn off comments to this post and ask people to continue to add to the previous ones.

One thing that seems clear to a lot of people is that too many chemists get PhD degrees. I'm not talking about the effect of this on the job market (more on that in a bit) so much as its effect on what a PhD is supposed to represent. So, here's my take on what a PhD scientist is supposed to be, and what it actually is in the real world. I'm going to be speaking from an industrial perspective here, rather than an academic one, although many of the points are the same.

Ideally, someone with a doctorate in chemistry is supposed to be able to do competent independent research, with enough discipline, motivation, and creativity to see such projects through. In an industrial applied-research setting, a PhD may initiate fewer projects strictly from their own ideas, but they should (1) always be on the lookout for the chance to do so, (2) be willing and able to when the opportunity arises, and (3) add substantial value even to those projects that they themselves didn't start.

That value is both creative and managerial - they're supposed to provide ideas and insights, and they're supposed to be able to use and build on those of others. They should be able to converse productively with their colleagues from other disciplines, which means both understanding what they're talking about and being able to communicate their own issues to them. Many of these qualities are shared with higher-performing associate researchers, who will typically have a more limited scope of action but can (and should) be creative in their own areas. Every research program is full of problems, and every scientist involved should take on the ones appropriate to their abilities.

So much for the ideal. In reality, many PhD degrees are (as a comment to the previous post said) a reward for perseverence. If you hang around most chemistry departments long enough as a graduate student, you will eventually be given a PhD and moved out the door. I've seen this happen in front of my eyes, and I've seen (and worked with) some of the end results of the system. The quality of the people that emerge is highly variable, consistent with the variation in the quality of the departments and the professors. Unfortunately, it's also consistent with the quality of the students. But it shouldn't be. The range of that variable shouldn't be as wide as it is.

There are huge numbers of chemistry PhDs who really don't meet the qualifications of the degree. Everyone with any experience in the field knows this, from personal observation. You will, I think, find proportionally more of these people coming out of the lower-quality departments, but a degree from a big-name one is still far from a guarantee. The lesser PhD candidates should have been encouraged to go forth and get a Master's, or simply to go forth and do something else with their lives. They aren't, though. They're turned loose on the job market, where many of them gradually and painfully find that they've been swindled.

Over time, the lowest end of the PhD cohort tends to wash out of the field entirely. There are, to be sure, many holders of doctoral degrees in chemistry who go into other areas because of their own interests and abilities. But there are also many jobs that make an outside observer wonder why someone with a PhD is doing them, and that's where many people end up who shouldn't have a doctorate in the first place. Others, somewhat more competent, hold on to positions because they're able to do enough to survive in them, if no more. While there are plenty of bad or irrelevent reasons for people not to be promoted over the years, some cases aren't so hard to figure out.

Those, then, are my thoughts on the doctoral degree. What can be done about this situation, if anything, will be the subject of a future post. I have another set of opinions on the Master's degree and its holders, which I'll unburden myself of a bit later on. Comments, as mentioned, should go into the discussion here.

Comments (0) + TrackBacks (0) | Category: Academia (vs. Industry) | Graduate School | Life in the Drug Labs | Who Discovers and Why

April 15, 2007

Doctorate or Not?

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Posted by Derek

There's been a lively discussion in the comments thread to this post about the differences between hiring PhD and associate-level chemists. Anyone who's interested in the topic should have a look, because there are a number of issues in play: chemical knowledge, ability to manage direct reports, adaptability, and more.

There's little doubt that non-Phds have an easier time getting hired. There's almost always a ceiling over their heads, rarely one as transparent as glass, but finding a place under it isn't as hard as finding one off to its side. One question that's come up is whether chemists with doctorates could (or should) apply for associate-level positions.

This has been done - but it usually involves deception. If you have a PhD on your CV, most places just aren't going to consider you for an associate job - thinking (probably correctly) that you're going to be more trouble than you're worth. The feeling is also, even in down job markets, that you're selling yourself short by going for these jobs, and that there must be some good reason why you're doing so. . .

I have personally seen a case that bears on this. Karl (as I'll call him) was a pretty good associate. Not (I'd say) the absolute best we had at the time, but definitely above average. A vacancy appeared in the PhD ranks in the group, and Karl stunned the group leader involved by marching in to his office and revealing that he actually had his doctorate, and that he was interested in applying for the position.

What happened to him? Well, he was fired. He was fired reluctantly, and people in the organization found him a position with a small company in the area, but he was fired. He'd lied on his job application materials, and the company's legal department had only to hear that before they ruled that there was no other choice. How could we deal with people who lied about other things on their applications if we kept him on?

The problem was that as things stood, Karl would have moved from being one of the best associates to being one of the lesser PhDs. His strengths and weaknesses at the time fit better for an associate position than as a lab head. And that brings up another question from the comment thread: are too many people going on to get doctorates? I have no idea myself, but I have to say, it's not an unreasonable thought. . .

Comments (120) + TrackBacks (0) | Category: Graduate School | Life in the Drug Labs

April 10, 2007

Sulfur, Your Pal. Mostly.

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Posted by Derek

I had a question the other day in my e-mail about various sulfur-containing functional groups in drugs. My answers, condensed, were as follows:

Sulfides: will always be under suspicion for oxidation in vivo. If that's your main mode of metabolism and clearance, though, then the problem can be manageable. Still, many people avoid them to not have to deal with the whole issue, and I can't blame them. I do the same. Since the reagents needed to prepare them tend to reek, it's a handy bias to have.

Sulfoxides: I spent quite a while on an old project turning out a whole line of these. I'm not sure if I'd do that again, though. Sulfoxides are interestingly polar, but they're also frustratingly chiral. If you need a specific right-hand or left-hand sulfoxide (and I did!), there are numerous not-always-appealing ways to get them. The other worry about them is that they can get either oxidized (up to the sulfone) or reduced back down to the sulfide. A good example of this problem is in the -prazole proton pump inhibitor drugs, which are probably the most prominent sulfoxides on the market. Some of them (like omeprazole) get oxidized, and others (like rabeprazole) get reduced. I've even heard of a chiral sulfoxide going in vivo and coming back out in the urine as the other enantiomer, via reduction and chiral oxidation. Many people prefer to avoid the whole issue - and after my experiences, I can't say I blame them here, either.

Sulfone: finally, a metabolically stable one. Sulfones have a reputation as rock-solid functional groups, at least when there aren't active hydrogens next to them. Of course, sometimes the compounds are also stable rocks that don't like to dissolve, but we have that problem with everything. I haven't come across anyone with an unkind word for sulfones.

Sulfonamides: If you're an experienced medicinal chemist, boy, have you cranked out some sulfonamides in your time. They're just so easy to make, and you can get so much structural variation out of them. But secondary ones (with a free NH) can get you into trouble in vivo, since they're so acidic. Acidic compounds can behave weirdly when they try to cross out of the gut or into cells, and have a reputation for hanging around in the blood forever. My bias has always been to go with sulfonamides that have fully substituted nitrogens, and I say let 'em rip.

So, those are my biases. Readers are invited to unload their buried feelings about sulfur functionality in the comments.

Comments (12) + TrackBacks (0) | Category: Life in the Drug Labs | Pharmacokinetics

March 29, 2007

I Want A New Nitro

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Posted by Derek

Quite a while ago (sheesh, five years - this is an old blog, as these things go!), I wrote about a "Chemical Wish List". There are a lot of elements and functional groups that nature has not provided us with, and we could really use them. The earlier post was a request for something the size of fluorine that's electron-donating instead of electron-withdrawing, but today I have another one for the list.

I want a nitro group, or something a lot like it, that's metabolically stable. Nitro's an odd duck, as the structure in its brief Wikipedia entry will show. That drawing is a compromise attempt to represent reality (dotted lines in chemical structures are a giveaway for that). You can draw other resonance structures, all of which approach the truth to greater or (mostly) lesser degrees. Basically, the two oxygens have more electon density on them that usual, and the nitrogen has less. Neither oxygen has a full negative charge on it, but they're closer to it than usual.

And that's what makes nitro interesting. It's quite a polar functional group, and compounds that contain it reflect that. Take a look at the simplest organonitro compound, nitromethane. It dissolves freely in water, and boils at nearly the same temperature, 100 degrees C. Boiling point is a fairly good surrogate for polarity, other things being equal, since it's measuring how well the molecules prefer each other's company in the liquid state, as opposed to flying off on their own in the gas phase. For comparison, methanol (CH3OH) boils at about 65 degrees C, and methylamine is wimpy indeed, fizzing away at about minus 6. Now, there are some molecular weight differences in there which can't be totally ignored, but there's no doubt that nitro is one polar group.

We need polar groups in medicinal chemistry. Those, along with the general shape of the molecule, are the biggest parts of binding energies to our in vivo protein targets. Nitro groups uniquely offer a positive charge right next to a forked arrangement of partial negatives, and I'm sure we could do a lot with that - if the darn things didn't get chewed up in living systems. That nitrogen is nearly as oxidized as it can get (well, there's nitrate anion, true), and there are plenty of systems in the body ready to bring it back down.

That's where the trouble starts. If you go all the way down from nitro, you end up with an amine (NH2). But the intermediates along the way - hydroxylamines, nitrosos, all that kind of thing - are rather reactive and nasty. Those are what give nitro groups their bad reputation in medicinal chemistry - too many of them, especially the ones where the nitro is on an aromatic ring, are experimental (or, gulp, real-world) carcinogens because of those metabolites. The same thing happens to aryl amines, too, because other enzyme systems can oxidize them up to the nasty middle steps. I don't think that they make it all the way up to nitro in vivo, but more perverse things than that happen in biochemistry all the time. For those who don't know this stuff and would like to know more, here's a nice presentation on the basics of drug metabolism - navigate down to #88 in the frame to get to the nitro section.

Now, it's not like there are no nitro-containing drugs. Putting the group on a five-membered heterocyclic ring is often a tolerable move, and there are plenty of examples of that working out. But there's always going to be some suspicion attached to the group, and you're never sure that things are going to work out, since human metabolism can differ from your animal models. Most medicinal chemists opt for caution, and don't put nitro groups on any of their aromatic rings to avoid heartbreak later on. (And of course, there are aliphatic nitros, but those have their own problems).

No, what I want is something that's the size, shape, and polarity of a nitro group, but is rock-solid to metabolism. Sort of a trifluoromethyl group with lots of charge on it. We could certainly have a good time with one of those. . .

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March 15, 2007

Lousy Reactions: Reader's Choice

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Posted by Derek

Here's a quick synthetic question for the lab jockeys in the audience: is there a name reaction that has never, ever worked well for you? The Skraup synthesis has a bad reputation, for example - I've never had the pleasure, but I've heard many stories of splattering dark crud and 20% yields.

I suppose we should distinguish between reactions that are supposed to work well and don't, and reactions that no one has ever claimed are nice (like the Skraup). There's a whole category of reactions that will give you 40 per cent yields when other methods will give you 90, but will also give you 40 per cent when everything else gives you zero. I can't say anything bad about those; they are what they are.

On the other hand, even more most reliable transformations can turn on you. I once had a primary alcohol that I just could not protect with a TBDMS group, a difficulty that made me feel like a complete hack until a disgusted colleague or two had to try it on the same substrate and I was vindicated. But silyl groups are usually pretty friendly. For now, let's take nominations for Least Reliable/Most Overrated Reaction. I'm curious to see what makes the list. . .

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February 20, 2007

Something From Nothing

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Posted by Derek

I have some down time here at the Hartford airport, which gives me a chance to talk about one of the routine, but pleasurable, things about doing organic chemistry: making stuff. By that I mean making something that most certainly wasn't there when you started.

For example, in the post the other day about the odors of various lab solvents, someone mentioned 2,2-dimethoxypropane. That's not in my top five, but it is pretty nice, and certainly distinctive. You can buy it by the liter, but it's also not hard to make (as grad students in underfunded academic labs know). You take some acetone, which as I mentioned the other day has a clear, strong solvent smell to it, and some methanol - thin and harsh. Add a couple of drops of sulfuric acid or the like, which you can forego enjoying the aroma of unless you're downright perverse), and heat it up.

