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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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March 22, 2011

A 200-Proof Shot of Medicinal Chemistry

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Posted by Derek

For the chemists out there in the crowd: have you been looking for a paper to read that's filled, beginning to end, with good, solid, old-fashioned medicinal chemistry? Look no further than this one, on recent reports of isosteres. This sort of thing is still the heat of med-chem as it's practiced in the real world - messing around with the structure of an active molecule to see what you can improve and what you can get away with.

If you're not a medicinal chemist, the idea of a bioisostere is some chemical group that can substitute for another one. Classic examples are things like swapping in a tetrazole ring for a carboxylic acid or an oxadiazole for an ester. Here are some examples - even if your organic chemistry is shaky, you can see the similarities across these structures. If it works, you can change the other properties of your molecule (solubility, stability, selectivity) for the better while still keeping the key features that made the original group valuable for activity. It's not something that just automatically comes through every time - sometimes there just is no substitute - but it works enough of the time to be one of the essential techniques.

Comments (10) + TrackBacks (0) | Category: Life in the Drug Labs


1. PJ Hansen on March 22, 2011 8:36 AM writes...

Thanks for the tip. The paper reminds me why I became a chemist. I'm a bit sad that I'm not paid to be one, but very glad I'm still employed.

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2. Rick on March 22, 2011 8:37 AM writes...

Makes me homesick. sniff...

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3. i'm your #1 fan on March 22, 2011 8:38 AM writes...

Derek, had me at isostere

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4. Vader on March 22, 2011 9:21 AM writes...


A curve of equal bogglement?

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5. Curious Wavefunction on March 22, 2011 12:17 PM writes...

The structures you linked to are indeed quite similar. Yet I always cringe when 2D similarity also leads to an assumption of 3D similarity.

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6. David Formerly Known as a Chemist on March 22, 2011 12:49 PM writes...

#1, PJ...

You took the words right out of my mouth. Sigh.

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7. Anonymous on March 22, 2011 1:10 PM writes...

The art and craft of medicinal chemistry, love it!

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8. Glen on March 22, 2011 1:51 PM writes...

Now you've got me jonesing for some more med chem! Love it!

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9. nitrosonium on March 22, 2011 2:57 PM writes...

anyone know much about tetrazine as an amide substitution (isostere???) in SAR?

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10. Ed on March 23, 2011 4:00 AM writes...

Maybe see Merck's work on Januvia as a start point - used the triazolopiperazine as an amide isostere

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