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 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 P<INF>2</INF>P<INF>3</INF> and P<INF>2</INF>‘P<INF>3</INF>‘ substituents had little effect on enzyme inhibition but greatly influenced the pharmacokinetic profile. As a result of these studies, the symmetrically acylated compound <BO>8a</BO> and its close analog <BO>24a</BO> bearing a methyl carbamate in P<INF>3</INF> and an ethyl carbamate in P<INF>3</INF>‘ position were identified as potent inhibitors with plasma concentrations exceeding antiviral ED<INF>50</INF> values 150-fold following oral application in mice.