American Chemical Society
jm960022p_si_001.pdf (345.73 kB)

Aza-Peptide Analogs as Potent Human Immunodeficiency Virus Type-1 Protease Inhibitors with Oral Bioavailability

Download (345.73 kB)
journal contribution
posted on 1996-08-02, 00:00 authored by Alexander Fässler, Guido Bold, Hans-Georg Capraro, Robert Cozens, Jürgen Mestan, Bernard Poncioni, Johannes Rösel, Marina Tintelnot-Blomley, Marc Lang
A series of aza-peptide analogs with a (hydroxyethyl)hydrazine isostere has been synthesized as HIV-1 protease inhibitors using a simple synthetic scheme. Structure−activity studies based on the X-ray of a previously described inhibitor−enzyme complex led to potent inhibitors with antiviral activity in the low-nanomolar range. The S-configuration of the transition-state hydroxyl group was preferred in this series. Small modifications of the P2P3 and P2‘P3‘ substituents had little effect on enzyme inhibition but greatly influenced the pharmacokinetic profile. As a result of these studies, the symmetrically acylated compound 8a and its close analog 24a bearing a methyl carbamate in P3 and an ethyl carbamate in P3‘ position were identified as potent inhibitors with plasma concentrations exceeding antiviral ED50 values 150-fold following oral application in mice.