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: Twitter: Dereklowe

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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 (8) + 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.

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

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?

Comments (133) + TrackBacks (0) | Category: Life in the Drug Labs

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.

Comments (109) + TrackBacks (0) | Category: Life in the Drug Labs

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.
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.

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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.

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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.

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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?

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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

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. . .

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

November 16, 2012


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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!

Comments (31) + TrackBacks (0) | Category: Life in the Drug Labs

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!

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

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 (38) + 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. . .

Comments (56) + TrackBacks (0) | Category: Life in the Drug Labs

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.

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

July 18, 2012

The Best Rings to Put in Your Molecules?

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Posted by Derek