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

Derek Lowe The 2002 Model

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

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

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September 30, 2010

The Hours You Put In

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Posted by Derek

Several people have brought this editorial (PDF) to my attention: "Where is the Passion?" It's from a professor at the Sidney Kimmel Center at Johns Hopkins, and its substance will be familiar to many people who've been in graduate school. Actually, the author's case can be summed up in a sentence: he walks the halls on nights and weekends; there aren't enough people in the labs. Maybe "kids these days!" would do the job even faster.

I'm not completely unsympathetic to this argument - but at the same time, I'm not completely unsympathetic to the people who've expressed a desire to punch the guy, either. The editorial goes on for quite a bit longer than it needs to to make its point, and I speak as someone who gets paid by the word for printed opinion pieces. It's written in what is probably a deliberately irritating style. But one of the lessons of the world is that annoying people whom you don't like are not necessarily wrong. What about this one?

One of the arguments here could be summed up as "Look, you people are trying to cure cancer here - don't you owe it to the patients (and the people who provided the money) to be up here working as hard as possible?" There's no way to argue with that, on its face - that's probably correct. But now we move on to the definition of "as hard as possible".

He's using hours worked as a proxy for scientific passion - an imperfect measure, to be sure. At the two extremes, there are people who are not in the lab who are thinking hard about their work, and there are people in the lab who are just hamster-wheeling and doing everything in the most brutal and stupid ways possible. But there is a correlation, especially in academia. (In many industrial settings, people are actively discouraged from doing too much lab work when they might be alone). If you're excited about your work, you're more likely to do more of it.

Unfortunately, it's hard to instill scientific excitement. And if anyone's going to do it at all, you'd think it would be the PIs of all these grad students. What surprises me is that more of them aren't falling back on the traditional grad-school substitute for passion, which is fear. The author does mention a few labs at his institute that have the all-the-time work ethic, and I'm willing to bet that good ol' anxiety and pressure have as much or more to do with their habits. And a little of that mixture is fine, actually, as long as you don't lay it on with a trowel.

So yes, I wish that there were more excited, passionate researchers around. But where I part company with this editorial is when it goes into get-off-my-lawn mode. The "You have to earn your way to a life outside the lab" attitude has always rubbed me the wrong way, and I've always thought that it probably demotivates ten people for every one that it manages to encourage. The author also spends too much time talking about the Good Old Days when people worked hard, with lousy equipment. In the dark! In the snow! And without all these newfangled kits and time-saving reagents! That makes me worry that he's confusing some issues. An idiot frantically digging a ditch with a spoon looks like a more passionate worker than someone who came through with a backhoe three hours ago, and is now doing something else.

Still, the point of all those time-saving kits is indeed to keep moving and do something else. Are people doing that? I'd rather judge the Sidney Kimmel Center by what comes out of it, rather than how late the lights burn at night. Is that the real "elephant in the room" that the editorial winds up invoking? That what the patients and donors would really be upset about is that not enough is coming out the other end of the chute? Now that's another problem entirely. . .

Update: Chemjobber has some questions.

Comments (138) + TrackBacks (0) | Category: Graduate School | Who Discovers and Why

September 28, 2010

Open Thread

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Posted by Derek

I'm out of touch at a meeting all day today, so I thought I'd put up a request thread. What topics would people like to see covered here in the coming days and weeks? I have some chemical biology posts queued up, and current events will always intervene, but if you have any other topics for a medium-to-long horizon, feel free to suggest 'em. Thanks!

Comments (63) + TrackBacks (0) | Category: Blog Housekeeping

Wisterone: A Structure I Can't Believe

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Posted by Derek

You don't see an awful lot of chemistry publications from Vietnam. So in a way, I'm reluctant to call attention to this one, in the way that I'm about to. But it's in the preprint section of Bioorganic and Medicinal Chemistry Letters, and some of my far-flung correspondents have already picked up on it. So it's a bit too late to let it pass, I suppose.

The authors isolate a number of natural products from Wisteria (yep, the flowering woody vine one), and most of them are perfectly fine, if unremarkable. But their compound 1 (wisterone) is something else again.
Wisteria%20compound.png
Man, is that thing strained. Nothing with that carbon skeleton has ever been reported before (I just checked), outside of things that you can draw as part of the walls of fullerenes. I have a lot of trouble believing that this compound exists as shown - and if it does, then it deserves a lot more publicity than being tossed into a list inside a BOMCL paper - even though that journal is now getting a reputation for. . .interesting structural assignments.

This thing could get you into Angewandte Chemie or JACS, no problem. But the authors don't make much of it, just calling it a new compound, and presenting mass spec and NMR evidence for it. The 13C spectrum is perfectly reasonable for some sort of para-substituted aryl ring, but this compound would not give a perfectly reasonable spectrum, I would think. Surely all that strain would show up in some funny chemical shifts? Another oddity must be a misprint - they have the carbon shift of the carbonyl as 190.8, which is OK, I suppose, but they assign the methylenes as 190.8, which can't be right. (The protons come at 4.48).

No, I really think something is wrong here. I don't have a structure to propose, off the top of my head (not without resolving that weirdo methylene carbon shift), but I don't think it's this. Anyone?

Update: just noticed that this is said to be a crystalline compound, melting point of 226-228. I find it hard to imagine any structure like this taking that much heat, but. . .it's a crystal! Get an X-ray structure. No one's going to believe it without one, and BOMCL should never have let this paper through without someone asking for at least that. . .

Comments (46) + TrackBacks (0) | Category: Analytical Chemistry | Chemical News

Nobel Season 2010

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Posted by Derek

As we head towards October, the thoughts of a very select group of scientists may be turning to their chances of winning a Nobel Prize - and the thoughts of the rest of us turn to laying odds on the winners. I've handicapped the race here before (here's the 2009 version), and that's one place to start a list. Another excellent roundup can be found over at Chembark, and another well-annotated one at the Curious Wavefunction. Meanwhile, Thomson/Reuters sent me their citation-voodoo list the other day, but to my eyes, they're always a bit off the mark.

So who are the favorites? Last year I mentioned Zare, Bard, and Moerner for single-atom spectroscopy, and I think that after a run of biology-laced prizes that a swing back over to nearly-physics is pretty plausible. If the committee is going to stick with nearly-biology, then perhaps humanized antibodies, microarrays, or chaperone proteins will make it in, but I really don't think that this is the year (in the Chemistry prize, anyway). On the chemistry/medicine interface, there's always the chance that the committee could turn around and honor Carl Djerassi after all these years, but that's the only med-chem themed prize I can see. I think the chances of a pure organic synthesis prize are very low indeed - and that includes palladium-catalyzed couplings, too, unfortunately. There are too many people deserving of credit there, "too many" meaning "more than three" for Nobel purposes, and not all of them are still alive.

