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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: Twitter: Dereklowe

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September 27, 2010

Workhorse Reactions

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Posted by Derek

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

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

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

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

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

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

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

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


1. barry on September 27, 2010 9:17 AM writes...

The field of medicinal chemistry is prone to episodic fevers. Many of us remember when it was predicted that Rational Design was going to replace Med. Chem. Eventually, it became one more important tool that Med. Chemists use. Then Combinatorial Synthesis was going to replaced Med. Chem. Now, it's one more tool that Med. Chemists use. In each case, we need specialists to use that tool best. Rational Design is still best done in collaboration with a Computational chemist, Combinatorial Chemmistry is still best done in collaboration with an array specialist.
The Med. Chemist need to know how and when to use each of these tools (and to understand Pharmacokinetics, and Toxicology, and the Enzymology of the assays, and Formulations...) but anyone who expects the Med. Chemist to be expert at each of these is living in the wrong world.

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2. CMCguy on September 27, 2010 10:25 AM writes...

And where is innovation and creativity in all this as I think the selection for the characteristics cited for array chemist frequently comes with inability to go much outside the box. These traits may be uncommon because most the chemists with such do not stay in Synthesis/medchem but go in to other areas where find they fit better like analytical, computational (ignoring dexterity criteria?) or even process chemistry. For discovery to lead anywhere guidance on what to make typically should not only be from what the commercially available inputs are rather needs critical and careful evaluation of SAR and potential as a drug. Combichem does have a place as a tool but unless some good old medchem sense is applied it rarely will be successful.

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3. Petros on September 27, 2010 11:56 AM writes...

Going further back QSAR was all the rage. When I started as a medicinal chemist J Med Chem was full of papers on QSAR. And Pfizer was very much into it in those pre-PC days

Topliss trees could be useful but all the equations full of fudge factors!

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4. befuddled on September 27, 2010 4:04 PM writes...

I'm going to go off topic here, ask why we're talking about talk about boring workhorse reactions when we could be offering speculations about the 2010 Nobel Prize.

I think the Medicine/Physiology prize is likely to be given, at least in part, for TLR receptors. Possible names: Medzhitov, Beutler, Hoffman, Akira. Really should go to Janeway, but it's too late for that.

It might be shared with Steinman for his work on dendritic cells.

I'd like to see it go to Nicole Le Douarin for her work in developmental biology, but I doubt it will happen.

I think it's still too early for the stem cell guys.

You could argue for a genome prize, but I don't think that will happen either.

Really don't know about chemistry. Chembark suggests people for nuclear hormone receptors, but I'm not sure how clearly you can narrow it to three people (can also be said about genomics; do you include Watson, Lee Hood, Ham Smith?)

I used to say Holm, maybe Munck, and Beinert for FeS clusters, but I see that it's too late for Beinert...

If it goes for bio-stuff, I think Chembark might be right about Carruthers and Hood or whoever (I don't know the players that well). That's a field that is so important, yet doesn't seem to have changed greatly over the years.

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5. Anonym on September 27, 2010 7:42 PM writes...

@ befuddled
The Simpsons made their own predictions on a recent episode, see Quite interesting picks.

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6. et on September 27, 2010 9:40 PM writes...

Are the ppl at stevenage trying to do a last minute ditch to avoid the "inevitable"? Synthetic bio is the way to go!

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7. cliffintokyo on September 28, 2010 4:05 AM writes...

Nice work if you can get it, for horses that is.....
As #2 noted, communication between out-of-box obstreperous chemistry TLs and very much in-box array specialists might be trouble.....

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8. J-bone on September 28, 2010 9:05 PM writes...


So that's how you get away with calling someone an a-hole in a scientific journal.

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9. kurt rambis nba on March 16, 2012 6:24 AM writes...

Noriu suzinoti ar gyd.├ů┬áveikauskiene gydo vaikus ar tik suaugusius?

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