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March 22, 2011
A 200-Proof Shot of Medicinal Chemistry
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.
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College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
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.
Permalink to Comment2. Rick on March 22, 2011 8:37 AM writes...
Makes me homesick. sniff...
Permalink to Comment3. i'm your #1 fan on March 22, 2011 8:38 AM writes...
Derek,
...you had me at isostere
Permalink to Comment4. Vader on March 22, 2011 9:21 AM writes...
isostere
A curve of equal bogglement?
Permalink to Comment5. 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.
Permalink to Comment6. 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.
Permalink to Comment7. Anonymous on March 22, 2011 1:10 PM writes...
The art and craft of medicinal chemistry, love it!
Permalink to Comment8. Glen on March 22, 2011 1:51 PM writes...
Now you've got me jonesing for some more med chem! Love it!
Permalink to Comment9. nitrosonium on March 22, 2011 2:57 PM writes...
anyone know much about tetrazine as an amide substitution (isostere???) in SAR?
Permalink to Comment10. 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
http://goo.gl/yJudP
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