The more I think about it, the more skeptical I am of a Nobel for dye-based solar cells (Grätzel et al.) or any form of asymmetric catalysis this year. If anything, the committee waits too long before recognizing things, and it's just too early for these (and some other ideas floating around out there). The Thomson/Reuters list seems to be very big on metal-organic framework materials, for example, and I just don't see it. Waiting too long is a problem, but giving trendy things out too soon can be an even bigger one.

On the other end of the scale, I used to confidently predict a Nobel for RNA interference (in one field or another), and they finally took care of that one. The only Nobel I feel similarly sure of is in Physics, for the "dark energy" finding that the expansion of the universe is accelerating. At some point that one's going to win - maybe when there's more of an explanation for it, although that could be a bit of a wait. This is an area where I and the Thomson/Reuters people agree (and a lot of physicists seem to go along, too).

Want to make your own odds? This Chembark post is a fine overview of the factors involved. Suggestions welcome in the comments from anyone who feels as if their psychic powers are tuned up. . .

Comments (45) + TrackBacks (0) | Category: Chemical News | General Scientific News

September 27, 2010

Charges in the TMS Diazomethane Case

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Posted by Derek

Readers may remember the case of Ronald Daigle, who died of exposure to TMS diazomethane a couple of years ago in Nova Scotia.

Sepracor, the company who owned the facility at the time, has now pleaded not guilty to five charges related to this accident. (Many more details at C&E News). This case appears (slowly) to be going to trial, so it'll be something to keep an eye on. . .

Comments (8) + TrackBacks (0) | Category: Safety Warnings

Workhorse Reactions

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Posted by Derek

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

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

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

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

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

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

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

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

September 24, 2010

Serendipity in Medicine

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Posted by Derek

I came across this book the other day, and bought it on sight: Happy Accidents: Serendipity in Modern Medical Breakthroughs. From what I've read of it so far, it's a fine one-stop-reference for all sorts of medical discoveries where fortune favored the prepared mind (as Pasteur put it). There are drug discovery tales, surgical procedures, medical devices, and more.

Even the stories I thought I knew well turn out to have more details. Albert Hoffman's famous discovery of LSD, for example - what I hadn't known was that some of his colleagues didn't believe him when he said he'd taken only 0.25mg of a compound and hallucinated violently for hours. (From what we now know, that was actually a heck of a dose!) So Ernst Rothlin, Sandoz's head of pharmacology, and two others tried it themselves. "Rothlin believed it then", Hoffman noted. Those days will never come again!

Comments (9) + TrackBacks (0) | Category: Book Recommendations | Drug Industry History

Avandia Goes Down: A Research Rant

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Posted by Derek

So now Avandia (rosiglitazone) looks to be withdrawn from the market in Europe, and heavily restricted here in the US. This isn't much of a surprise, given all the cardiovascular worries about it in recent years, but hindsight. Oh, hindsight: all that time and effort put into PPAR ligands, back when rosi- and pioglitazone were still in development or in their first few years on the market. Everyone who worked on metabolic diseases took a swing at this area, it seems - I spent a few years on it myself.

And to what end? Only a few drugs in this class have ever made it to market, and all of them were developed before we even knew they they hit the PPAR receptors at all. The only two that are left are Actos (pioglitazone) and fenofibrate, which is a PPAR-alpha compound for lack of any other place to put it. Everything else: a sunk cost.

Allow me to rant for a bit, because I saw yet another argument the other day that the big drug companies don't do any research, no, it's all done at universities with public funds, at which point Big Pharma just swoops in and makes off with the swag. You know the stuff. Well, I would absolutely love to have the people who hold that view explain the PPAR story to me. I really would. The drug industry poured a huge amount of time and money into both basic and applied research in that area, and they did it for years. No one has to take my word for it - ask any of the academic leaders in the field if GSK or Merck, to name just two companies, managed to make any contributions.

We did it, naturally, because we expected to make a profit out of it in the end. The whole PPAR story looked like a great way to affect metabolic disorders and plenty of other diseases as well: cancer, inflammation, cardiovascular. That is, if we could just manage to understand what was going on. But we didn't. Once we all figured out that nuclear receptors were involved and got busy on drug discovery on that basis, we didn't help anyone with any diseases, and we didn't make any profits. Big piles of money actually disappeared during the process, never to be seen again. You could ask Merck about that, or GSK (post-rosiglitazone), or Lilly, or BMS, or Bayer, and plenty of other players large and small.

No one hears about these things. We're understandably reluctant to go on about our failures in this industry, but the side effect is that people who aren't paying attention end up thinking that we don't have any. Nothing could be more mistaken. And they aren't failures to come up with a catchy slogan or to find a good color scheme for the packaging - they're failures back at the actual science, where reality meets our ideas about it, and likely as not beats them down to the floor.

Honestly, I don't understand where these they-don't-do-any-research folks get off. Look at the patent filings. Look at the open literature. Where on earth do you think all those molecules come from, all those research programs to fill up all those servers? There are whole scientific journals that wouldn't exist if it weren't for a steady stream of failed research projects. Where's it all coming from?

Note: previous posts about PPAR drug discovery can be found here, here, and here. Previous posts (and rants) about research in the drug industry (and academia, and the price of it all) can be found here, here, here, here, here, here, here, here, and here.

Comments (49) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Industry History | Regulatory Affairs | Why Everyone Loves Us

September 23, 2010

Delightful, But It Apparently Works

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Posted by Derek

And I now present today's winner of the Ugliest Molecule To Actually Show In Vivo Efficacy. Here, just in time for lunch, is Torin-1, a selective mTOR inhibitor. Yowza.
torin.jpg

Comments (30) + TrackBacks (0) | Category: Chemical News

Chemical Biology - The Future?

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Posted by Derek

I agree with many of the commenters around here that one of the most interesting and productive research frontiers in organic chemistry is where it runs into molecular biology. There are so many extraordinary tools that have been left lying around for us by billions of years of evolution; not picking them up and using them would be crazy.

Naturally enough, the first uses have been direct biological applications - mutating genes and their associated proteins (and then splicing them into living systems), techniques for purification, detection, and amplification of biomolecules. That's what these tools do, anyway, so applying them like this isn't much of a shift (which is one reason why so many of these have been able to work so well). But there's no reason not to push things further and find our own uses for the machinery.

Chemists have been working on that for quite a while. We look at enzymes and realize that these are the catalysts that we really want: fast, efficient, selective, working at room temperature under benign conditions. If you want molecular-level nanotechnology (not quite down to atomic!), then enzymes are it. The ways that they manipulate their substrates are the stuff of synthetic organic daydreams: hold down the damn molecule so it stays in one spot, activate that one functional group because you know right where it is and make it do what you want.