After a few hours at a gentle boil, you can distill off the product. It's a clear liquid, and looks identical to the solvents you started with. The first clue is the different boiling point, and the second is the smell - strong and somewhat herbaceous. It's new, all right, and you made it with your own hands. (This sort of distillation has its own pleasures, which I'll go on about in another post sometimes - I really haven't done much of it in recent years, and that's a bit of a loss).

The effect is even more dramatic when you have liquid starting materials that produce solid crystalline products. All chemists enjoy crystals - if you don't, you either shouldn't get into synthesis, or you should strongly consider getting out. Having a forest of bright needles or beveled plates come out from what was, a few hours before, a mixture of thin, smelly liquids is something I've never tired of. It's something that would have passed for magic a few hundred years ago, and in a way, it still is.

Well, I've just been unexpectedly upgraded to first class, so this is already looking like a good trip. I'll try to blog some during the conference tomorrow, when I get a chance.

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February 18, 2007

Wake Up and Smell the Solvents

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Posted by Derek

It's now been nearly three weeks since I smelled any ethyl acetate or acetone. Those were the two last vapors I was exposed to in my former lab, as I cleaned out some dirty flasks, and those are two of the most common solvents that organic chemists breath in. Neither of them is particularly hard to deal with - acetone has a clear, penetrating solvent-y smell, and ethyl acetate, as a typically fruity ester, comes close to being pleasant. There's plenty worse out there. Hexane and methylene chloride are all over the place in a typical synthetic lab, too, and they're a bit less appealing with their flat paint-cleaner character. (They're rather less appealing from a toxicology standpoint too, for that matter).

Of the other common lab solvents, THF has a rather pungent ethereal smell - not something you'd line up for, by any means, and diethyl ether itself fills up your nose with great speed and thoroughness. Somehow, there's rarely a thin whiff of ether in the air - it's either nothing or a choking blanket of the stuff. Acetonitrile is something you'd think would have an interesting reek, but it defies expectations (and breeds doubt as to the broad-spectrum utility of the human nose) by having absolutely no smell at all.

Many of the really polar solvents have that feature. DMF has a smell to it, but it's surely traces of dimethylamine that account for most of it - in my experience, the pure stuff doesn't have much character at all. DMSO is the same way. There's something oddly scented there, and you can tell as it takes up olfactory room that you're not smelling regular air, but it's not as strong as you'd figure. As with DMF, you have to wonder how much is due to traces of impurities, such as reduced sulfur compounds, of which it wouldn't take much.

And the most pleasant of the bunch? Pure ethanol, for my money. It's not pleasure by association, either, because I don't really drink at all (and never have). But straight ethanol's combination of fruitiness and pungency is unique and appealing. Its cousins don't make the cut. Methanol's dim and harsh, and the propanols are no improvement: n-propanol (an uncommon solvent) is rather nasty, and isopropanol (the well-known rubbing alcohol smell) is not unpleasant, but rather strong, clinical, and somehow alien. n-Butanol, for its part, is quite foul in the manner of butyl compounds everywhere. Our noses have it in for straight four-carbon chains, and there's nothing to be done about it. Nope, it's ethanol, and it's not even close. Any other nominations?

Comments (61) + TrackBacks (0) | Category: Life in the Drug Labs

January 14, 2007

Problems and Solutions

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Posted by Derek

I had some e-mail from a graduate student in a good lab the other day, and I thought the questions raised were worth a blog post. He wrote:

One thing which stands out to me is your enthusiasm for chemistry,
after having been in pharma for a while. This is something which I am
afraid I might lose getting out of academics. I actually was strongly
leaning academically until recently. It just seems the chemical problems you
would be presented in industry are very vanilla....the problem is I
really don't have a good grasp on what these are (especially in drug
discovery).

Then I imagined in drug discovery, you can use any chemistry you want,
so the "cutting edge" (i.e. new organometallic transformations with way
too much expensive catalyst) is still very relevant. I guess I'm just
curious how you stay as passionate about the science as you are. Do you
see this/has this changed since you started in industry? As you move up
the ranks and further from the bench does chemistry get less and less
important?

These are definitely worth asking. My reply was:

?As for the enthusiasm part, I may be a little bit odd, but not all that much. There are still plenty of people who enjoy what they're doing.

But part of it is realizing that chemistry is a means to an end in the drug business, not an end in itself. People are enthusiastic about finding something that works as a drug - that's why we don't mind mundane reactions as much, because those give you a lot more shots at making a drug than something that needs 2 days to set up. Of course, if you do nothing but (say) make sulfonamides all day, every day, you'll go nuts. But things vary too much for that to be a problem (most of the time). There's always another new structure idea that you have to figure out how to realize, another new core to work on, etc.

And the chemistry problems are just as knotty as you'd get in academia - how do I set these stereocenters, how do I do this reaction selectively so I can avoid a protecting group, etc. Sometimes they're on a different wavelength as well: How can I make this stuff in fewer steps? How can I avoid that evil mercury reagent? How do I get this stuff to form the right polymorph? How can I get to an intermediate that'll let me sit back and crank out a few analogs, instead of making everything from the ground up?

But, as I said, chemistry is means to an end. And the non-chemical problems are a lot harder: how do I get these compounds to have higher blood levels? (Next question - why are they so low now? Do they not get in through the gut, or are they getting whacked by the liver, or are they partitioning into some other tissue, or getting hosed out extra fast by the kidneys?) Why does this compound work, but the one without a methyl group kill the rats? (I've had that exact situation - truth be told, we never did completely figure out what was going on. . .) Why does this thing work so much better in mice than rats, and which one is going to be more predictive of humans - if either? And so on.

So, in a way, the chemistry problems take up less of your time the further on you go. Biology and development problems pick up the slack, and then some."

I'd be interested in hearing other takes on these, and I'm sure my correspondent would, too. Any industrial readers care to add some details?

Comments (11) + TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs

January 7, 2007

Good Stuff and Bad Stuff

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Posted by Derek

It's been a while since I opened up the floor on a general question, so I thought I'd toss a couple out. Since thoughts of leaving one company and starting up at another (yet-to-be-determined) one are much on my mind, I'd like to target the industrial side of my readership with these:

What's the one thing about your company's research culture that you'd change if you could?
This can range from things that just plain get on your nerves all the way up to grave structural failures that you think will eventually take the whole place down. You don't necessarily have to offer a solution, partly because too many of those might involve building a catapult to launch specific people into the trees, but if you have something specific in mind, feel free. "Buy enough crates to ship the entire (X) Department to Zanzibar", though, isn't necessarily the appropriate level of specificity, but hey, if that would do the trick. . .

And then there's:
What's one research-related thing that you think your company really gets right?

Even companies with problems generally have at least one or two parts that seem to be working well. Uncommon examples would be particularly useful, because there might actually be something that everyone else could swipe.

Comments (25) + TrackBacks (0) | Category: Drug Industry History | Life in the Drug Labs

January 3, 2007

You'll Be Safe Under Here. Maybe.

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Posted by Derek

I see that there's a new edition of the book that organic chemists just call "Greene"; otherwise known as "Protective Groups in Organic Synthesis". This is the fourth, and I'm of an age to remember the first one back in about 1981, when I was still an undergraduate. The new volume could swallow the old one whole - it must be five times the length. Back then the book had some competition, but now it has none at all.

For the non-chemists in the crowd, a protecting group is the molecular equivalent of masking tape. It's a temporary group that you tack on to some reactive part of a molecule to keep it from messing things up while you work on the rest. Ideally, this would be something totally selective for the functionality you're trying to protect, which goes on easily and comes off just as lightly without affecting anything else. Oh, and it has to stand up to every other kind of reaction known to science along the way. That protecting group does not yet exist, or if it does, no one's told me about it. But there are some pretty decent ones, depending on what you're asking them to put up with before their removal.

Everyone who does organic synthesis has to use these things at some point. Because I did carbohydrate-based synthesis in my grad school work (all those hydroxyl groups), I had to use the things constantly, and the trick was to keep them straight and removable in each other's presence. But it's safe to say that no one likes using them. There's a persistent feeling of. . .well, inelegance that attaches to them, no matter how nifty the conditions used to apply and remove them. After all, that's two more steps added to your synthesis, and two which more or less cancel each other out after all that work.

You can't help but think that really advanced organic chemistry will find a way around such problems. We aren't there. For now, it's duct-taped umbrellas, cement-spotted plastic domes, and jammed-on crash helmets for our molecules, and not much we can do about it. Greene's book has all the ugly but necessary details anyone needs.

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December 28, 2006

Cleans Down to What Should Be the Shine

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Posted by Derek

One of the main things I'm going to have to do when I get back to my lab is clean it up. That's not something that I spend much time on, under ordinary conditions. For one thing, I don't run as many reactions as I used to, so it doesn't get dirty as fast. But I'm not someone who makes a clean lab bench my goal at the end of each working day, that's for sure. There are messier people at the Wonder Drug Factory, but there are neater, too.

In fact, I distrust lab benches that look as if you could safely make a sandwich on them. Those, as far as I can see, indicate too much cleaning and not enough real work - or, in the larger sense, too much of a concern for appearances at the expense of what matters. You don't want your lab bench to be a tourist attraction (or a standing joke), much less a safety hazard. But it doesn't (shouldn't!) be a showpiece, either, because to people who really understand the way research works, you're sending the wrong message.

I remember straightening up my lab once at a former job, and afterwards I noticed several people outside in the hall near my door. "What are you people doing loitering around?" I called out, and Stu McCombie (yep, that McCombie - he worked down the hall from me) answered "We're taking bets on how long your lab is going to look like that!"

"Well," I told him, "as soon as I start doing some real work in here it's going to go straight downhill." "That's what makes it a sporting bet," said Stu, "No one know when that's going to be!"

Comments (13) + TrackBacks (0) | Category: Closing Time | Life in the Drug Labs

December 11, 2006

Old School? Same School!

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Posted by Derek

I was looking through some old pictures the other day, and found a set that were taken in my grad-school lab, back in the mid-1980s. One thing struck me, because I'd always had a mental picture of my bench being an impossible mess: it wasn't that bad. "You call that clutter?" I thought. "I'll show you clutter!" My desk, on the other hand, was indeed a mess, and I haven't been able to surpass it. (Equal it, yeah, OK, every few months. But not surpass it).

I think one reason the bench didn't look so bad was because there just wasn't enough money for it to reach its full potential. After all, I only had a certain number of round-bottom flasks, with no more set to arrive, so I had to be vigilant about transferring things to vials and doing the dishes. When you have drawers full of the things, though, you can afford to cut loose a bit. The same goes for other lab supplies - I didn't have a lot of spare boxes of pipets and disposable test tubes sitting around back in the old lab, because we tried not to dispose of them so cavalierly.

The other thing that hit me about these shots was that I could easily do what I do now using that same equipment. I'd like a Biotage or Isco chromatography system, true, neither of which had been invented back then. But most of the equipment is exactly the same - round bottom flasks, Erlenmeyers, rota-vaps, sep funnels, TLC plates - everything you need. (Bet you didn't know you could buy some of that stuff at Amazon, eh? That sure hadn't been invented yet, either. . .)

I don't know whether to be happy that all the things I've learned have stood by me so well, or to be a little worried that my field isn't a bit more dynamic. It's a good thing I don't have any lab photos from the 1960s for comparison, because that might just tip the balance.

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October 29, 2006

Family Portraits

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Posted by Derek

In his book The Periodic Table, Primo Levi mentioned in passing that "chlorides are rabble". That struck me as very well put, and is proof enough (should anyone need one) that Levi had a real feeling for his chemistry. The reason that comes off so well is that when you look through a chemical catalog, if there's only one salt of a given element available, it's almost always the chloride. They're common, in every sense of the word.

The kinship of the positive ions, the elements themselves, are well known. That's how Mendeleev worked out the periodic table, and generations of chemistry students are taught about the similarities among its columns. It's all true, of course, but there are subtle kinships of the counterions, too, a faint Y axis to the strong X of the elements.

