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Just by chance I came across the following simple substitution: a phenol--->indole change, where the NH of the indole functions like the phenolic OH in hydrogen bonding situations but avoids the unfavourable glucuronidation. Certainly not a general solution, but a useful one that may work in some cases
Reference:
5-, 6-, 7- and 8-amino-2-(N,N-di-n-propylamino)-1,2,3,4-tetrahydronaphthalenes: centrally acting DA and 5-HT1A agonists
European Journal of Medicinal Chemistry, Volume 28, Issue 9, 1993, Pages 693-701
P Stjernlöf, T Elebring, B Andersson, A Svensson, K Svensson, A Ekman, A Carlsson and H Wikström
A phenol is a weaker HB acceptor and stronger donor than an aliphatic alcohol. This means a phenol is more likely than an aliphatic alcohol to function purely as donor which is what you'll need for the indole trick to work.
ReplyDeleteCorrect. Although I am not sure how the other two extra ring carbons will mess up the geometry needed for optimal Hbonding.
ReplyDeleteThe phenol/oxime pharmacophore, that has been be popping up a lot recently in BRAF inhibitors, serves as a HB donor to the calalytic Glu and also a HB acceptor from the backbone NH of the DFG (possibly also the catalytic Lys, ...but at 3.8Ang...).
ReplyDeleteSo my question is, aren't both groups metabolically labile and, if so, what does this mean for in vivo potency?
I don'k know anything about the metabolic lability of oximes although I'd worry about them being electrophilic in the same way I would worry about ketones. An oxime will look a bit different to a phenol from the viewpoint of a conjugation enzyme such as a UDP-glucuronosyl transferase in that it has a hydrogen bond acceptor N next the the hydroxyl. This may help or make things even worse.
ReplyDeleteA selection of possible phenol bioisosteres
ReplyDeletehttp://homepage.mac.com/swain/Sites/CMC/DDResources/Bioisoteres/aromatic_bioisosteres.html