All sorts of synthetic enzyme attempts have been made over the years, with varying degrees of success. None of them have really approached the biological ideals, though. And in the "if you can't beat 'em, join 'em" category, a lot of work has gone into modifying existing enzymes to change their substrate preferences, product distributions, robustness, and turnover. This isn't easy. We know the broad features that make enzymes so powerful - or we think we do - but the real details of how they work, the whole story, often isn't easy to grasp. Right, that oxyanion hole is important: but just exactly how does it change the energy profile of the reaction? How much of the rate enhancement is due to entropic factors, and how much to enthalpic ones? Is lowering the energy of the transition state the key, or is it also a subtle raising of the energy of the starting material? What energetic prices are paid (and earned back) by the conformational changes the protein goes through during the catalytic cycle? There's a lot going on in there, and each enzyme avails itself of these effects differently. If it weren't such a versatile toolbox, the tools themselves wouldn't come out being so darn versatile.

There's a very interesting paper that's recently come on on this sort of thing, to which I'll devote a post by itself. But there are other biological frontiers beside enzymes. The machinery to manipulate DNA is exquisite stuff, for example. For quite a while, it wasn't clear how we organic chemists could hijack it for our own uses - after all, we don't spend a heck of a lot of time making DNA. But over the years, the technique of adding DNA segments onto small molecules and thus getting access to tools like PCR has been refined. There are a number of applications here, and I'd like to highlight some of those as well.

Then you have things like aptamers and other recognition technologies. These are, at heart, ways to try to recapitulate the selective binding that antibodies are capable of. All sorts of synthetic-antibody schemes have been proposed - from manipulating the native immune processes themselves, to making huge random libraries of biomolecules and zeroing in on the potent ones (aptamers) to completely synthetic polymer creations. There's a lot happening in this field, too, and the applications to analytical chemistry and purification technology are clear. This stuff starts to merge with the synthetic enzyme field after a point, too, and as we understand more about enzyme mechanisms that process looks to continue.

So those are three big areas where molecular biology and synthetic chemistry are starting to merge. There are others - I haven't even touched here on in vivo reactions and activity-based proteomics, for example, which is great stuff. I want to highlight these things in some upcoming posts, both because the research itself is fascinating, and because it helps to show that our field is nowhere near played out. There's a lot to know; there's a lot to do.

Comments (33) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | Chemical News | General Scientific News | Life As We (Don't) Know It

September 22, 2010

Synthetic Chemistry: All Mined Out?

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Posted by Derek

In the wake of yesterday's revelation about the latest breakthrough in amide formation, one point that's come up is whether we getting into the era of diminishing returns in finding new synthetic methods.

My opinion? We may well - but we shouldn't have to be. It is true that we know how to do an awful lot of transformations. And I'd also subscribe to the view that we can, given no constraints of time, money, or heartbreak, synthesize basically any stable organic molecule that anyone can think up. In what we're pleased to call the real world, though, constraints of money and time (related by a similar equation to Einstein's mass-energy one) are always with us. (Heartbreak, well, that seems to be in constant supply).

So even though we can do so many things, everyone realizes that we need to be able to do them better. That applies even to amide formation. There are eleventy-dozen ways to form amides in the literature. But as some of the comments to yesterday's post show, sometimes you have to go pretty far down the list to get one that meets your needs. There is no set of conditions that is simultaneously easy, fast, cheap, nonracemizing, nontoxic, tolerant of all other functional groups, and generates a benign waste stream. Finding such a universal reaction is a fearsome goal, especially considering the number of alternatives that have already been tried.

This is why stoichiometric samarium metal is such a ridiculous idea. There are a lot of good ways to form amides. And there are a lot of lesser-known ways that might save you in tough situations. And there are lots of stupid, crappy ways. The world does not need another one of the latter. So what does it need?

Well, if you're going to stick with amide formation, you're going to have to find something closer to that ideal reaction, which won't be easy. Several other transformations are in that same category - lots of alternatives available, so something new had better be good. There are, though, plenty of other reactions that don't work so well, where improvements don't require you to approach so near perfection. A person's time might be better spent there than on trying to find the Perfect Amide Reaction, although the impact of finding the latter would probably be greater. Neither possibility excuses time spent on finding Another Lousy Amide Reaction.

And there are a lot of transformations that we can't do very well. Turn a phenol into an aromatic aldehyde in one step. Selectively epoxidize aromatic double bonds. Staple a secondary amine in where an aliphatic C-H used to be. Fluorinate at will. You can go beyond that to reactions that you can't even think up a mechanism: go around a benzene ring, switching out carbon for nitrogen. Pyridine, pyrimidine, pyrazine. . .I have no clue how to do that, or if it's even possible. Change a given oxazole into its corresponding thiazole. Turn a methoxy back into a methyl group. And so on - we sure can't do those, and the list goes on.

Hard stuff! But there are plenty of non-science-fictional possibilities out there, too. An eye to applications beyond pure synthetic chemistry helps. Look, for example, at Barry Sharpless and the copper-catalyzed triazole formation (click chemistry). That's a nice little transformation, and there are people who probably would have just made a nice little Org Lett paper out of it if they'd discovered it themselves. But it's such a versatile way to stitch things together that it's finding uses all over the place, and the end is not in sight. The world could most definitely use more chemistry that can take off in such fashion, and surely it's out there to be found.

I realize that we had this discussion just back in August, and earlier in the summer. But it keeps coming up. Seeing someone form amides with a pile of elemental samarium brings it right back to mind.

Comments (42) + TrackBacks (0) | Category: Chemical News | Who Discovers and Why

September 21, 2010

Want To Make an Amide? Have I Got Good News For You!

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Posted by Derek

Y'know, this is what I call an incremental improvement in the synthetic repetoire. I noticed this new paper in Tetrahedron Letters by its title, and read the whole thing just to make sure that I wasn't missing something.

Yep, that's right: someone has come up with a new way to form amides by reacting acid chlorides and amines. "But hold on," you say, "I thought that acid chlorides and amines form amides like an unstoppable juggernaut, which grinds to a halt only when enough HCl is given off to take the remaining amine out of contention". Well, you'd be right about that: but that's because you didn't think of using samarium metal as an acid scavenger.

Because that's what it seems to be here. The authors report that you have to pretty much use a full equivalent of samarium to get the high yields - control experiments with only 1/3 equivalent didn't work so well. What I wish they'd done is run the freaking control experiments with triethylamine. Or Hünig's base. Or pyridine. Or potassium carbonate, or aqueous 0.1N NaOH, or resin-bound nanocrystalline cesium complexes prepared in ionic liquids through renewable green chemistry whatchamacallits - in fact, with damn near anything else except stoichiometric metallic samarium, of all things. Well, OK: zinc and indium didn't work. I stand corrected. Give these folks another four or five Tet Lett papers, and they'll work their way back to baking soda. Only it'll be samarium bicarbonate, with any luck.

Perhaps I'm being unfair here. But really, amide formation is not a problem that is crying out for a new solution. It's really very, very, well worked out, and the number of options available for the experimentalist are nearly beyond counting. But now there's samarium metal. So if you're looking for the most expensive way you can think of to react an acid chloride with an amine, one that will make your labmates question your sanity and a reaction that will probably be a separate item all on its own come your next annual performance review, then go to it.

Oh, and one more thing: if you bother to read the experimental section, which apparently no one did, the procedure is titled: "General procedure for the homocoupling of terminal alkynes". Wrong samarium reaction, guys.