Most of the chlorides are quite boring - white powders, almost invariably. The more chromatic elements still manage to do something for you: nickel chloride, for example, is a vivid green (copper less so), and chromium (III) chloride is a striking metallic-flake purple. But if you can't get colorful with elements like those, your counterion is a total loss, anyway.

Fluorides are almost never colorful, but they have a tough nature about them, reflecting their ultimate-hard-anion character. Iodides are the other end of the scale - that's such a big, fluffy ion that it hardly seems bound at all sometimes. Even light is enough to mess with it, and it's a rare iodide that doesn't have a warning on its label to keep it out of the sun, for fear of it turning brown in a death-tan of oxidation to free iodine.

Sulfates are nearly as boring as chlorides, but with a bit more character to them. Nitrates (similar salts from a strong acid) have a much different feel to them, since when you're working with them you can never quite get the thought of explosions out of your mind. It's not completely accurate, but it's still true that you could mix potassium sulfate with sulfur and charcoal forever and never discover gunpowder. The word "nitrate" itself has a menacing sound that it'll never lose.

If you want real problems, though you have to turn to even more loosely bound, oxygen-rich things like bromates, iodates, and (above all) perchlorates.
That's about as bad as it gets inside the confines of inorganic chemistry - to get crazier, you have to trespass into organicky things like azides. Most of the organic counterions, though, are carboxylate salts, which are relentlessly similar to each other. No explosions here - if there's one salt of a element that's guaranteed to be more yawn-inducing than its chloride, it must be the acetate.

These are all classical ions, known for centuries. The fluorides are probably the most nouveau of the lot, since even though some of them occur naturally, most of them had to wait until the industrial development of the element later on in the 19th century. But that led in the 20th to all sorts of odd creatures that (so far as I know) are never found in natural minerals at all. The higher fluorides, things like tetrafluroborate and hexafluorophosphate, have only human fingerprints on them. When you work with those salts, you've thrown your lot in with the synthetic, the man-made, the new and improved. Even weirder ones are surely on the way.


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October 10, 2006

Five Things I Haven't Used in Years

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Posted by Derek

1. A Soxhlet extractor. It's not that I don't like them, it's just that I haven't had the need for one. We used to use one to wash polar products out of all the gunked-up salts from big lithium aluminum hydride reactions, and I once used one to slowly wash a more soluble impurity out of a powdery mixture of isomers. I think some of my younger colleagues have hardly ever seen one, which I find vaguely depressing.

2. For that matter, a liquid-liquid extractor. I had one of these built for me back in grad school that came up to my waist if I set it up on the floor. A week's worth of ethyl acetate washing did wonders for my crude material, which was about as crude as it's possible to get, since it was obtained by destructive vacuum distillation of corn starch. I'll have to go into that story in detail some time.

3. An infrared spectrometer. Last time I put something into an IR, I swear, it must have been nearly seventeen years ago. It's a perfectly good, perfectly reasonable analytical technique that's just been totally swamped by NMR and LC/mass spec technology. It still does some things very well (like tell you if you have a nitrile or not), bu as far as I can tell, no one cares.

4. A polarimeter. I've narrowly dodged this one over the years, but I think I haven't had to get an optical rotation since about 1996. You want to avoid chiral centers if you're making pharmaceuticals, and if you have chirality, you want to buy it in your starting material. And if you have doubts about your enantiomeric purity, you want to use something like chiral HPLC and not trust the specific rotation. Tiny bits of impurity with huge rotations can totally throw the number off. Stick with techniques where the error terms are linear and don't have exponents in them.

5. Cyclic voltammetry. One of my first projects in grad school bid fair to wander off into physical organic chemistry, at least until we found that the effect we were trying to explain didn't exist in the first place. I tried all kinds of odd techniques to get a handle on the (nonexistent) anomaly, and that included wandering down to the electrochemists in the other hallway. It didn't hurt that the grad student who ran the apparatus was really cute. But cute electrochemists are thin on the ground, in my data set, anyway.

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October 1, 2006

Test Your Skills!

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Posted by Derek

Are you qualified to be a medicinal chemist? Take this simple quiz!

1. You synthesize a new drug candidate. It won't even dissolve in hot DMSO. Do you. . .
(a) Chuck it into the chemical waste, because it's never going to be a drug
(b) Wonder if it's clean, because you're never going to be able to get it down the LC/MS
(c) Send it in for the assays, because you never know.

2. You've just received the results of a crucial in vivo test of your project's best candidate. It was exactly as active as powdered drink mix. Do you. . .
(a) Blame the animal group for fouling up the dosing
(b) Blame the PK group for fouling up the results
(c) Feel a sense of relief that maybe there's an assay that you might have managed to finally kill

3. Your compound kills mice. But it makes rats fat and happy. Do you. . .
(a) Feel a sense of relief that at least your main tox species is still in the running
(b) Close your eyes, hold your breath, and scale up for the dog
(c) Wonder what it would do to Kevin Trudeau?

4. You need to make a competitor's compound, but their patent synthesis just doesn't work. Do you. . .
(a) Stare out the window, muttering things about disclosure of best mode
(b) Set up a literature alert, hoping for a process patent application to clear things up
(c) Rub your hands together and send the synthesis out to a contract lab, turning it into their problem?

5. Your lab has been assigned a yearly minimum number of analogs for performance review. Do you. . .
(a) Tell your group to send in every intermedidate compound, even the smelly unstable brown ones
(b) Feel a sense of relief that at least they're not asking for a quota of active compounds
(c) Reach for the big bottle of DCC, 'cause if it's amides they want, it's amides they'll get

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September 19, 2006

By Any Other Name

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Posted by Derek

There's a paper in the latest Ang. Chem. that will be of interest to everyone who's into the way that various chemicals smell. And hey, what organic chemist isn't?

It's by a flavor and fragrance chemist, who lists many tables of compounds that have very minor structural variations but completely different smells. One noteworthy example is geraniol, which is a large component of the scent of roses. Adding a methyl group next to its primary allylic alcohol coverts it to an analog with an "intense fungal odor", which I don't think I'm going to be lining to up sample any time soon. And you'd have thought that the smell of geraniol would be pretty robust - you can saturate the allylic double bond, and it's still rosy. Take that compound and substitute an aryl group for the isobutenyl on the other end - still rosy. But don't mess with that primary alcohol.

The take-home lesson is that there are no major SAR trends in odor that you can count on. A substitution that works in one series can do nothing when applied to a closely related compound, or it can take the odor off in a completely unexpected direction. That aryl-for-isobutenyl switch I mentioned, for example, isn't silent if you try it on benzylacetone (4-phenyl-2-butanone). The starting ketone smells "sweet and floral", but the corresponding methylheptenone is described as "pungent, green, herbaceous".

The reason for all this craziness is that there are hundreds of olfactory receptors, most of which appear to respond to huge numbers of compounds as agonists. (There's that induced fit again)! And it's not like the agonists all smell the same, either. There also appear to be multiple binding sites involved, and possibly other protein cofactors as well. The structural complexities are bad enough, but there are probably neural processing effects laid on top of them, which makes the author predict that "consistently accurate prediction of odors will not be possible for a very considerable time". He's quick to point out that it's not like the flavor and fragrance industry has to money to underwrite the work needed to do it, either.

Does this remind you of anything, fellow medicinal chemists? If the perception of smell is the physiological readout in this case, how different is this from all the physiological states we're trying to produce with our small drug molecules? How well do we really understand their binding, and how much can we trust our SAR models? Hey, the fragrance people have big advantages on us - they can immediately test their molecules just by sticking them under their noses, which is like a five-second clinical trial with no FDA needed. And they're still as lost as geese. A lot of the time, so are we.

Comments (24) + TrackBacks (0) | Category: General Scientific News | Life in the Drug Labs

August 3, 2006

The Last Word on Eerie Glowing Labs

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Posted by Derek

My posts on lab photography (here and then here) stirred up comment from all over the place, split about evenly between people on either side of the camera back. Most of the scientists agreed that the shots I complained about are silly-looking, but it was correctly pointed out that if researchers who felt that way would speak up while the pictures are being taken, we'd see fewer examples of the form.

The comments from photographers, which appeared after the original posts here, on various other discussion sites and in e-mail, were more varied. Some agreed that the purple glows were an overused device, and said that they weren't using them any more. Others said that they wish that they could drop them, but that their clients (art directors and PR people) wanted things the way they usually are: bizarrely colorful. A few photographers thought that they were just fine, and a related (and larger) fourth group pretty much told me to stick to talking about things that I might have a chance of understanding.

After taking in all these suggestions, even a couple of physically implausible ones, here's my summarized take on the issue:

First off, we shouldn't necessarily blame the photographers, many of whom (as just mentioned) are giving their paying customers what they want, whether they think it's a good idea themselves or not. The observation was made, with great vigor, that publicity shots are not photojournalism.

I take the point, which was also made to me by my seven-year-old son one day when he noticed that the pictures of hamburgers on highway billboards bear little resemblance to what lands on your table down at Burger Chute. The thing is, the burger photographers are there to make the product look better, and the people who cook them presumably don't think that the billboards look completely ridiculous. Scientists, though, find the colored-spotlight school of photography laughable - but again, let's not blame the photographers. The problem lies elsewhere.

To some people, many of whom work in some form of public relations, nothing says "laboratory" quite like colored spotlights. The intention is to grab the eye, and the problem is that regular laboratory life doesn't do that very well. If we want to lose the special effects, we're going to have to either come up with a less ridiculous way to make an eye-grabbing picture, or convince the PR people that the light shows aren't doing the job. (In which case, we're going to need something to suggest in that first category anyway).

Some ideas have been offered, such as trying to get shots of real things that happen to be colorful: fluorescent TLC plates and large color-banded chromatography columns, perhaps. It's true, though, that in many labs there aren't even that many opportunities. But even getting people to switch to some of the various neon-colored disposable gloves would be less laughable than having their entire labs glowing behind them. Unusual camera angles and other compositional tricks have also been suggested, but these will always come at a cost in time and effort which may not be payable. The problem is, real art directors and brochure layout people will have to be exposed to the results of these ideas before we know if any of them are effective.

What's that? You say that perhaps we should check with the broader public who will actually be viewing the eventual brochures to see what they think? Nonsense - what do you think a public relation person's job is, if not to give the public what the PR department is sure it will like? Next!

As for convincing these folks that the standard rainbow shots aren't desirable, well, that might be a hard sell. There's an invisible line between "useful visual shorthand" and "grating stereotype", and the discussion quickly devolves into unresolvable matters of taste. For my part, I'm sure that I'm right in thinking that these shots are uselessly cheesy, but I could end up in an elevator with someone who's equally sure that they're eye-catching and effective. And science is far from the only profession to suffer from this problem, as a query to any real police officer about the realism of prime-time police dramas will make clear. It may be that in the end, we're stuck with the otherwordly glows whether we like them or not, or whether they do any good or not.

Perhaps we can even go beyond blaming the PR people and blame the whole culture (always a popular move). For hundreds of years, the image of the scientist has been only a flicker away from that of the magician. For many people, what we do in our labs might as well be sorcery for all they understand it. And how many mad scientists have haunted pulp novels and cheap movies over the years? Is it any surprise that we end up with eerie lights washing over us? What else would you expect?

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July 16, 2006

The Future is Unwritten

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Posted by Derek

What I would miss, if I had to go into another line of work besides research, would be the surprises. I'd miss other things, but that might be one of the first. At this point, I don't know what I'd do with a job where I always knew what was coming. I should clarify that - I'm well aware that if, say, I was the head chef in a restaurant, that I wouldn't know what order was coming in next, or how many we were going to be hit with at once. But people would mostly order things that were on the menu, wouldn't they? No one would come in and demand stir-fried sargasso on a bed of wood chips or a coelocanth en croute.

But that level of craziness can be achieved in a good research project. What I enjoy is the occasional result that just makes no sense at all, that reminds us that we really don't know what we're doing. This happens all the time in chemistry - it's a very inexperienced organic chemist who thinks that everything's under control. There's no reaction so reliable that it can't turn on you under the right (wrong) conditions, and as the process chemists know, there aren't many that can't be tamed if you're willing to spend enough time and money. To partially make up for those, there are also times when something works wonderfully even though you gave it almost no chance.

