A new class of HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimicking scaffold.
Novel HIV-1 protease inhibitors encompassing a tertiary alcohol as part of the transition-state mimicking unit have been synthesized. Variation of the P1'-P3' residues and alteration of the tertiary alcohol absolute stereochemistry afforded 10 inhibitors. High potencies for the compounds with (S)-configuration at the carbon carrying the tertiary hydroxyl group were achieved with Ki values down to 2.4 nM. X-ray crystallographic data for a representative compound in complex with HIV-1 protease are presented.
Ekegren
Jenny K
JK
Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
Unge
Torsten
T
Safa
Mayada Zreik
MZ
Wallberg
Hans
H
Samuelsson
Bertil
B
Hallberg
Anders
A
D000438:Alcohols / Q000737:chemistry*; D002460:Cell Line; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000302:isolation & purification; D006801:Humans; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009154:Mutation; D013237:Stereoisomerism
D000438:Alcohols; D017320:HIV Protease Inhibitors; D016333:HIV Protease