Comments (66) + TrackBacks (0) | Category: Chemical News | The Scientific Literature

September 20, 2010

Sodium Hydride As Oxidant, Again?

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Posted by Derek

Many readers will remember the "sodium hydride as an oxidizing reagent" story from last year. (For the non-chemists in the audience, the problem here is that sodium hydride is most certainly not what you'd think of as an oxidizing reagent, quite the opposite, in fact. Seeing the paper's title was, for an organic chemist, a bit like reading about a new way to sweeten drinks with vinegar).

This was famously live-blogged over at Totally Synthetic and picked up on around the chemical blog world. The current thinking, though, is that adventitious oxygen is really doing the work here. If you run the reaction under strict inert atmosphere conditions, you get no more oxidation. (And it still doesn't appear that any note has been added to the original JACS paper). Update - make that no note added to the abstract page. The paper itself is still accessible, although it does have notes that it was withdrawn.

Well, now we have another one. This paper in press in Tetrahedron Letters claims oxidation of benzoins to benzils with good ol' sodium hydride. In this case, anyway, the authors (from Korea) did try running the reaction under inert atmosphere, and saw their yield go down. Their proposed mechanism involves molecular oxygen, in fact, and is quite plausible. (I've seen anion-oxygen chemistry myself - if you deprotonate Strecker amines of benzaldehydes, you'll convert them into amides via oxygen in your solvent, that is, if you don't saturate things with inert gas first). Still, I'd rather that they titled this paper differently, since it's not sodium hydride that's doing the oxidation here. You could probably get this to happen with NaHMDS, t-butoxide, or the base of your choice.

And, weirdly, the authors (as far as I can see by going over the PDF) manage not to cite the original JACS NaH oxidation paper at all. You'd never think that anyone had tried this before, especially not in one of the most high-profile chemical journals in the world, just last year, with plenty of added press coverage. What does it take a get a paper cited? Update: given the withdrawn-but-still-available status of the original, this becomes a trickier question. The earlier paper seems to have clearly gone through the same sort of chemistry, but the mechanism - and thus the point of the whole paper - was misassigned. Do you cite it, or not?

Comments (14) + TrackBacks (0) | Category: Chemical News | The Scientific Literature

J. Whoozat Sci.

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Posted by Derek

Not long ago I wrote about a Chinese journal that said that about a third of its submissions turned out to contain plagiarized material. Journal publishing in that country is apparently a real swamp, and the Chinese government has taken the publishers by surprise with an announcement that they're going to drain it:

Li Dongdong, a vice-minister of state and deputy director of the General Administration of Press and Publications (GAPP) — the powerful government body that regulates all publications in China — acknowledged that the country's scientific publishing had a "severe" problem, with "a big gap between quality and quantity", and needed reform.

Opening a meeting of scientific publishers in Shanghai on 7 September, Li announced that by January 2011, new regulations will be used to "terminate" weak journals.

Precisely how this reform will work is the subject of hot debate. . .News of the regulation startled many of the publishers at last week's meeting.

I'll bet it did, particularly those publishers who are turning out junk. And believe me, you know if you're publishing a crappy journal full of papers that no one reads. As that Nature News article goes on to detail, China is full of "campus journals", which exist only for the local grad students and the like to accumulate lines on their publication record. A colleague of mine used to call such titles "The Journal of Our Results", and that's right on target.

But while I can understand China's desire to upgrade its sometimes embarrassing scientific publishing world, I have to worry about the way that they're choosing to do it - not that it doesn't fit the best traditions of the Chinese government, mind you. This sit-still-while-we-fix-you approach may work in the short term, but if there's a demand for the Journal of Our Results (from authors, if not readers), then won't such titles just spring back up again under different names? As longtime readers here will easily be able to guess, I'd prefer a more market-oriented solution.

If the committees evaluating publishing records decided not to value such journals, much of their reason to exist would presumably vanish. While it's true that there's no perfect way to evaluate journals, a situation like China's - overrun with Journal of Whoozat Technical Colleges, 98% stocked with multi-part papers from the faculty of Whoozat - would seem to be waiting for everyone to just stop pretending. This let's-be-honest-here approach would let the people publishing this junk continue to exist, but they'd probably have to find a better business model.

As it is, just shutting these people down doesn't do anything for the let's-pretend side of the market, which I presume will continue to exist. And it'll probably be filled by the all-new Proceedings of the Whoozat Academy, Whoozat Letters, Acta Whoozatica, and who knows what else.

Comments (9) + TrackBacks (0) | Category: The Scientific Literature

September 17, 2010

Put In Another Methyl Group: A Villanelle

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Posted by Derek

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

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

Put In Another Methyl Group: A Villanelle

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

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

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

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

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

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


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

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

Spread of the Pun Virus

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Posted by Derek

Are we going to see this in all the Wiley-hosted European-based journals? Angewandte Chemie has specialized, as has been noted many times, in wince-worthy puns in its article abstracts.

Today I take a look at ChemBioChem and find this. No one is safe.

Comments (17) + TrackBacks (0) | Category: The Scientific Literature

The Life of a Key Opinion Leader

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Posted by Derek

Here's an uncomplimentary look at the whole concept of "Key Opinion Leaders" in drug marketing. I think this part gets at the real reason many people agree to do this (and a lot of other things besides):

"It strokes your narcissism," says Erick Turner, a psychiatrist at the Oregon Health and Science University. There is the money, of course, which is no small matter. Some high-level KOL's make more money consulting for the pharmaceutical industry than they get from their academic institutions. But the real appeal of being a KOL is that of being acknowledged as important. That feeling of importance comes not so much from the pharmaceutical companies themselves, but from associating with other academic luminaries that the companies have recruited. Academic physicians talk about the experience of being a KOL the way others might talk about being admitted to a selective fraternity or an exclusive New York dance club. No longer are you standing outside the rope trying to catch the doorman's eye, waiting hungrily to be admitted. You are one of the chosen.

Although, as the piece makes clear, it's more about the life of not-quite-key opinion leaders. As with every club, there are inner rooms and outer rooms. . .

Comments (7) + TrackBacks (0) | Category: Why Everyone Loves Us

September 16, 2010

Live-Blogging Arena's FDA Committee Hearing

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Posted by Derek

San Diego newspaper blogger Keith Darce is doing it here. The meeting should start up again about 1 PM Eastern. So far, the company and the FDA staff have been presenting reviews of the Lorcaserin data. The committee member questions don't look particularly encouraging. . .

Update: the committee votes "No", 9-5. We'll see what the agency itself does. I expect the same outcome.

Comments (7) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

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

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Posted by Derek

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

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

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

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

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

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

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

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

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

September 15, 2010

Intermediates

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Posted by Derek

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

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

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

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

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

September 14, 2010

Lorcaserin in Trouble

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Posted by Derek

The FDA committee that will be looking over Arena's lorcaserin for weight loss has released its briefing information, and there were some nasty surprises therein. A memo states that the drug did not satisfy the mean efficacy requirements that the FDA has laid down for obesity therapies, and satisfied the categorical efficacy one "by a slim margin".

