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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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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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September 29, 2008

Why Don't You Just. . .

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Posted by Derek

For the most part, the biologists on a drug discovery project expect us in the med-chem labs to be able to make pretty much anything we need to make. Actually, I don’t have to go that far – the other chemists more or less expect that, too. Chemistry’s a big field, with a lot of reactions and techniques, and if you want some particular structure badly enough, there are usually ways to get to it.

But not always, and not always by routes that you’re willing to put up with. That’s especially true early in a project when you need some robust chemistry to turn out a lot of diverse analogs quickly, so you can have some idea of which parts of the molecule are most important. Synthetic trouble at this stage is frustrating for everyone involved.

I was on a project a few years ago that ran into this exact problem. Compounding the pain was the way the lead compound looked when it was up on a screen during a meeting: small, perfectly reasonable, easy to deal with. Hah! It was a werewolf, that thing. None of the ideas that we had ever worked out the first time, and many of them never worked out the last time, either. Meeting after meeting would take the same format when there were outside managers or other chemists present: “But why don’t you just. . .” “We did. It doesn’t work.” “But then you should try. . .” “We know. We tried that. It doesn’t work.” “Well, OK, but then you could always come around and. . .” “We could. If it worked. But it doesn’t.”

New chemists would be added on to the program to try to get things moving, and they’d always come in rolling up their sleeves, muttering “Do I have to do everything myself around here. . .” How do I know? Because I was one of them. Within a month or two, though, I was in the same shape as everyone else on the project, looking at a bunch of NMRs and mass spec traces and trying to figure out what went wrong. Meanwhile, helpful folks would wander past the whiteboard and ask me how come we hadn’t tried the reaction that had just failed for the eleventh time. Eventually we learned to offer the more persistent questioners a supply of our starting material so they could solve the problem themselves and be heroic, but nothing ever came of that.

The project managed to stagger to a clinical candidate, but ran into mechanistic problems in the more advanced animal models. (That was really the hot fudge topping on the whole sundae – this was one of those therapeutic areas whose definitive animal models were too complex and costly to run until you were absolutely sure you had The Compound). I haven’t run into one quite like this since, and with any luck, I never will.

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


COMMENTS

1. CMC guy on September 29, 2008 10:16 AM writes...

It is so true that Syntheses always seem to look great on paper (whiteboard) but somehow manage to not work so well in the lab. In grad school it gets written up as "Routes to" but in Industry the situation is usually less forgiving.

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2. emjeff on September 29, 2008 10:26 AM writes...

I'm not a chemist, but the scenario sounds familiar in my experience in early phase clinical development. Some people will leave the team, and a new person will come on to replace them. The first few meetings are painful, as Johnny (or Jane)-come-lately has all sorts of helpful suggestions about how things could have been done differently. The constant need to justify decisions that were made by other people after a lot of careful thought to a person who's been on the project for mere minutes can wear on one quickly...

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3. processchemist on September 29, 2008 10:30 AM writes...

This reminds me of a project I've been involved with. At the end of 90's after the Allegra case it was quite hard to find a pharma/biotech asking for low prices in change of absurd milestones or, better (or worse) high royalties. The company I was working for signed for a project of this kind with a small small biotech asking for the cheapest price for a scale up.
There was something wrong in the transmitted synthesis (isoamayl nitrite solution in acqueous HCl, for example). To keep the cost as low as possible the project manager established no small scale validation of the transmitted synthesis but small scale test for every single step followed by a fast scale up. After 40 days of work the first three steps were working (with a different chemistry). After 45 days there was 3 Kg of intermediate 3 (two more steps to the target). After 60 days no sign of life for steps 4 and 5. After 70 days I was not more on the project. 5 months later I was quitting the company. 7 months later somebody told me that finally from the 3 Kg somebody obtained 2 gram of target.

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4. milkshake on September 29, 2008 12:34 PM writes...

