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Life in the Drug Labs

A 200-Proof Shot of Medicinal Chemistry

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.

10 comments on “A 200-Proof Shot of Medicinal Chemistry”

  1. PJ Hansen says:

    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.

  2. Rick says:

    Makes me homesick. sniff…

  3. i'm your #1 fan says:

    Derek,
    …you had me at isostere

  4. Vader says:

    isostere
    A curve of equal bogglement?

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

  6. David Formerly Known as a Chemist says:

    #1, PJ…
    You took the words right out of my mouth. Sigh.

  7. Anonymous says:

    The art and craft of medicinal chemistry, love it!

  8. Glen says:

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

  9. nitrosonium says:

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

  10. Ed says:

    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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