Well, that was known. I said as much back in May of last year, and didn't the Arena fans ever give me an earful about it. What wasn't apparent was the two-year rodent tox. The briefing document raises questions about the number of malignancies that showed up in these rats, and that's not good. The safety profile of any drug in this area has to be very clean, especially if the efficacy is borderline.

As for the big worry about any serotinergic compound in this area, 5-HT2b heart valve trouble, the briefing document isn't too reassuring there, either. The FDA staffers note that the company didn't run a positive control in the animal models, and didn't look at proliferative markers during the human clinical trials. They conclude that "the FDA has not definitively concluded that lorcaserin is devoid of valvulopathy-related cardiac effects in animals".

Frankly, I think that the tox/efficacy combination is likely to sink the drug's approval chances. There are other problems, but this is the big one. The market seems to be agreeing - Arena's stock is getting hammered today. I look forward to hearing from the various people who were after my hide about this.

Comments (39) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

How Much Compound?

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Posted by Derek

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

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

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

A New Way to Approve Drugs

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Posted by Derek

Who are our customers in this drug business? Well, sick patients, naturally. But their physicians, too, since they're the ones who will be writing the prescriptions. And the insurance companies, of course, since in most cases they're the ones who will be paying at least some of the bill. But the customer before we get to all that is the FDA.

Not many other industries have a gatekeeper that absolute. Every product has to be submitted and given an explicit, detailed review, with a thumbs-up or thumbs-down at the end of it. Imagine a car maker putting together a New Model Authorization package for each new model of light truck for Approval To Sell in the fall, or waiting for the Committee On SUVs to define the review criteria for Truck-Like Four-Door Crossovers before any of them can be sent to the dealers. A fast food chain wants to offer a new Double Taco Burger? Fine - submit the paperwork, and the agency will get right on it. The review committee on Fake Mexican Entrees meets in March.

The reasons for all this are no mystery. Anything that can directly affect a person's health, in either direction, is going to have a lot more oversight than the new Double Taco Burger, which will probably not kill you, although you may wonder about that forty minutes later. But given that we're going to have a large, complicated regulatory regime for new drugs, do we have the right large, complicated regulatory regime?

Steve Usdin and the team at BioCentury have a good article out that asks just this question. Since we were talking around here about the conditional approval for Avastin in metastatic breast cancer, that's a good example of how this new system might work: instead of binary decisions, the whole thing is adaptive.
Adaptive%20regulation.jpg
The idea is to set things up so that decision-making data can be generated more quickly, and so that these decisions can be modified based on later findings. The big push in the early phases of the clinic would involve biomarkers - and yes, I know that everyone's been trying to do that, with rather mixed success. But the plan here is not to add on biomarker work, but to make it an integral part of every clinical program, with stored samples (and incentives to share them), and a clear regulatory framework for what the FDA wants to see in each case.

But since biomarkers aren't easy to come by, the next part of the plan is wider use of conditional approval and adaptive clinical trials. Another way to speed things up with adaptive designs would be to run several new therapies in a given space simultaneously, re-assigning patients as the more effective candidates show themselves. If the trials are going on continuously, the barriers to getting in on them would be lower than they are under the current system, where everyone has to start their own work from the ground up. Again, the idea is to be able to make some sort of decision as early as feasible, with the option of going back if later data don't pan out. (That's the key mental adjustment in the whole thing, actually - the willingness to act on the belief that, if done well, enough of these early decisions will turn out to be the right ones to outweigh the ones that aren't).

Conditional approval would have to be coupled with restrictions on marketing until more data came in - you couldn't just go crazy as soon as possible. But it would work both ways - a company would get wider authorization as the numbers got better, or would have to narrow things down or even pull a compound altogether. This would be a big adjustment for the public to make, frankly - I can already see the editorials going on about making the entire American public a group of test subjects, and so on. But you know, they already are: every compound that makes it to market is still an investigational drug, no matter what anyone might think.

There's more at that BioCentury link, and I encourage anyone who's interested to read it all. I think that there's a lot of merit in these ideas myself, although getting them implemented in the real world won't be easy. There's also the worry that half-implementing them would leave us with a system that's no better (or subtly worse) than the one we have now. Thoughts?

Comments (13) + TrackBacks (0) | Category: Regulatory Affairs

September 13, 2010

You May Not Be Interested In It - But It's Interested In You

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Posted by Derek

Like any blog owner, I check the traffic on my site. It follows the working day, with peaks during on weekday lunchtimes, in case you're wondering: I can see both the East and West coasts kicking back with sandwiches and some blog time. And I can see when some post has really revved up the readership, or brought in hordes of outside links. (Yep, "Things I Won't Work With" is the champion in that category). I can also see when a topic has failed to do either of the above.

Patent law is the champion there. That's both understandable and sort of a shame, because it is, of course, of huge importance to the drug industry. And it can also be quite interesting, once you get into it a bit. But there's no doubt that it can also make you wish that you'd listened to Momma and gone to truck-driving school like she always wanted. Many chemists just try to avoid dealing with patent questions, or rely on a few rules of thumb that they've picked up over the years, accurately or not.

Well, there's now a book that might do a lot of us a lot of good. I've been looking over The Chemist's Companion Guide to Patent Law, by Chris Miller and Mark Evans, and I think that the field has been needing something like this for a long time. It was published just last month, and one of the authors had Wiley send me a copy. I'm in the process of reading it cover to cover, and it's staying on my reference shelf.

The title is accurate; it's a top-to-bottom look at the major features of patent law as it applies to the business of chemistry. Freedom to operate, patentability (two very different concepts), claim structure, prior art, enablement, obviousness, inventorship, infringement - all the key concepts that, frankly, almost all working chemists turn out to be a bit hazy on when you get down to details. (And law, inevitably, always gets down to the details). It's illustrated with numerous examples from recent cases, structures and all, and with plenty of very realistic hypotheticals. For example:

Imagine that you are a chemist who has been laboring to find a compound that is capable of inhibiting a very important pathway in a human disease state. After many years of hard work and false leads, you find a compound - compound 4 in Figure 7.9 - that appears to possess all of the necessary attributes. However, your information scientist reports that there are prior art references that disclose a total of three different Markush structures, each of which encompasses your compound as shown in Figure 7.9. The prior art references that contain these three genera provide the general methods of making the compounds, and the preparation is enabled for one skilled in the art. A few specific examples have been made that fall within genus 1 (and hence genera 2 and 3 as well) of the prior art, but your exact compound has not been specifically disclosed. The question is now whether compound 4 is anticipated and rendered nonpatentable per se. . .

Sound familiar? For most experienced drug discovery chemists, it sure will. As the authors go on to say, a Markush that has so many variables that it can be expanded to eight wazillion compounds isn't something to really worry about - you're supposed to be able to "at once envisage" the later invention if it's going to wipe out patentability. On the other end, a direct claim of only one compound - yours - is clearly a direct hit. But what about that huge area in between? If you don't know what it means to reference the Petering case in this area, you should.