If the chemistry has random elements, then you can imagine how things start to act once you move toward living systems. The dosing behavior of a new compound is, almost without fail, impossible to predict, and a stone solid fortune is waiting for anyone who can say different and prove it. Tiny changes to a molecule's structure will suddenly make its blood levels soar (or flatline completely), and if we knew that that was going to happen, we wouldn't have run the experiments, would we?

Toxicology is, without question, the poster child for unexpected results. As I've said before, if you don't hold your breath when your drug goes in for tox testing, you haven't been doing this very long. I had a project once where adding a single methyl group to the a molecule changed it from being an infallible overnight rodent-killer to something that could be given for two weeks straight at ten times the normal dose. Clearly we managed to slip out of whatever protein target it was dealing death, but these things can't be modeled or predicted.

What would I do with myself if I knew how these things were going to come out? What scientist could stand it? I can picture a nightmare world of time-to-make-the-donuts folks in lab coats, shuffling in to press the buttons and turn the cranks to produce yet another winner. It'd be like watching a baseball game where every batter hit a home run. Medicinal chemistry's not going to get there in my lifetime, but if it ever threatened to, I'd pack up and move off to the frontier, wherever in the scientific world that might be by then, to the place where I could once again look at my results and say "Well, why the @#$! did that happen"?

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July 11, 2006

More Purple Radiance

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Posted by Derek

Hmm, my post on colored-spotlight lab photos seems to have hit a couple of nerves. I note that a few photographers have defended their gel-shooting ways in the comments:

"Photos help create interest in your work. Adding a little Hollywood glitz is the price you pay if you want to continue getting paid."

And:

"As a photographer, I would only note that my colleagues and I simply may have been trying to make the pictures interesting enough to bring *more* people in to read the stories. Which, of course, is where they would learn about what you were actually doing.

The profile of scientists is far too high as it is, I think. I doubt you can safely walk the streets in anonymity these days. The last thing you guys need is more visibility, what with all of the unsolicited, excess grant money rolling in. I mean, how can a scientist burn through that kind of green with just 24 hours in a day?

. . .Amazingly in the 21st century, some photographers are still trying to increase the interest and visibility levels of science.

What a waste."

Well, let's clear up a couple of things. First off, fortunately, I'm not dependent on grant money. I work in industry, for a very large company, and we raise and spend our own cash. And believe me, we have no problem burning money - it's trying to figure out how not to burn all of it that occupies our time. That means that what I'm really dependent on is people buying our drugs, and on my lab (and the others like it) coming up with new ones. Interestingly colored pictures of our work will do very little to advance either of those.

Second, although I didn't make a big point of it, this brochure was (as mentioned in the first paragraph) in-house. Its target audience was people who already work for the company, which made the colored gels even more laughable than they would be otherwise. This wasn't for the local newspaper's color front page. There was no public outreach involved.

But as for that, well, that's one reason I have this blog. I'd found over the years that almost no one I met had any idea of what it was like to do drug discovery research, so I jumped at the chance to talk about it. Much of what people think they know is incorrect, too - if my salary depended only on what a good opinion people have of drug companies, I'd be in trouble. No, I think it's great for people to find out what this job is like - I just think that glitzed-up photos are a poor way to do that.

Why? For one thing, they're a cliché. These shots have been a joke for many, many years among scientists, and if you tried to count up all the purple glows (or red-green-blue colored flasks) out there in print, you'd never finish the job. I think that for every person who (unaccountably) finds such a picture compelling enough to read the accompanying article, there must be two who flip past it in boredom. They've seen it a thousand times before; it's not an eye-catcher any more.

But that's a practical matter. A larger one is the problem of falsification. It's not just that our labs don't look like that, although they sure don't. It's that one group of viewers will take away the wrong message (that lab work is constantly exciting and dramatic, like on TV), and another more suspicious group,will take away another wrong message: that it's so boring that it has to be tarted up to be bearable at all.

The truth's in between. Exciting stuff happens, but it doesn't happen the way a screenwriter (or an art director) would lay it out. And while the exciting stuff isn't happening a lot of routine work is getting done, and a lot of dead ends are explored in what is (in retrospect) horrible detail. The job takes a particular personality type, and if you get frustrated easily or have a short attention span - in other words, if you're the type who needs the stimulus of bizarre colors to find something worth looking at - then it's not going to work out well for you as a career.

I'll close with one other photographer's comment:

"Science is about accurately representing data. Photography is about making an interesting image.

True enough, although photography - not promotional photography, admittedly - can also be about accurately representing reality. But what would a bunch of photographers think of some pictures allegedly showing them at work, but with no cases of equipment in sight, no encumbering battery packs or extra camera bodies. . .just dynamic-looking poses of them holding cameras which, for some reason, are glowing orange and green and purple? If you won't do that to each other, why will you consent to do it to us?

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July 7, 2006

Memo to the Public Relations Department

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Posted by Derek

After seeing a recent in-house promotional brochure, I'd like to issue a brief request on behalf of my fellow researchers. This is addressed to all professional photographers: please, no more colored spotlights.

I know that you see this as a deficiency, but scientists do not work with purple radiance coming from the walls behind them. Not if we can help it, we don't, and if we notice that sort of thing going on, we head for the exits. In the same manner, our instruments do not, regrettably, emit orange glows that light our faces up from beneath, not for the most part, and if they start doing that we generally don't bend closer so as to emphasize the thoughtful contours of our faces. When we hold up Erlenmeyer flasks to eye level to see the future of research in them, which we try not to do too often because we usually don't want to know, rarely is this accompanied by an eerie red light coming from the general direction of our pockets. It's a bad sign when that happens, actually.

I know that your photos have lots more zing and pop the way you do them. And I'm sorry, for you and for the art department, that our labs are all well lit (with boring old fluorescent lights, yet), and that we all wear plain white lab coats (which tend to take over the picture), and that our instrument housings are mostly beige and blue and white. It would be a lot easier on you guys if these things weren't so.

But that's how it is. And when you get right down to it, you're actually doing us a disservice by trying to pretend that there's all sorts of dramatic stuff going on, that discoveries are happening every single minute of the day and that they're accompanied by dawn-of-a-new-era lighting and sound effects. We'd rather that people didn't get those ideas, because the really big discoveries aren't like that at all. It doesn't make for much of a cover shot, but if one of us ever does manage to change the world, it'll start with a puzzled glance at a computer screen, or a raised eyebrow while looking at a piece of paper. Instead of getting noisier, everything will get a lot quieter. And if there are any purple spotlights to be seen, we won't even notice them. . .

Update: A follow-up post is here, written after several comments by photographers came in. . .

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June 7, 2006

Best When Used By. . .

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Posted by Derek

Most of the things we use in an organic chemistry lab can sit around for reasonable periods of time. I've used reagents from bottles that are older than I am (OK, this was twenty years ago, so it's getting a bit harder to do). As long as the stuff isn't air- or moisture-sensitive, it can hang around a long time. That lets out the violently reactive things - don't expect to find the same piece of potassium metal you left if you're silly enough to leave it out while you answer the phone, for example. (In fact, you'd better pick up a fire extinguisher on the way back, just on general principles).

But there are some reagents that don't react with air, but rather react with themselves, which can make them particularly hard to handle. If the reaction is exothermic, things can get dangerous. The heat given off by the first bit that reacts tends to set off some others, which really gets a good amount going, and ba-doom. Even if you're not in the ba-doom category, there are some things that you need to look out for. Styrene, for example, is always sold with some free-radical inhibitors in it, because if it gets a chance for a radical chain reaction to start, the whole bottle will seize up into a warm gunky block of polystyrene. (That's for small bottles - larger ones won't be able to transfer their heat so well to the surface of the container and can make a much bigger mess).

Benzaldehyde isn't so violent, but it slowly forms a six-membered-ring trimer on standing. Update: I've been carrying this idea around for twenty-five years now, but it's wrong. The nonaromatic aldehydes love to trimerize, but benzaldehyde and the other aromatic ones don't. The solid gunk is benzoic acid, from air oxidation, which is a separate category of How Reagents Go Bad. Old bottles can have some crusty crystals of the stuff around the neck of the bottle. The reagent is one of those things that you really have to distill before using it if you want to trust your results. Update: This point is definitely still true!

The extreme case in the self-condensation category is probably cyclopentadiene. It does a Diels-Alder reaction with itself first chance it gets, so it's always sold as the dimer. If you want the pure monomer, you have to distill for it. The dimer cracks thermally, so the vapor condensing at the top of the still is a different substance than the stuff down in the pot. Collect it, keep it on ice, and use it - the diene's a ware that will not keep.

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May 11, 2006

A Day at the Rota-Vap

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Posted by Derek

I've been spending a good part of the last couple of days rota-vapping down toluene. Why would I do such a thing, you ask? Because I ran a big column in the stuff, first time I've ever done that, I think. The chemists in the audience will guess that I examined many alternatives before settling on this one, and they are correct. Toluene's not especially toxic or smelly, but it is rather high-boiling compared to most of the solvents that we use for purifying things. You have to turn your water bath up and allow for plenty of time when you're taking a lot of it off. In this case, it turned out to be by far the best solvent for separating two closely running compounds.

Here's how I got there - it's a good illustration of a day-to-day chemical problem. I wandered through all sorts of common (and uncommon) solvent mixtures, checking each by thin-layer chromatography (a quick way to see if things separate). In ethyl acetate/hexane, the standard brew, you could just tell that there were two things in there after running a TLC plate three times. Switching to ether/hexane, which sometimes does the trick, was no help. Straight dichloromethane gave too fast-runnig a spot, and mixtures of dichloromethane-hexane didn't separate anything. Chloroform/hexane, on the other hand, wasn't too bad - not as good as toluene, but at least you could see some daylight in between the two spots. Isopropanol/hexane did no good at all.

I was trying here to run a bunch of different solvent types. Hexane is a common theme, since it's pretty much the plain vanilla of solvents. More polar stuff is added to it, and you see what happens. In this case, an ester co-solvent did a little bit of good, but ether and alcohol additions did nothing. Chlorinated solvents showed some promise - well, at least chloroform did. But it's an oddity, more polar than the others of its kind. Toluene was the only aromatic solvent I tried (it's really the only convenient one for chromatography), and something about its flat shape and electron clouds did the trick. This stuff is brutally empirical.

So toluene it was, with a little ethyl acetate at the end to speed the latter spot along. I got some mixed fractions, naturally, but quite a few clean ones, certainly enough for my purposes. (If I get bored or desperate, I can go back and re-run the mixed ones).

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April 20, 2006

Sulfurous Stenches: A Connisseur's Guide

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Posted by Derek

Inspired by Dylan Stiles' tribute to sodium ethanethiolate, I present Lowe's Guide to Sulfur Aromas:

Hydrogen sulfide: rotten eggs. No more, no less, and plenty of them. Rather more toxic than cyanide, but at least you can smell it coming more easily.

Dimethyl disulfide: not, as these things go, really all that bad. If you smelled it coming out of your refrigerator, you wouldn't be pleased. But compared to the others on the list, it's tolerable - perhaps the cleanest of the sulfur odors. And many organic chemists associate it with a successful Swern oxidation, which gives it some points.

Ethanethiol: the prototype of the class. All the basic sulfur-stink notes - skunky and intestinal. Very volatile, too, which really gives it a quick wallop, but at least it doesn't stay around forever. I had a grad school reaction that used this stuff neat as the solvent, so I know whereof I speak.

Cyclopropanethiol: not sure if you can buy this, but we made it in my lab a few years ago. Smells like a fire in a garlic warehouse - very sharp and penetrating. Notably different from its acyclic brethren.

Propanedithiol: two SH groups in one! Has the same general character as the other lower alkylthiols, but with a darker, more penetrating note. Lasts forever due to its high boiling point.

n-Butylthiol: since butyl groups reek in general, the butylthiol has a special kick all its own. Very rich and skunky indeed, and it sure does hang around.

t-Butylthiol: used as the odorant in natural gas lines, so you know it has something to recommend it. Nasty and overpowering at 100% concentration.

beta-Mercaptoethanol: rather similar to ethanethiol, but the extra OH group gives it some real staying power. Sort of the "sun and sport" version of the parent compound.

