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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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January 22, 2014

A New Book on Scaffold Hopping

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Posted by Derek

I've been sent a copy of Scaffold Hopping in Medicinal Chemistry, a new volume from Wiley, edited by Nathan Brown of the Institute of Cancer Research in London. There are eighteen chapters - five on identifying and characterizing scaffolds to start with, ten on various computational approaches to scaffold-hopping, and three case histories.

One of the things you realize quickly when you starting thinking about (or reading about) that topic is that scaffolds are in the eye of the beholder, and that's what those first chapters are trying to come to grips with. Figuring out the "maximum common substructure" of a large group of analogs, for example, is not an easy problem at all, certainly not by eyeballing, and not through computational means, either (it's not solvable in polynomial time, if we want to get formal about it). One chemist will look at a pile of compounds and say "Oh yeah, the isoxazoles from Project XYZ", while someone who hasn't seen them before might say "Hmm, a bunch of amide heterocycles" or "A bunch of heterobiaryls" or what have you.

Another big question is how far you have to move in order to qualify as having hopped to another scaffold. My own preference is strictly empirical: if you've made a change that would be big enough to make most people draw a new Markush structure compared to your current series, you've scaffold-hopped. Ideally, you've kept the activity at your primary target, but changed it in the counterscreens or changed the ADMET properties. That's not to say that all these changes are going to be beneficial - people try this sort of thing all the time and wipe out the primary activity, or pick up even more clearance or hERG than the original series had. But those are the breaks.

And those are the main reasons that people do this sort of thing: to work out of a patent corner, to fix selectivity, or to get better properties. The appeal is that you might be able to address these without jettisoning everything you learned about the SAR of the previous compounds. If this is a topic of interest, especially from the computational angles, this book is certainly worth a look.

Comments (1) + TrackBacks (0) | Category: Drug Development | Patents and IP | Pharmacokinetics


COMMENTS

1. Paul on January 22, 2014 4:56 PM writes...

Strictly speaking, it's not known to be solvable in polynomial time. P=?NP is still an open problem.

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