There's a lot of good stuff in this book. It's not always light reading, but it's the most readable treatment of some very complex patent issues that I've seen. Patent attorneys know everything in it (or they flippin' well should), but if you're a chemist, you probably don't. I've learned quite a few interesting things myself in the few days I've been looking it over. Every industrial chemistry department should have a copy.

Comments (25) + TrackBacks (0) | Category: Patents and IP

September 10, 2010

Sanofi-Aventis: It's $69/Share, And That's Where It Stays

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Posted by Derek

Despite a number of reports yesterday and over night that Sanofi-Aventis had raised their offer for Genzyme shares, they're saying now that they've done no such thing. It's the same $69/share offer that was made public, and they're apparently lobbying the larger Genzyme shareholders to make them see the wisdom of the offer.

So if it's not going to be a bidding war, then most of the interesting stuff is going to be taking place behind the scenes. Will some of the big investors decide that S-A's offer is better than trusting Genzyme's management? Or will hang with the current team? Or (most likely, in my opinion) will they make no commitments to anyone while they wait to see if the offer gets higher (after more pressure is applied)?

Comments (7) + TrackBacks (0) | Category: Business and Markets

Cut-and-Paste Your Way to Publication

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Posted by Derek

The topic of plagiarism in scientific journals has come up here several times. In recent years, automated systems for checking similar blocks of text have become available, and a number of journals now run their submissions past such software.

The first journal in China to sign up for the most well-known of these (CrossCheck) is the Journal of Zhejiang University–Science. I'll freely admit that I'd never heard of it, not that I've heard of a lot of the Chinese-language journals. But I also have to take my hat off to them, both for using the plagiarism-detection service and especially for writing in to Nature with the results.

Since October 2008, they've found "unoriginal material" in 31% of all their submissions, a number they themselves call "staggering". (Here's an earlier report on their progress). The letter mentions some possible cultural problems, such as Chinese students traditionally being asked to copy things word-for-word from authorities, but I'd guess that there's plenty of the good old publish-or-perish at work here, too. At any rate, congratulations to them for publicizing such problems; that's the only way they'll ever get any better.

Comments (17) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

September 9, 2010

PLX4032: The Good News and the Bad News

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Posted by Derek

There's been a lot of excitement about PLX4032, which has shown some dramatic effects against late-stage melanoma. Very few therapies have done anything at all in that patient population, so on that level, the excitement is justified.

The compound is an azaindole targeting a mutated form (V600E, that is, glutamate for valine at amino acid 600) of B-RAF, a well-known cancer kinase target. The compound seems to be very selective indeed for this form, with no significant activity at wild-type RAF or other kinases (That glutamic acid makes all the difference). Update - that's overstating the case; see the comments section). A significant proportion of melanoma cases show this mutation, as it turns out.

Testing it out in the clinic has not been easy. As this Nature News piece details, one key was to come up with a better formulation than the original one. I can well believe it - azaindole kinase inhibitors are not the most tractable molecules on the planet, and PLX4032 doesn't look any less like a brick than the rest of 'em. (Update: fixed link to structure). The initial trials were done with crystalline material, which I'll bet doesn't dissolve worth a hoot, but the later runs were done with some sort of microprecipitated powder, which seems to behave better. They managed to get up to 720mg b.i.d., which is the sort of load you associate with antibiotics and similar horse pills, before dose-limiting tox set in.

Most of the patients in the study had the V600E mutation; the few that didn't showed no effects whatsoever. (And yes, this is an ethical study, because the standard of care for late-stage melanoma consists of everyone standing around wringing their hands). But of the group with the mutation, about 4/5ths of them showed partial or complete regression, which is unheard of.

Here's the bad news: that regression doesn't last. Of the people who responded to the drug, that response lasted from 2 to around 18 months. (And keep in mind, there were people with the mutation who also showed no response at all, for reasons that are totally unclear). What seems to be happening is either the tumor cells are mutating around the effect of PLX4032, coming up with yet another B-RAF variation, or there could be some cells around from the start that escape its effects (and then take over). We don't have survival data yet, but the best guess is that the drug will add a few months to the lives of these patients. It's not a cure, and that's the bad news.

But on the other hand, it's the first time anything has done much of anything for such patients. If we can find out why some of the V600E tumors don't respond, or better characterize the ones that re-occur after treatment, that could point the way to something more significant. That's not going to be easy - but it's not impossible, either. It's a start, for sure.

Comments (26) + TrackBacks (0) | Category: Cancer

Merck vs. J&J: It's Come to This, Eh?

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Posted by Derek

I've been waiting for over a year now to find out what's going to happen between Merck and J&J. The Schering-Plough acquisition was ludicrously structured as an acquisition of Merck in order to try to finess the rights to Remicade (infliximab) and its follow-up golimumab. These lucrative TNF-alpha antibodies were part of a deal with Schering-Plough, but under a provision that if the company experienced a "change in control" that the rights would revert back to J&J.

Thus the eye-rolling it's-SP-buying-Merck stuff. (Never mind that Fred Hassan was able to exercise parts of his own contract that related to a change in control of Schering-Plough). Well, as Jim Edwards writes, the issue is now going to arbitration. Merck has filed a disclosure on this with the SEC, apparently in response to repeated questions from investors.

Most everyone has expected the two companies to come to terms somehow, but that doesn't seem to be happening. According to that filing from Merck, the arbitration process started in late May of last year, so both companies have known that this was coming for quite some time. The fact that J&J hasn't blinked makes one think that they expect to prevail, and thus have no interest in agreeing to any deal that's more favorable to Merck.

Well, the language says "late September", and the whole process should go on for a couple of weeks at most. Some very expensive lawyers are donning their ceremonial armor as we speak. Let the games begin!

Comments (19) + TrackBacks (0) | Category: Business and Markets

September 8, 2010

Ancient Chemistry Comes Back to Life?

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Posted by Derek

The ACS journals page has a "20 Most Accessed" list, which can be an interesting thing to examine. The current one has some articles I've read and enjoyed, such as the guide to molecular interactions that was in J. Med. Chem. earlier this year. And there are synthetic methods in there, and a review of molecular gastronomy, some total syntheses, surface chemistry, and something on wastewater treatment. All fine.

But what's the deal with all the old pyridine chemistry? There's a 1962 paper on pyridine oximes on the list, a 1955 one on pyridine mercurials, of all things, and weirdest of all, an 1897 (!) paper on pyridine periodides.

Why this stuff is showing up on the most-requested list for 2010 is a complete mystery to me. Maybe I'm just slow today, but can anyone think of a reason, since I can't?

Comments (8) + TrackBacks (0) | Category: Chemical News

Outsource to China, Then Move There?

