Novel prodrug approach to amprenavir-based HIV-1 protease inhibitors via O-->N acyloxy migration of P1 moiety.
We have developed a new approach to prodrugs, which utilizes a pH-induced intramolecular O-->N migration of an acyloxy group in carbonate moiety to a free amino moiety at neutral pH. This method is exemplified by facile rearrangement of highly water-soluble prodrug 3 to carbamate 4, a close analogue of HIV-1 protease inhibitor Amprenavir. The O-->N acyloxy migration is unprecedented in the context of prodrugs and it enables a high atom economy due to recycling of the 'pro' moiety.
Kazmierski
Wieslaw M
WM
GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA. wieslaw.m.kazmierski@gsk.com
Bevans
Patricia
P
Furfine
Eric
E
Spaltenstein
Andrew
A
Yang
Hanbiao
H
D002219:Carbamates; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D005663:Furans; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D007202:Indicators and Reagents; D011355:Prodrugs; D013449:Sulfonamides; C095108:amprenavir