I found myself several times in a situation when somebody pased on me a procedure to scale-up, one that was clearly unfinished and/or from a patent example that screamed "prophetic".

If you are a contract scale-up small company you end up burned easily - especially if you try to underbid everybody else on price. I think the only way to bid on this kind of situation is to offer a small-scale, pilot run first.

I heard of hilarious mishap that occured at a small company that was doing Tauber oxidation of phenol to quinone using Fremy's salt. This stoechiometric reagent is very expensive and not stable at all. It was supposed to be done in aqueous solution so they did not think putting the solid reagent ino a reactor that was stil wet after the cleanup was bad thing to do. A self-catalysed exotherm decomposition commenced and $20k worth of Fremy's salt went up in brown smoke; fortunately no-one was hurt.

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5. chemguy on September 29, 2008 7:18 PM writes...

Unfortunately what winds up happening is that everyone looks at you like you're some kind of a hack if you don't get it to work.

I also remember once being asked by an upper level manager on the clinical side "WHY DON'T YOU JUST make compounds that are safe"?

All this further proves the point, that management and investors don't really have the stones to support the really tough chemistry. The current state of small molecule drug discovery is such that we've barely scratched the surface.

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6. Led light on September 29, 2008 7:44 PM writes...

Reminds me of the questions you often get at seminars where a grad student or postdoc talks about problems with, say, a carbonyl reduction. Some bright spark will stick up his hand and say "did you try cyanoborohydride?" or some equally obvious reducing agent. *Sigh* yes we tried that.

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7. François Auguste Victor Grin Yard on September 30, 2008 6:13 AM writes...

When I am well into some frustrating chemistry, I find it is annoying but useful to have some naive input. One can get fixated on the manifold branches and forget to revisit the basics. The corollary of this is the utility of having some kind of complete and up to date database of what chemistries have been done so the neophyte can be directed to a place where the obvious questions can be satisfied in silent contemplation.

chemguy: Isn't that a Dilbert strip, where Dilbert tells the PHB that a sticking point in the project had been overcome on the tenth attempt, and the PHB asks why Dilbert didn't try the way that worked first?

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8. RTW on September 30, 2008 7:56 AM writes...

#7 Can I suggest an Electronic notebook?

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9. Tea E A Bee on September 30, 2008 8:13 AM writes...

RTW: Can I suggest an Electronic notebook?

Yes, that is an excellent front end to a complete database. The problem is that the model of enotebook/database makes a whole lot of sense - until management gets the estimate. Then it's "Well, maybe we can get along with paper for another year."

Derek, how about a thread about the current state of chemically-intelligent databases?

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10. Sili on September 30, 2008 10:25 AM writes...

I almost think you've told this story before. Not that it can't bear repeating.

Does help to remind just what a sucky chemist I was.

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11. John Spevacek on October 1, 2008 8:35 AM writes...

Any one have a connection to the afterlife? I'm sure Woodword would be able to make it.

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12. CMC guy on October 1, 2008 10:59 AM writes...

#11 JS in a way Woodward still does live on and is till contributing via many great publications and multple students/post-docs that went though his labs. IMO that is probably the greatest legacy that someone in academia can have. I was taught by one such person so have an indirect connection.

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13. processchemist on October 1, 2008 11:42 AM writes...

#12

The total synthesis of reserpine by Woodward was an astounding masterpiece. Maybe his counterpart on the industry side has been the the Merck Bile Acid Cortisone Process. All with no NMR, LC-MS, HPLC. And I fear we're talking about lost arts.

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14. CMC guy on October 1, 2008 6:06 PM writes...

processchemist nice thoughts; I know Merck once was such a force in cutting edge Process Development. We do seem to be spoiled with all the modern tools and is amazing what was acheived without benefit of such. Its even more impressive to repeat a (German) pre-WW1 procedures and confirm they got the products only characterized by a MP and appearance back then.

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