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Posted by Derek

Yesterday's note on the increasing costs in China led several commenters to mention that the cost savings of outsourcing work are never exactly what the percentages might lead you to think. Time zone problems, miscommunication, supply problems, and all the other things that can slow down work at a distance take their cuts. You have to keep a close eye on such factors, and also on what tasks you're asking your outsourcing partners to do.

So, what about the companies that are trying the project-leaders-here lab-workers-there approach? With all the chemistry being done overseas, you really have to keep on top of things. In fact, I've recently heard that some of the people in Merck's outsourced-chemistry area have been asked to consider relocating to China in order to keep things going smoothly.

I have this secondhand, so I'd be glad to get more (or more correct) details. But from what I heard, these requests have not gone over well, as you might imagine. Anyone on the ground at Merck want to fill the rest of us in?

Comments (23) + TrackBacks (0) | Category: Business and Markets

September 7, 2010

China Outsourcing: Getting More Expensive, Fast?

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Posted by Derek

Back in May of this year, I wrote that:

. . .Everyone keeps mentioning that "China isn't as cheap as it used to be". And that's going to continue, I think - I'm not expecting them to reach US/EU cost levels any time soon, but the bottom-line advantages of doing contract work there, which a few years ago were immediately apparent, are starting to become more of a matter for thought. . .

I went on to wonder if some of the big investments in China might turn out to come on line about the time the cost advantages disappeared. Well, it's happening right on schedule. Via FiercePharma, we have this piece from Life Science Leader:

A 30% to 50% cost savings was the main driver for sourcing starting materials, intermediates, APIs, and (to some extent) finished drugs. Cheaper labor, tax advantages, undervalued currency and lower capital, and overhead costs all contributed to this. All of these advantages are expected to erode in the coming years as inflation in China rises, currency appreciates, and tax rebate structures start to evolve. . .

. . .With these changes China’s current gross cost advantage of 30% to 50% could easily go down to 13% to 25%. Factor in supply chain complexity (lead times and inventory implications), rising costs of quality assurance, and upcoming stringent environmental regulations, and Western pharmaceutical companies will start to rethink their China outsourcing strategies. Accommodating for these factors, the net cost advantage for some pharmaceutical firms could easily vanish.

This does not mean, of course, that pharma outsourcing is going away. It's just going to keep moving to the cheapest suppliers that can deliver the goods. India may well pick up some of this business (although their costs will be increasing as their wages rise), and other countries could well move into this space. (Thailand? The Philippines?) And then their costs will gradually grow, as they get richer, and someone else can move in. No, no one gets to sit back, set things on automatic pilot, and watch the money roll in, which is how it should be.

Comments (22) + TrackBacks (0) | Category: Business and Markets

Columns Outside The Doors

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Posted by Derek

Nature Reviews Drug Discovery has an article on behavior in large drug organizations, which they put together after interviewing a long list of current and former R&D heads. Many of the recommendations are non-startling (find ways to reward people who are willing to take calculated risks, encourage independent thinking, all those things that are easy to write down and hard to implement). One part near the end caught my eye, though:

Companies should examine what we term the 'columns outside the doors' phenomenon and the subtle impact that this form of recognition might have on entrepreneurial behaviour. Smith described this phenomenon, which occurs across the world: as start-up companies become successful, they are relocated from humble laboratories to grander buildings with columns outside their doors. Interestingly, such edifices often violate the observed inverse square relationship between communication among scientists in laboratories and the distance between these laboratories. We offer this insight more as a provocative thought than as a firm recommendation.

And what what reminded me of was a very similar observation by C. Northcote Parkinson, of Parkinson's Law fame:

The outer door, in bronze and glass, is placed centrally in a symmetrical facade. Polished shoes glide quietly over shining rubber to the glittering and silent elevator. The overpoweringly cultured receptionist will murmur with carmine lips into an ice-blue receiver. She will wave you into a chromium armchair, consoling you with a dazzling smile for any slight but inevitable delay. Looking up from a glossy magazine, you will observe how the wide corridors radiate toward departments A, B, and C. From behind closed doors will come the subdued noise of an ordered activity. A minute later and you are ankle deep in the director’s carpet, plodding sturdily toward his distant, tidy desk. Hypnotized by the chief’s unwavering stare, cowed by the Matisse hung upon his wall, you will feel that you have found real efficiency at last.

In point of fact you will have discovered nothing of the kind. It is now known that a perfection of planned layout is achieved only by institutions on the point of collapse. . .

It is by no means certain that an influential reader of this chapter could prolong the life of a dying institution merely by depriving it of its streamlined headquarters. What he can do, however, with more confidence, is to prevent any organization strangling itself at birth. Examples abound of new institutions coming into existence with a full establishment of deputy directors, consultants and executives; all these coming together in a building specially designed for their purpose. And experience proves that such an institution will die. . .

Readers may have a few examples in mind from the drug industry. (The freshly constructed labs at Sterling, for example, completed around the time that Kodak was wiping the place out, are well spoken of). So, those of you in temporary quarters, jammed into buildings that don't quite work, may not be as bad off as you might think.

Comments (25) + TrackBacks (0) | Category: Drug Industry History | Who Discovers and Why

September 6, 2010

Day Off

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Posted by Derek

Science (and blogging) will march along without me today, in honor of Labor Day in the US. I hope it doesn't get too far out ahead, so I can catch up.

I'm home preparing for a big dinner of some of my native Arkansas food (catfish and hushpuppies), planting flower bulbs, and teaching my two children to play seven-card stud high-low poker. Busy, busy, busy.

Comments (3) + TrackBacks (0) | Category: Blog Housekeeping

September 3, 2010

Metformin Against Cancer?

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Posted by Derek

It's always good to hear about an older compound that may be doing good things that we didn't realize. The current example is metformin, the diabetes drug known to many by its brand name Glucophage, but a generic compound for some years now. Evidence has recently been accumulating that patients taking it over the long term may well have lower incidence of several types of cancer, which is a refreshing change from the usual creeping realizations in this business. (There's a reason for that - the opportunities to mess something up inside a cell, something you probably didn't even know was there, are far, far, more numerous than the opportunities to make something work the way you want).

A new paper may well have tracked down a mechanism for this effect, which adds to the sense that it's real. Here's a summary of the work - it looks like an mTOR-driven process, which is plausible. Specifically, it seems to inhibit the TORC1 pathway, though at least two different mechanisms. That's an important player in nutrient sensing and cellular growth, among a bewildering variety of other things, and the whole mTOR area has been the subject of oncology research for quite a long time now.

Metformin (and related biguanides) might be acting on it in a very useful way. Mice exposed to a known lung-cancer agent were substantially protected by pretreatment with the drug. What's not clear yet is if that direct TORC1 effect is the reason, or if it's a more general downstream effect having to do with metformin's effects on glucose levels and insulin signaling. If it's the latter, there are tumor lines that should (unfortunately) be able to evade the problem, specifically ones that have their PI3K signaling cranked up already, so it's going to be quite interesting to see how metformin does protecting against those. As has been noted many times, nutrient sensing, insulin signaling pathways, carcinogenesis, and mechanisms of aging are tangled together in ways that it's very much in our interest to unravel. (mTOR specifically is right in the middle of it, apparently).