Mercaptoacetic acid: ugly, sharp, acrid reek, also with plenty of endurance. Nothing to recommend it.

Thiophenol: you've smelled it, if you've smelled burning rubber. But imagine the pure essence of burning rubber, distilled and bottle for your pleasure. Very long-lasting, too.

Mercaptopyridine: since pyridine reeks to the skies, and thiophenol is so awful, you'd expect the worst from this combination. But it has no smell whatsoever, by some trick of fate. Surely that's for the best.

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April 12, 2006

The Process of Process

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Posted by Derek

Mentioning HMPA the other day prompts me to talk a bit about the relationship between the two branches of drug-company chemistry: discovery and process. I'm in the first camp - I've done a little of the second, but nothing hard-core. At most companys, there isn't too much crossover, because the two kinds of work are quite different.

Discovery, as you'd figure, involves a lot of different reactions, on different substrates, all to the end of making a lot of different products. Our targets are constantly changing, particularly in the first stages of a new program. If the synthesis of some analog doesn't work out well for us, often the best solution is to drop it and make something else. There's generally something just as good on the list that hasn't been done yet. We like easy, reliable reactions, because those help us generate the widest variety of compounds in the shortest amount of time (and with the least amount of work, come to think of it).

Process chemistry comes into the picture when something has been seriously considered as a clinical candidate, and there's a need to make large, reproducible batches of it. They work on one molecule, and they beat the stuffing out of it. The route that the medicinal chemists used to make the candidate is almost never the best that can be found - at least I've never heard of a case yet where it was. There's always room to use cheaper reagents, higher-yielding reactions (and fewer of them), and solvents that can be dealt with on large scale. And there's the reproducibility issue, too. A synthesis that gives you 90% yields four times out of five and 40% the other time is a disaster. That's an average of 80% yield, but the process chemists would be much, much happier with a lower-yielding route that gives exactly the same yield (with the same degree of purity) every single time.

The process gang will ditch solvents like tetrahydrofuran or (God help you) ether for things like toluene and ethyl acetate. They'll try to get rid of those low-temperature dry-ice cooled reactions, because they'd much rather work in a regular ice bath if possible. All those chromatography steps will be attacked, because they hate running columns on that scale, and who doesn't? Crystallization, precipitations, filtering through a plug of silica gel - anything but running a long column and cutting fractions. If you're a considerate medicinal chemist, you'll have thought about these issues beforehand rather than just throwing the whole problem over the wall when you're done with it. That's why I never use HMPA, because either my reaction can do without it, or we can do without my reaction.

When the quantities involved get serious, some people will step in and see if the entire approach needs to be torn up. There are drugs out there that have had five or ten different routes to them over the years. You don't want to make the whole program depend on finding a new one, but it's worth some work on the side. By this time, the chemistry is moving on to another world in the pilot plant, where the hard-hatted crew worry about issues like starting on the top floor reactor so they can gravity-filter into the room below. When you start thinking about the viscosity of your reaction mixture and the shape of the pipes it's going to be running through, you've moved into the world of chemical engineering.

But meanwhile, people like me are back in the med-chem labs, starting another project on a totally different series of molecules. We're weighing out a hundred milligrams of this and that, trying things out in five-mL flasks to see if they work. It starts again.

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March 27, 2006

Cleaning Out the Hood: An Internal Monologue

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Posted by Derek

Man, is this hood of mine scuzzy. . .these things suck in dust all day long, and it all piles up in layers on the bottom. Spilling silicone oil back there doesn't seem to help much either, gotta say. Of course, if all the dust from the lab is being pulled in here, where's all of the dust out on my bench coming from, eh?

And this two-liter round-bottom flask, which has its share on it: that's from, like, 2003 or so. The project before the project before the project before this one. Give or take. I really should get this stuff out of it, but there must be fifty or sixty grams in there. And scraping that out would be a nightmare. And dissolving it wouldn't be a lot of fun, either. And I'm not completely sure that I remember what the stuff is. Argh.

Then there's this rig back here, my phosgene trap. I can get that out of here, 'cause with any luck I'll never have to use phosgene on that scale again. Of course, as soon as I break it down and clean it, someone across the hall will discover the New Wonder Lead Structure on our project, something so hot that we all have to switch over and start working on it, and the second step to make it will require a bucket of phosgene. Never fails. I haven't been doing this for seventeen years for nothing, y'know.

Or have I? You'd think by this time I'd learn to label flasks like this one over here. Those sure are some nice crystals. Makes me think that they must be leftover sodium sulfate or something. Take a bit out and see if it's water-soluble - if it is, it's junk, 'cause I haven't made anything water-soluble in I don't know when. Where were crystals like these when I needed them, back in grad school? Kept trying to grow some for X-ray work, and all I could get were these fluffy little needles, fine as frog hair.

This, on the other hand, is not as fine as frog hair. Look at that - whatever this brown junk in here is, it sure isn't doing that rubber septum on top any good. Live an evil life, and you'll come back as a rubber septum. Or maybe a vacuum pump trap. Oh yeah, that's that chlorosulfonic acid reaction. No wonder the septum looks like that. Reaction didn't do a thing, though - how can you heat something up in neat chlorosulfonic acid and not have it do something? Against the laws of nature, that is. But you know, taking grief from Nature is kind of the job description around this place. . .

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March 20, 2006

Grad School, Blogged

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Posted by Derek

I spent the day giving the Wonder Drug Company good value for their money - cranking out a load of intermediate for other folks on the project and getting analytical data on some other samples. And talking about that sort of thing reminds me to link to a chemistry blog that I wasn't aware of until recently: a grad student named Dylan Stiles, who's working for Barry Trost out at Stanford.

Stiles is running just the kind of blog that I would have if. . .well, if the Web had existed back in 1985 when I was a grad student. Actually, it was probably a good thing for my graduate career that it didn't, come to think of it. That's the era of the "old timey" NMR machine in this post of his, which makes me wish I could find a photo of what we considered an old-timey machine. Ah, here we go: scroll down to the middle of the page, to the picture under "1976-1977". I used one of those things, and no, you didn't have to load coal in the back of it and wait for the boiler to fire up. It just looks that way.

At any rate, Stiles talks about the reactions he's running, with drawings and schemes, and takes photos of the crystals he gets and other oddities around the lab. I really wish I could do something similar once in a while. I obviously can't talk much, though, about (for example) the heterocycle I finished up today, except to note that the reaction used an unseemly amount of straight hydrazine, like nearly half a liter, and I was very glad to see the back of it. And I'd like to show some photos, too, but the Wonder Drug Factory has a "no camera" policy, and I can see why, what with chemical structures drawn all over the place.

But there would be some things to show off: I dropped a big stirbar right through the side of a one-liter pear-shaped flask the other day, for example, producing a perfect Pyrex analog of a gourd birdhouse. All I need to do is flame-polish the hole and find a way to stick a stopper permanently into the ground glass joint, which is a task that I've always seemed to be pretty skilled at, and I'm in business. See what you're missing?

Anyway, give Stiles a look if you're a hard-core organic chemistry geek like me, and if anyone knows of some other chemistry grad student or post-doc blogs, please send them along. I need to differentiate my blogroll a bit more, and that would be a fine category to have.

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February 14, 2006

First Slide, Please

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Posted by Derek

I spent a good party of my day today in various meetings, but (fortunately) I didn't have to present anything at any of them. There have been some close calls over the years.

Back at a former company, I sat down in one of our group meetings, idly wondering who was going to be presenting today. What a pleasant surprise to find out that it was me! "I asked Derek a couple of weeks ago to put something together on this approach to our binding data that he's been working on. . ." said my boss, as I looked at him in dawning terror. Yes. . .yes. . .he did do that, didn't he. . .it's all coming back to me now. . . I had nothing prepared, nothing at all. Actually, I had very little to talk about in the first place, because the approach he was referring to hadn't yielded anything interesting. I'd dropped it just a couple of days after he'd asked to talk about it. Now, if I'd remembered that I was supposed to present, I could have at least left some doubts in people's minds about whether I was on to something. But as I staggered through a grim chalk talk, the true state of affairs became horribly clear.

Not all of these situations have ended in disaster. I recall a meeting where a number of us were presenting on our current projects. I had just been put in charge of a new one, which fact had somehow not registered on me as I wandered in to the conference room ready to hear from everyone else. After the first couple of speakers, a tiny bell went off in my head. I turned to a friend of mine sitting next to me and took a look at the agenda: yep, there I was. Coming up after two more speakers. Well, now.

I excused myself and sauntered over to the door. As soon as it closed, I bolted for my office and threw together a fast handful of slides (fortunately, I had the makings already, otherwise I'd have been doomed for sure). I returned in plenty of time, and gave what was a much more coherent presentation than it had any business being. Procrastination is one thing, but putting the presentation together twenty minutes after the meeting had started - that still stands as my record, and I've no desire to break it.

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February 5, 2006

Stream of Consciousness

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Posted by Derek

You know, people make sulfonamides all the time. . .we love sulfonamides in med-chem, right? So why can't I make a simple little sulfonamide off this heterocyclic system, eh? OK, right, there aren't any examples of these things in the literature - not last time I checked, anyway - so maybe there's a reason, but having no examples in the literature is the whole reason I'm trying to make 'em in the first place.

Right. . .send this one down for LC/MS anyway, maybe there's some of the right stuff in there and at least I'll know what it looks like. Yikes, that doesn't dissolve worth a hoot in straight methanol; if I send down a cloudy vial like that they're going to beat me with sticks. Maybe some acetonitrile. . .if this were really a sulfonamide, wouldn't it dissolve better in methanol, anyway? Ah, who am I kidding, these compounds do whatever they want to. If I ever write a book on heterocyclic chemistry, and God forbid, I'll divide them into two kinds of ring systems: friendly and hostile.

Yeah, that'll sell. I'd do better with that idea I had in grad school: "Quantum Mechanics: A Hand-Waving Approach". There's a real market for that one, and by now a hand-waving approach is exactly what I'd be capable of. Man, I remember that course - sitting there doing integrals for particle-in-a-box problems until midnight, and when I tried to go to sleep my brain was still integrating by parts. Couldn't turn it off. What a relief when I woke up and it had finally stopped - never had that happen again, and I've stayed away from quantum so as not to take any chances. What a mess that was - I'd forgotten so much calculus that I had to re-learn, and it had been what? Four years? It's only been twenty since then; I'm sure I'd be a real whiz.

Of course, it was while I was sitting there at my desk in that ancient lab, staring at those integrals that I looked up and saw a kilo jar of benzidine on the shelf right next to where I was sitting. Benzidine. . benzidine. . .that rang a bell, and then I realized, oh yeah, bladder cancer, benzidine's the one that gives you bladder cancer, and here I am camped next to a pony keg of the damn stuff. If I tried to order that through our system now a bunch of sirens would probably go off.

They should have gone off, anyway, when I ordered that new reagent from Big Jim's Discount Chemicals, or whoever it was, some outfit I've never heard of. Month and a half later, and it hasn't shown up. The inventory system keeps sending me e-mails, "Please Enter This Overdue Order". I should set up an auto-reply: "Please Put It In Your Ear". But if I did that, odds are that I'd end up sending it to everyone in the department somehow. . .hard to see the upside of that. And that reagent was going to be the thing to make these sulfonamides. . .aargh, sulfonamides. . . .

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February 1, 2006

The Good New Days

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Posted by Derek

I've been working on a longer post on antisense drugs (which, in case you're wondering, are different - most of the time - from nonsense drugs), but it's not quite ready yet. Home life and the Wonder Drug Factory are keeping me hopping these days.

The other day I was talking about old-fashioned reactions that we still use all the time, and I can testify to that from recent experience. I've been messing around with Grignard reagents all week, for one thing. But one of the comments to that post mentioned that I shouldn't give people the impression that those reactions are all that we use, and that's a good point.

For example, I've said before that if I had to pick one type of reaction that's run every day now that wasn't well-known when I was in graduate school, it would be a palladium-catalyzed coupling. The most commonly run is the Suzuki reaction, and we've been doing those all week, too. I would absolutely hate to do without this family of carbon-carbon bond forming methods - in fact, it's hard to imagine how we ever did.

