AZA-PEPTIDE ANALOGS AS POTENT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE INHIBITORS WITH ORAL BIOAVAILABILITY

A series of aza-peptide analogs with a (hydroxyethyl)hydrazine isoster e has been synthesized as HIV-1 protease inhibitors using a simple syn thetic scheme. Structure-activity studies based on the X-ray of a prev iously described inhibitor-enzyme complex led to potent inhibitors wit h antiviral activity in the low-nanomolar range. The S-configuration o f the transition-state hydroxyl group was preferred in this series. Sm all modifications of the P2P3 and P-2'P-3' substituents had little eff ect on enzyme inhibition but greatly influenced the pharmacokinetic pr ofile. As a result of these studies, the symmetrically acylated compou nd 8a and its close analog 24a bearing a methyl carbamate in P-3 and a n ethyl carbamate in P-3' position were identified as potent inhibitor s with plasma concentrations exceeding antiviral ED(50) values 150-fol d following oral application in mice.