These results (both the new mechanistic study in mice and the retrospective clinical observations) would seem to strongly suggest trying metformin out in patients with a high risk of developing various sorts of cancer. It also suggests that, other things being equal, Type II diabetics might want to use metformin to take advantage of its apparent side benefits. A protective effect would be very welcome news indeed - it's terribly difficult to do anything about most tumors once they've occurred, and the best thing would be for them not to appear in the first place.

Oh, and one more thing. If everyone had followed Sidney Wolfe's advice when metformin first came out - not to use it - we wouldn't have found out about these effects at all. Would we?

Comments (23) + TrackBacks (0) | Category: Cancer

September 2, 2010

Posters and Pickiness

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Posted by Derek

Blogging time is short today, since I'm on a deadline to produce a couple of posters for presentation. These are for an internal hoe-down, unfortunately, so I won't be able to share the fruits of my labors with everyone out there in the readership. With any luck, though, they'll turn into public presentations/publications eventually, though.

As far as I'm concerned, posters are quite a bit harder to work up than a talk. They really should stand by themselves, for one thing, so you can't fill in any holes verbally. And narrative flow is harder: there's no chance to go back and re-emphasize or contrast with later slides, because the whole thing is sitting out there, with no guarantee of what order people will use to see its parts. (I find that narrative is one of my main weapons in a presentation, so going without it is always tough).

I care about design, too, probably more than I should, so a poster also presents complications there. If visual cues wander a bit from slide to slide through a presentation, that's not good, but it's not fatal, either. But when everything's up there on one sheet, the messages really have to be consistent: same fonts, same colors, same rotations, views, and angles, etc.

But at these times I try to remind myself of what happened to a friend of mine many years ago. She was working on a poster for an ACS meeting, and took it to her PI to look over. "Yes, yes, that looks good", came the word, "but could you perhaps take this part over to here? And emphasize this a bit more? And. . ." So she went back and made the changes, and took the poster back for a re-check. "Much better! Yes. . .but I wonder if maybe this part should be bigger? And did you find a way to include those results where. . ." Back for another round.

After another iteration of this, she caught on. She started taking an unchanged version back to the PI, and after another couple of rounds of seeing the exact same poster, it was finally pronounced ready for viewing. Saves time, saves effort - try it when you can!

Comments (23) + TrackBacks (0) | Category: Graduate School | The Scientific Literature

September 1, 2010

How Long Would It Take - If Everything Worked?

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Posted by Derek

Over at BoingBoing, they're investigating the question: "How long would your PhD have taken if everything worked the first time?" I have to admit, it took me a few minutes to adjust my head to that idea, since God knows, nothing in my PhD ever looked like working the first time.

And it's a hard one to answer, because I had to do some backtracking, as so often happens in total synthesis. This was of the "Dang it all, turns out I can't install that carbon at that step, so I'm going to have to go back, put it in earlier, and hope the downstream stuff still works" variety. (Not all of it did, of course). So how do you account for tactical moves like that? There are several layers.

How long would it have taken if I'd chosen the right move each time, and each reaction worked on the first shot? Even then, that's a tricky one, because one typically runs things on a test scale and then on larger amounts as the ground firms up beneath you. So if things had worked every time, just fine, and I'd scaled up as soon as they did each time. . I'd say around a year. Maybe even nine months; it's hard to say, because the concept of everything working is so alien.

Then one could ask, how long would it take to run through the chemistry in your dissertation, straight through, knowing what there is to know about it? In that case, it would be shorter. Just flogging away at the procedures, nonstop, and having nothing go wrong along the way (hah!), I think you could beat through everything in mine in two or three months. Boy howdy, would I hate doing that.

What does that leave out, then, of a degree that took me four and a half years? (A flippin' short span, I might add, considering some of the other degrees coming out of my old group). Well, there are all those false starts down synthetic routes that ended up painting me into corners. Being carbohydrate-based synthesis, many of those were protecting group problems, but there were a couple of rip-the-whole-sequence-up episodes, too, when things just wouldn't go any further. And there were things like finding out that a base camp of material I'd stored in the freezer had gone to hell anyway, in the dark, under argon. And realizing that a TBDMS group had up and migrated on me, such annoyances as that, which also involve proving that it happened and making sure that I knew where everything was still attached.

And there's an awful lot of time spent just getting each reaction to work - six or eight or ten ways to bring in a methyl group. Four or five different reduction conditions. All those choices, every time: borane THF or borane-dimethylsulfide? Swern or PCC? Hydrogenation catalysts, Lewis acids, finding out that switching from BuLi to KHMDS when making methylene Wittig reagent changed the yield of alkene from 10% to 90%. Chip, chip, chip, at every step along the way. At the time, it seemed as if my legs were mired in not-so-fresh concrete, three feet deep across the lab. Looking back, though, I think I must have been flying. . .

Comments (28) + TrackBacks (0) | Category: Graduate School

Scientia Est Experientia

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Posted by Derek

Chad Orzel has a post up on the two halves of physics, and about how people tend to forget one of them: the experimentalists. I think he's right, and the problem is the glamorous coating that began to stick to theoretical physics in the early 20th century (and has never completely flaked away).

Several things led to that split: the startling predictions of relativity and quantum mechanics, borne out by experimentalists right down to the most unlikely-sounding results, for one. The Manhattan Project, which was a triumph of engineering, but was seen, I'd say, by many in the general public as sheer theory somehow made real. The personal fame of people like Einstein, and the fame of later practitioners like Feynman and Hawking. All of this made experimental physicists seem either like 19th-century relics, or (more often) made them confused in the public's mind with theorists from the very beginning. (The only post-1900 physicist that I can think of who was both a great theorist and a great experimentalist was Enrico Fermi). Update - qualified that to take care of off-the-charts figures like Isaac Newton.

Chemistry, on the other hand, has always been an experimental science in the public mind. Say "chemist", and people think of someone in a lab coat, in a lab, surrounded by chemicals. "Theoretical chemistry" is not a phrase with any popular currency, as opposed to "theoretical physics". Even many chemists tend to think of someone who spends all their time on theory as being close to a physicist, or even a mathematician.

Some of the practitioners don't do much to clarify matters. Witness the great Lars Onsager, who really was a chemist (and won the 1968 Nobel for it). But his PhD dissertation, which had to be whipped up when Yale discovered he didn't have a doctorate, was (disconcertingly) on Mathieu functions, and Yale's math department said that they'd be glad to grant him the degree if the chemists had any problem with it. Very few people are competent to read all of Onsager's Collected Works.

I agree with Orzel, though, that experiment is the beating pulse of any scientific field. That's the worry that some people have had about physics in recent years, that it's strayed into areas where experiments cannot help. Chemistry will, I think, never have that problem. But we've got others.

Comments (18) + TrackBacks (0) | Category: Who Discovers and Why