But even though it's been around since 1979, not many people ran these reactions in the mid-1980s when I was in grad school. Palladium chemistry was seen as this exotic stuff that did weird things, and did them mostly in the hoods of organometallic chemists. As that decade wore on, though, the Suzuki and other such couplings became better known, and they just completely conquered the world in the 1990s. Now there are whole sections of the chemical catalogs devoted to them. You probably could buy about a half-dozen arylboronic acids back in 1985, but an entire industry has sprung up around such things now. And since new improvements and extensions keep coming all the time, the catalogs will surely look even stranger in another fifteen years.

My only real complaint about the Suzuki reaction is that there are so many ways to run it - solvents, catalysts, additives, temperature. You can generally get it to give you some product, no matter what conditions you choose. But in many cases, optimizing it to a reproducible high yield is like black magic. My pet theory is that any given palladium coupling reaction can be made to run in over 90% yield, if you're just willing to devote enough of your life to finding out how. Most of the time, I take what they give me and move on.

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January 17, 2006

Gimme That Old Time Reaction

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Posted by Derek

Many of my readers are professional chemists, but many aren't. For those who've only had sophomore organic (or less), it sometimes comes as a surprise to find out that we actually use a lot of those reactions that you have to learn.

That's a strange thing about chemistry as compared to most of the other hard sciences. I don't think that much that you learn in a second-year physics class comes up in the day-to-day life of a physicist, and the same goes (and how) for most biologists. But I'm here to tell you: we professional organic chemists really do Fischer esterification, the Knoevenagel condensation, and a lot of those other ancient reactions. Not just once in a while, either - we do 'em every day of the week. My lab, for example, has been wrestling the last few days with forming and using a particular Grignard reagent, and Grignards have been a standard part of undergraduate labs for generations.

Why do we stick with these moldy reactions? Because they work, for one thing. Reducing an aldehyde with sodium borohydride, for example, is a procedure that's been around for a good forty years. But it's a mighty rare aldehyde that won't reduce cleanly with the stuff. It's fast, it's cheap, and it's generally easy to clean up the reaction, so why not?

Another reason is that these reactions are close to the fundamental principles of organic chemistry. If you're going to make an ether from an alcohol, for example, it's hard to see how that's going to happen without an oxygen attacking a carbon center somewhere along the line. I mean, you're forming an oxygen-carbon bond, so you can't avoid it. And oxygen is so electronegative, you have to figure that it's going to have some sort of negative charge built up on it, so it's going to be attacking something with a partial positive charge. . .and there's the good ol' Williamson ether synthesis, the classic nucleophilic substitution. To have a completely different ether synthesis, you'd almost have to have a completely different form of oxygen.

And that brings me to an observation that I've made before - that you can be a fine medicinal chemist using nothing but reactions from a sophomore organic textbook. It's a bit humbling to realize that, because catching on to that fact tells you where chemistry stands in drug discovery: not as an end in itself, but as a means to an end. And if those means turn out to be reactions that an eighty-year-old grandmother could learn to run, and that are older than she is on top of it, well, fine. We're not here to use the latest hot reaction, unless it can speed up making a drug. Because that's the point.

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December 23, 2005

Sort Of Like A Wine Cellar

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Posted by Derek

As you may have noticed from the all-times-of-day posting schedule around here the last few days, I'm already on vacation. I'll return to the Wonder Drug Factory on January 3, and I'm already glad that I wrote myself my traditional note reminding me what I was doing and where things are. I'll continue to post here reasonably often until then, although there will be a missed day or two while my kids jump up and down on top of me. And I have to take time, naturally, to deal with questions such as the one just asked by my son, who wanted to know if anyone has taken one of those half-eaten cookies you find on Christmas morning and tried to "get some of Santa's DNA".

One of my first acts on returning to the lab will be to clean the place up a bit. I have detritus from two or three past projects scattered all over the place, and it doesn't need to be where it is. Some of it is going to go right into the red waste can, of course. Heck, some of it should have gone right in the red waste can right after it was made, but you don't have any way of knowing that at the time. But some of it will go to a (theoretically) more useful place.

In a chemistry research department, people are always making batches of intermediate compounds, often in reasonable amounts (5 to 100 grams, say). These are things that you can't buy from any supply house. Often they're based on chemical scaffolds that have already been shown to be useful in one or more projects, and have functional groups hanging off of them that are ready to be elaborated. This is valuable material, and you don't want to throw it away. What our department has done, like many others, is set up a catalog of these things and a central place to store them. I need to move a bunch of these home-made wonder drug building blocks out of my hood and down the hall, so that someone can possibly make use of them. And I could use the space - everyone comes out ahead.

That'll give me the elbow room to work on my current project, and to keep moving along (once again) on my side project, which I haven't spoken about much recently. Instrumental difficulties and other things have slowed it down, but it's most definitely still alive, and will (I hope) start off in several directions come January.

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December 5, 2005

Home Sweet Home

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Posted by Derek

Chemistry labs aren't known for the diversity of life forms - other than chemists - that inhabit them. It's true that I used to see the occasional mouse run across in an old building I worked in, and no, it was a little grey wild-type, not an escaped C57 Black from downstairs.

Now, once you get over to the desk areas, the usual array of plants do just fine. I have a paphilopedilum orchid that's come into bloom (looking very much like this), six or eight other orchids that are all doing fine, and a bougainvillea that's just finished a bloom cycle. In the spring I start a trellis on the sunny wall - last year I had morning glories blooming all over the place in here, and suggestions are welcome for the next crop.

So it's not like the atmosphere in the lab is toxid, although I wouldn't move the orchids into the fume hood, most likely. It's just not a place with a lot of natural habitats. But habitats are where you find them, as I realized when I saw a bottle of phosphate buffer cloud up on me the other day. (That's a well-known problem to real biologists and other power users; only a hack like me would leave phosphate buffer sitting around on the bench for weeks).

But phosphate I can believe as a growth medium. How do I explain some of the other things that show up? For example, I think there's something growing in a plastic bottle of saturated ammonium chloride down the bench from me, which would be impressive. My wife once saw something gaining a foothold in some saturated brine, presumably some halophilic organism escaped from the Dead Sea.

And my most alarming case, seen at a previous job in New Jersey, was a large, dark, fluffy ball of fungus floating in a bottle of saturated sodium bicarbonate. This stuff wasn't just hanging on in there, it was enjoying itself and reaching for more. There were two or three inches of solid bicarb on the bottom of the solution; it probably couldn't wait to get down and hit the mother lode. "That's a Jersey mold!" exclaimed a labmate.

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November 10, 2005

. . .And That Settles It

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Posted by Derek

You know, after all the philosophical wrangling that's gone around here the last couple of days (I refer to those record-setting comment threads below), I have to say that there's something about scientific research that I really appreciate: things get resolved.

Not everything gets resolved, true, which is also part of the fun. But enough things do get settled to provide a person with a sense of accomplishment. In medicinal chemistry, we have to come to some firm conclusions about things, for example: Is Drug Candidate X more efficacious than Drug Candidate Y? How long does it last in the blood after an oral dose? Is it more toxic? What will it cost to make?

Naturally, there's room to argue about the details of all those things. Try "efficacious", for example - in which model of the disease are we talking efficacy? Efficacious by which biological criterion? Are those both the right ones to use to try to predict clinical success, or are we just kidding ourselves? (A constant temptation, that). The other questions can be exfoliated in the same way. Which species are we measuring blood half-life in? Is that the relevant one? How long do you think the half-life should be, and why do you think so?

And you'll have to define "toxic" in the same manner that you had to define "efficacious". Toxic at what level, in what way, and in what species? Is that result relevant to man, or just another stupid distraction? How do you know, and just how much are you willing to bet on that opinion? A million dollars for multiweek tox studies? Tens of millions to get started in clinical trials? Hundreds of millions to get the thing to market? The whole company if you're wrong even after that?

No, there's enough uncertainty to keep things lively, all right. But there are still a lot of things that get settled along the way, once and for all. This reaction really is more reliable than that one. That chiral methyl group really is pointing in that direction. This compound really does bind more tightly to the target than that one and no, we really, really aren't going to develop that other one that just killed off all the rats. After a week of philosophical tug-of-war (for which I have only myself to blame; no one forced me to write about Intelligent Design), I do enjoy the certainties of a clean NMR spectrum

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October 30, 2005

Gooooaaaal!

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Posted by Derek

I do a fair amount of complaining (maybe I could just stop and put a period there. No?) about how people don't realize the difficulty of taking an idea for a new drug all the way to the market. But I shouldn't be the tiniest bit surprised, because depictions of research skip most of the work. How would anyone who doesn't do this stuff realize how time-consuming it is?

When I started doing real lab experiments, it struck me that I was spending an awful long time purifying messy reaction mixtures and trying to make sure that I'd made what I thought I'd made. Now, twenty-odd years later, it seems like I spend a awful lot of time doing those same things. There's no way around either one of them, but you'd never know it from virtually any depiction of scientists at work. Having a character spend three days running a chromatography over again (and again) because the peaks aren't well resolved doesn't advance the plot very well, does it? There's nothing page-turning about combining a long run of messy mixed fractions, evaporating out all the solvent - which always takes much longer than you thing it will - and sending them down yet another column, which will generate a few pure cuts and another heap of mixed fractions.

These delays are found in every operation of a research lab, and they scale in a fractal-type manner. Five-minute tasks have at least a minute's worth of delay in them (waiting for the thick syrupy starting material to dissolve so you can toss a magnetic stir bar in there without getting it stuck), and five-month tasks have at least a month's worth (figuring out why the large batch of material for the serious toxicology runs doesn't dissolve as well in the dosing vehicle as all the other batchs). And the five-year tasks? Try an extra year of enrollment for the pivotal clinical trials on for size.

So asking a drug researcher how they could have worked for X years without ever producing a drug is a bit like asking a soccer team: "You booted that ball around the field for ninety minutes and didn't even put the thing in the net?" Nothing plays defense like nature can.

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October 26, 2005

The Latest in Pharmaceutical Technology

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Posted by Derek

I've been spending some time with a batch of compound recently, boiling it in ethyl alcohol all day long. I distill out the ethanol, then add more and boil it up again. And again. Why am I being so darn productive, you ask? Well, this is some material we received from a contract synthesis company, and while it's the right stuff, it came to us with nearly 10% chloroform in it. You find these things out by taking NMR spectra of the outsourced stuff as soon as you get it in, and preferably in more than one solvent. Trust but verify and all that, particularly from the low bidder.

Deuterated chloroform is a common solvent for NMR spectra, and it always shows a greater or lesser peak for the plain stuff. If we'd only run the spectrum in that, we might have just written it off as an ugly bottle of NMR solvent, but it's rather more difficult to explain its presence in a sample run in, say, DMSO. As it turns out, it's a contaminant left over from the last step of the synthesis, and it's the sort of thing you'd think that a day or two on the vacuum pump would take care of. After all, it's pretty volatile stuff, right?

Well, not in this case. This is one of those times when the solvent seems to have decided to work its way into the crystal lattice of a compound, because that chloroform's not going anywhere without a fight. This compound is not the most soluble stuff in the world, but hot ethanol gradually does the trick. Thus the repetitive distillation. Of course, now the compound is cut with ethyl alcohol instead of chloroform, but that's a much more benign thing to feed the rodents come assay time. Drunken mice we can allow for, but not ones that have been chloroformed from the inside out.

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September 27, 2005

Tribes

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Posted by Derek

There are some pretty big cultural divides in the drug industry. The preclinical research people and the development people always think that they have one of the biggest, but that's not true. They do argue a lot, but the arguments are phrased in terms that each side understands. "Your synthetic route can't provide enough compound" "You're testing at too high a multiple for a toxicity dose" - these are worthy points to disagree on. Someone's going to win, and someone's going to lose, and both parties will know it, and they'll know why. That's why the discussions are so intense.

Try the space between marketing and research - now there's a canyon for you. During the periodic attempts to get these two groups to work with each other, each one feels as if it's making First Contact with an alien race. Marketing is such an imprecise world compared with the physical sciences (which are so cut-and-dried compared to marketing, as far as they're concerned) that sometimes they just talk past each other.

But for real extraterrestrials (as far as the research folks are concerned), you just have to go to HR. Of course, they feel exactly the same about us. Part of that is because the scientific habit of asking "Hmmm. . .I wonder if that's true?" doesn't make many HR presentations go more smoothly. I'll admit that it's hard to get real data on how well most human resources initiatives and techniques actually work, but you wouldn't know that to talk to some of the more enthusiastic practitioners. What's interesting is how they're generally just as perky about the next managerial fad, which generally comes along every three to five years.

I'm certainly not saying that scientists would be any good at the HR jobs, although we'd probably be better at theirs than they would at ours. Still, putting us in charge of problems that can't be settled by collecting more data probably isn't a good idea. Then there's the personality problem. Even though the real crazies are found mostly in academia, plenty of industrial researchers have people skills that need some fine sandpaper work and a coat of rustproof primer. No, you don't want a bunch of chemists and biologists running that shop. . .but just who do you want running it?

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September 18, 2005

A Sensitive Guy

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Posted by Derek

Well, my poison ivy has abated, which is good news on several fronts. Besides the obvious one, it also means that I wasn't exhibiting a reaction to a particular reagent that I was using a lot of at the same time, an aryl isocyanate. Those are reactive little creatures, and they're known to bother some people. I'm very glad it wasn't an immune response to it, because (a) I still need to do reactions with the stuff and (b) I've never become sensitized to any lab reagent, and I'd hate to start now.

Probably the closest I've ever come was back in graduate school. I had a long synthesis that started with a tosylation reaction of a protected sugar. For the non-chemists, that's a way to convert an alcohol group into something much more reactive, and it uses a reagent called para-toluenesulfonyl chloride. Since even organic chemists don't like wandering around all day saying mouthfuls like that, it's abbreviated in the lingo as tosyl chloride.

And it reeks. It has a peculiar nasty sweetish smell, penetrating and hard to get out of your nose, particularly when you're crystallizing a kilo of the stuff. As I wrote in passing here, it was very easy to get fed up with that step. It got to the point that the smell gave me an instant headache, right up between the eyes. That's no longer the case, but I don't enjoy working with it to this day.

The other reagent that I couldn't take for a while isn't known as a sensitizer. When I was a teaching assistant during my first year, one of the sophomore organic labs was the preparation of phenyl Grignard reagent. They did that in good ol' diethyl ether, probably because it's cheap as dirt. Never mind that it's one of the most volatile (and flammable) solvents you can possibly use, and never mind that there were about two fume hoods for thirty students, so everyone just banged away out on the benchtops. The air practically got wavery with ether fumes, and why the whole place didn't go up is a real stumper.

I was teaching three lab sections a week that term, as fate would have it. After the first one, I had a headache from all that damned ether. That kicked in immediately during the second lab section the next afternoon, and I was really feeling awful by the end. Came the third section, and when the first gust of ether hit me I nearly hurled my lunch into the nearest sink. I just couldn't take it. I spent the whole afternoon teaching from out in the hall, asking people to hold up their flasks while I squinted at them and yelled encouraging advice. I only came into the lab to cruise from one side of the room to the other while holding my breath.

No, I couldn't take the smell of ether for a while after that one (it doesn't bother me now at all). But then, I spent my first week as an summer undergrad in Dale Boger's group (1982) surviving mostly on the contents of a jar of peanut butter, and it was a year or so before I could face that again, too. Academic chemistry does toughen you up.

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August 24, 2005

Having the Hands

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Posted by Derek

After working so many years in organic chemistry labs, I notice that I have all these little motions and flourishes in my technique. For example, when I'm draining the bottom layer out of a separatory funnel, I always drain it down almost to the bottom, and stop. Then I swirl it around a little bit, because there's always some of the bottom-layer solvent that's still stuck to the sides and hasn't crept down yet. That quick swirl knocks it down, along with any droplets that were holding on to the meniscus at the top. Then I take the stopper out, wiping it edgewise across the ground-glass joint to catch any dripping solvent, and always put it on the side area of my stir plate. Only then do I drain the remainder of the bottom layer. And every time I turn the stopcock off, I automatically reach up with the flask or test tube I'm using and swipe it across the tip of the funnel, to catch the drop that's always hanging there.

I don't usually pay attention to these things in such Proustian detail, but I got to thinking about all the lab habits I've built up in the last 25 years or so (I'm counting back to my undergraduate days.) These things are instant signs, in any field, of someone who's been doing it a long time. They have a set of automatic routines that work and have always worked, and they don't need to think about them any more.

I couldn't tell you, for example, when the last time was that I poured something into the top a sep funnel whose stopcock was left open, although in my first years in the lab I did that a few times (to loud curses.) I'm past all that. Now, I make the advanced mistakes.

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August 9, 2005

Differences Between Academia and Industry, Pt. 4

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Posted by Derek

You hear an awful lot about teamwork when you're in industry. (Personally, my fist clenches up whenever I here the phrase "team player", but perhaps that's just me.) But there's a bit of truth in all this talk, and it's something that you generally don't encounter during graduate training.

As a chemistry grad student, you're imbedded in a chemistry department, and most outside groups will either be irrelevant or there to service things for you. Getting along with people outside your immediate sphere is useful, but not so useful that everyone makes the effort. But pharmaceutical companies have a lot of different departments, and they're all pretty much equal, and they are all supposed to get along. You've got your med-chem, your pharmacology, the in vivo group (or groups, who may be stepping on each other's toes), metabolism, PK, toxicology, formulations. . .as a project matures, everybody gets dragged in.

These other folks do not see themselves, to put it mildly, as being put on earth to service the medicinal chemistry group. They are very good at detecting the scent of that attitude, and will adjust theirs accordingly. (Some of them already have filed chemists in the "necessary evil" category.) For the most part, no one is supposed to be able to pull rank on anyone else, so in order to get things done, you'll have to play nicely with others.

Not everyone figures this out. I watched someone once whose technique of speeding up the assay results for his compounds was to march down to the screening lab and demand to know where his procreating numbers were, already. No doubt he thought of himself as a hard-hitting, take-charge kind of guy, but the biologists thought of him, unsurprisingly, as a self-propelled cloaca. His assay submissions automatically got moved to the "think about it until next Tuesday" pile, naturally.

Earlier entries in the series can be found here.

Comments (7) + TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs

August 3, 2005

Let's Check This Blank Page, Here

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Posted by Derek

I think that most of the large (and some of the small) drug companies have by now made the switch to electronic lab notebooks. It couldn't have come too soon for me. My merits as a scientist are up for debate, but my virtues as a record keeper are inarguable: I stink.

And have stunk, for some time. Back to graduate school, actually, which is the first time I seriously had to keep a notebook. Looking back at my first-year books by the time I left, I could see the decline in promptness and experimental detail. Man, were those first few months of experiments ever well-documented! Too bad none of them were worth anything, but that's the sort of joke that science plays on us.

My first years in industry were fair to good, but I tended to backslide. Setting up experiments is fun, as chemists know, much more fun than writing them down, and certainly a lot more fun than working them up and purifying the products. So I'd go the post-it-note route - writing down the amounts and a brief structural scribble to remind me, and put that on the appropriate notebook page. To remind me, you know, when I got around to writing it up, which would be Real Soon Now. Need I add that some of these things were as intelligible to me as Hittite tablets by the time that day arrived?

It got to the point at my former job that I once took a lab notebook home to Tennessee over Christmas. That, of course, is a mighty violation of good sense and legal protocol, and if I'd lost the thing, who knows what they would have done to me. Do not try this, if you're still using hard-copy notebooks. But there I was, back at my parent's kitchen table, writing up reductive amination reactions, one after the other.

The electronic notebook has kept me honest. I type much faster than I can write by hand, for one thing, so I actually put a few more details into my experimental procedures. All the analytical data is tied to the procedure, so I can't manage to lose that, either. The structures are all done with chemical drawing software, bless it, which means that you cut, copy, and paste 'em when you're working in a related series of compounds. A far, far superior system. Now I just have to generate some results worthy of it. . .

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August 1, 2005

Seven Questions

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Posted by Derek

As a drug discovery project moves along, we synthesize lots of new compounds, test them, and pick the best ones to make in large quantities. Simple, eh? Try your hand, then, at some of these questions, all of which have come up in the course of my career so far:

1. If you're running an experiment in vivo, and your control compound (from a competitor) is a highly active, hard-to-beat standard - how do you interpret your results when you know that this compound has made it to market and is no great shakes in human patients?

2. What do you do when you have to make a large batch of some compound for advanced pre-clinical work, and there's only one person in the whole department who can really get the crucial reaction to work? Do you tell people that you have a good large-scale route, or not?

3. How about a bit earlier in the game - how do you deal with it when you have a high-yielding, clean route to a key intermediate that lots of your people are using, but it uses a reaction that you know, for a fact, that the scale-up group won't touch later on?

4. How do you handle things when your primary biological assay keeps acting up - by factors of five to ten? Do you normalize the numbers to a standard each time and hope for the best, or do you start to doubt the usefulness of the whole assay?

5. For bonus points, how do you tell which numbers you've been getting are closer to the truth - the ones that say your compounds are really active, or the ones that say that they stink?

6. How do you interpret things when the in vivo assay tells you that your compounds have wonderfully long durations of action, but the blood levels tell you that they completely disappeared from circulation long before?

7. What does it mean when your best compound is intolerant of even slight structural changes? Do you just run with it (after all, you only need one compound, right?) Or do you hammer away trying to find something that can be safely modified in order to have a back-up?

Are there right answers? Well, presumably. I know what answers I'd give to some of these, but I make no guarantees that they're the right ones. . .

Comments (8) + TrackBacks (0) | Category: Drug Assays | Drug Development | Life in the Drug Labs

July 25, 2005

Hydrogenation Made Easy?

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Posted by Derek

I recently saw a demonstration of a gizmothat promises to make catalytic hydrogenation easier. If it works, it's about time. This is an ancient reaction (the standard apparatus is pretty much unchanged since the 1920s), but it's still extremely useful. But nobody likes to run the darn things.

For the non-chemists in the crowd, the idea is that hydrogen gets added to a bond (or bonds) in your molecule. So a carbon-carbon double bond gets reduced to a single bond, for example, or a triple bond to a double. (Unless you're careful, though, that triple bond is going to go all the way down without stopping.) You can even reduce aromatic rings down to their saturated counterparts, which was the very reaction I was speaking about the other day (taken a hexagon-with-a-circle drawing down to a plain hexagon.)

And it doesn't have to be C-C bonds that you reduce. N-O bonds are particularly labile to the reaction, so nitro groups get turned into amines, among other things. And some single bonds, especially those near aromatic rings, can just get completely cleaved, which is the basis for a lot of protecting group chemistry that people use to tape down reactive parts of their molecules for a while.

To do all these neat things, you need a metal catalyst, whose efficacy correlates nicely with their cost. Platinum, for example, is a fine one. Palladium, its blood relation, is very widely used. Nickel, rhodium, and iridium have their uses, and from there you go off into some real esoterica. These things are sometimes used just as fine metal powders, but often they're furnished as a fine dispersion on some sort of solid support - powdered charcoal or alumina, for example. Good ol' 5 per cent palladium on carbon is probably the most often used hydrogenation catalyst in organic chemistry.

You might get the impression from all these variations that the field is lacking in rigor. You would be very correct indeed. Tom Goodwin, my undergraduate organic chemistry professor, accurately described it as "witchcraft." The real atom-by-atom mechanism of the reaction is known in broad detail, but many key things are still obscure. Hydrogenations can vary not only according to the substrate molecule and the metal, but according to its solid support (and its loading on it), the solvent used in the reaction, the temperature, the pressure of the hydrogen gas in the vessel, and the source of the hydrogen itself.

It's that hydrogen gas that causes the uneasy feelings about the reaction. Hydrognations have been responsible for untold minor fires in labs all over the world, and once in a while a major one. Hydrogen is famously flammable itself, but there are other problems. Once the metal catalysts are saturated with the gas, they often glow red-hot on exposure to air, which is not so good when you have lots of organic solvent around. The "Raney nickel" catalyst comes already soaking in hydrogen, and a classic way of seeing if it's still good is to wipe some of the wet powder on a paper towel. If it bursts into flame when it dries, it's fine.

I've instantly singed the hair from the upper joints of my fingers through misjudgment of these little details. (Another hard-to-forget experience with hydrogenation apparatus is here. If this contraption works as advertised, perhaps my nerves will have one less thing to jangle them.

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June 15, 2005

How Safe Is This Stuff?

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Posted by Derek

Prompted by a comment to the benzene distillation post, I've been searching for some accident rate or life expectancy data for organic chemists. It's not easy to find. I'm pretty sure that the American Chemical Society collects this sort of thing (and since they have a group rate for term life insurance, it would seem that someone has looked into the matter), but the numbers don't seem to be public. Anyone know of a source?

My belief is that organic chemistry isn't a particularly hazardous profession. The risks go down as you get out of graduate school, where there's much less supervision, in facilities that are often not the most up to date, with many more dangerous people running around. We've weeded out most of the really deadly folks here in industry, and I'm sure that there's a steep power-law distribution that has them accounting for way more than their share of trouble.

Almost every serious accident I've ever been around has been someone's fault - that is, as opposed to JOOTT (Just One Of Those Things.) Nope, the bad ones have all been due to someone screwing up, generally in a way that made independent observers groan and shake their heads afterwards. Distilling things that shouldn't be distilled, making things on a scale that they shouldn't be made (with the available equipment), grievously mishandling fiery and corrosive reagents, setting up closed systems and cranking the heat up on them - that's the sort of thing I mean.

And as far as I can tell, the best way to improve your safety record is to get rid of the people that seem capable of doing this stuff. The worst ones aren't particularly trainable, anyway; you're much better off without them. "Against stupidty, the Gods themselves contend in vain", and no safety program is going to stand a chance, either.

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May 25, 2005

The Voice of Experience

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Posted by Derek

During a meeting today, some of us were making a decision about whether or not to take a look at a particular series of compounds in some assays. I spoke up, saying "Hey, if we've got 'em, why not? Never talk yourself out of something that's easy to test."

"The voice of pragmatism", said someone else, and I responded "Darn right!" It's a real temptation in this business to think that you know more than you do. The alternative, a realistic appraisal of just how lost you (and everyone else) is, can be a bit disconcerting, and that's why I think people overvalue their expertise. "Those compounds never work," "We did something like that before," "We already know what the answer is" - these are the sounds that people make when they're trying to sound wiser than they probably are.

I have to look out for these tendencies in my own work, too. I've seen enough different sorts of projects that I do have some valuable experience to draw on. But not all of it is valuable all the time, and it's very hard to know when you're being fooled by a false correlation with something that's happened before. I don't know when something is going to be orally active, and I don't know what its blood levels are going to be like. Much as I would like to, I don't know exactly how a given compound binds to its protein target, and neither, in almost every case, does anyone else. I sure can't predict toxicity, either, and it's not for lack of motivation. One of the most valuable things I can take away from all my experience is the willingness to step back and let the results sort themselves out.

Now, there are times when you really shouldn't try something. But those times occur much less frequently than you'd think, and usually for lack of time or resources. But if both of those are available, I'm up for taking a flyer on all kinds of odd stuff. Some of the best things I've ever done looked pretty weird while I was doing them, that's for sure. But I'm at the point in my career where I'm less concerned about looking like a fool, so perhaps my best work is still to come.

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May 16, 2005

Cuprate Voodoo

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Posted by Derek

I may talk a good game, but don't let me fool you: I really don't understand some of the things that happen in my lab. I was talking with some colleagues the other day, and told them about a reaction I had in my PhD work. I was using a so-called "higher-order cuprate" reagent, which you make from copper cyanide and lithium reagents, and it worked just fine for me the first time out.

And then it worked just fine again, on a larger scale, and then it worked just fine one more time. And at that point, it stopped working, forever. I never got the tiniest bit of product out of the reaction again, only starting material and varioius forms of junk. It was as if someone had turned a switch.

We're supposed to be able to work these problems out, and I tried. I checked my solvents, my starting materials, and my technique. I analyzed my lithium reagents, and I tried every bottle of copper cyanide we had. Then I made my own, the most beautiful copper cyanide you'd ever want, assuming that you'd ever want some. Result, zilch. I reversed field, thinking that I'd used an old bottle which might have some oxidation products in it that made things work. But aging the stuff by heating it in an open flask didn't help, either. Nothing did. I kept looking at my flask of product from before, a key intermediate in my synthesis, and wondering how on Earth I'd ever made it.

Well, as I finally wrote in my dissertations, "cuprate reagents of all sorts were abandoned after this experience." I never did find out what happened, and eventually worked out another way to get the product (which reminds me, if anyone out there needs to use dimethylmagnesium, talk to me - have I got a recipe for you!) Organometallic reagents are famous for being tricky, but you'd think that a science as old as organic chemistry - we are a science, right? - would be able to deal with such problems. Maybe not.

(Note: the structure and reactivity of all kinds of cuprate reagents have been the subject of food fights for many years. Here's a sample, but if you're not seriously into organometallic chemistry you're going to feel as if you'd stepped into a room full of people discussing Zoroastrian theology. A later and less contentious look at the field can be found here as a PDF.)

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April 20, 2005

Sneaking Out for an Interview

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Posted by Derek

There was a good question asked in the comments to the previous post on first job interviews: what do you talk about when you work at one company and you're interviewing at another?

Well, I've done that myself, more than once (note to my current co-workers: not in the last few years, folks.) And it can be tricky. But there are some rules that people follow, and if you stay within their bounds you won't cause any trouble. That's not to say that my managers wouldn't have had a cow if they'd seen my old interview slides at the time, but I was at least in the clear legally. Here's how you make sure of that:

First off, it would be best if you could confine your interview talk to work that's been published in the open literature. That stuff is, by definition, completely sterilized from an intellectual property standpoint, and you can yammer on about it all day if you want. The downside is that published work tends to be pretty ancient stuff by the time it shows up in a journal, and you've may have done a lot more interesting things since then. (The other downside is that published projects are almost always failed projects.) Work that's appeared in issued patents is also bulletproof, of course, but it suffers from the same time-lag disadvantages.

Second best is work that's appeared in patent applications. This stuff hasn't been blessed by the patent office yet, so things could always change, but it's at least been disclosed. When you talk about it, you're not giving away anything that couldn't have already been downloaded and read. (Of course, you do have to resist the temptation to add lots of interesting details that don't appear in the application.)

If you've at least filed the applications, then you can still be sort of OK, since they're going to publish in a few months, anyway. This is a case-by-case thing. If the company you're interviewing at is competing with you in that very field, you'd better not give them a head start. But if you're talking antivirals at a company that does nothing but cardiovascular and cancer, you should be able to get away with it. It would be best if you didn't disclose full structures - leave parts of the molecules cut off as big "R" groups and just talk about the parts that make you look like the dynamic medicinal chemist you are.

The worst case is "none of the above." No published work worth talking about, no patent applications, no nothing. I actually did go out and give an interview seminar under those conditions once, and it was an unpleasant experience. I had to talk about ancient stuff from my post-doc, and it was a real challenge convincing people that I knew what was going on in a drug company. I don't recommend trying it.

But I don't recommend spilling the beans in that situation, either. I've seen a job interview talk where it became clear that the speaker was telling us more than he really should have, and we all thought the same thing: he'll do the same thing to us if he gets a job here. No offer.

Comments (3) + TrackBacks (0) | Category: Academia (vs. Industry) | How To Get a Pharma Job | Life in the Drug Labs

April 18, 2005

A Smelly Riddle

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Posted by Derek

Here's a chemical puzzle for you: all of us who have worked in an organic chemistry lab can agree, I think, that pyridine reeks to the skies. My descriptive powers aren't up to conveying its smell, because it's really unique - foul, penetrating, and like nothing else but pyridine.

And we'll have no trouble agreeing that thiophenol is a stinker, too. It's one of the prototype stinkers, actually, since it's the main smell of burning rubber. (Imagine that aroma concentrated and ready for use in a bottle, and you've got thiophenol.) Now, what if we take those two structures and combine them?

You'd figure that, say, 2-mercaptopyridine would be impossible to take. But it has no smell whatsoever. (Some of you may be ready to e-mail me about how this compound isn't completely an SH, that it has some thioamide character. But before you do that, recall that thioamides are unbearable, too.) No, this seems to be a case of smells cancelling out at our nasal receptors. For whatever reason, a molecule with the combination of a pyridine nitrogen and an aromatic thiol doesn't set off our sensors.

And that's a good thing, considering what it would be like. Now, I guess you could make a one-molar solution of thiophenol in pyridine, and that would do the trick. I'll bet nothing would cancel out then! Fortunately, I've never come across that reagent combination, and if I ever do, I'll find something else that urgently needs my attention. . .

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March 30, 2005

Lost Arts

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Posted by Derek

(This is an update of a three-year-old posting - it seemed like a good time to bring it back.)

Since I was speaking about NMR, it's a good thing for chemists to remember that this tool wasn't always there for us. For those of you not in the field, I can say without exaggeration that we'd have to close up shop without it. It's so valuable that it's crowded out older, perfectly reasonable techniques like infrared spectroscopy.

Fellow chemists, raise your hands: Who's taken an IR spectrum in the last six months? OK, you folks who are characterizing compounds for your dissertations can put yours down. Anyone from Switzerland who's writing a paper for Helvetica Chimica Acta (where every new compound is characterized practically down to how it tastes) can put their hand down, too. Anyone left?

I didn't think so. It's a lost art. I haven't taken one since the late 1980s, myself. It's true that you can see all sorts of structural information in an IR, but why would you bother? NMR will tell you the same thing and plenty more at the same time, things you could stare an an infrared spectrum until your eyes cross and never be able to determine.

For an even more lost art, consider ultraviolet/visible spectroscopy. Go back to the 1940s and 50s and the journals are full of UV/Vis spectra, reproduced in all their near-featureless glory. I took a few of these as an undergraduate, and I don't recall ever doing any since. Inorganic chemists can be interested in these wavelengths, but darn few synthetic organic chemists are.

But don't get me wrong - I'm not asking to return to the days when those techniques meant something. Far from it. But every so often, when we're complaining that the NMR machine is taking an extra couple of minutes to automatically run our sample, it's worth taking a minute to think about the alternative.

Comments (4) + TrackBacks (0) | Category: Life in the Drug Labs

March 27, 2005

Ten Questions

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Posted by Derek

1. Did the American Chemical Society realize, when it started the journal Organic Letters, that all it would manage to do is turn the competing Tetrahedron Letters into a European journal and force libraries to subscribe to both of them?

2. Can there be a more worrisome lab nickname than the one given to one of my wife's former co-workers, a radioisotope user known as "Mister Chernobyl"?

3. What percent of chemists are the same type as me: willing and able to start new reactions all day, just so long as I don't have to work them up and purify the products?

4. Are there still undergraduate organic chemistry courses that do a lot of the old qualitative tests in their lab sections - Tollens reagent and all that? (I deeply hope that no one answers "yes" to this one.)

5. When you're scheduled to speak with a visitor from academia, is there any more surefire conversation starter than "How's the funding going?"

6. Have I really been looking at the same gel in all those molecular biology lab presentations over the years, or does it just seem that way?

7. Will I ever have cause to use a spinning-band distillation column again in my lifetime? (Bonus question: at what point will I be the only person in my workplace to have ever seen one of the things?)

8. Did anyone ever actually use those crazy bar-code things, condensed versions of the tables of contents, that the Pergamon journals used to have on their first pages? (This is equivalent to wondering if anyone's ever made the "Mock Apple Pie" recipe on the Ritz cracker box.)

9. Is there any reagent more pyromaniacal than dimethyl zinc? (The stuff makes most of the other flame-spouting reagents look like chicken broth.)

10. Could there be anything less likely to attract members of the opposite sex than readin