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

• Published in: Journal of medicinal chemistry 1996-08, Vol.39 (16), p.3203-3216
• Main Authors: Fässler, Alexander, Bold, Guido, Capraro, Hans-Georg, Cozens, Robert, Mestan, Jürgen, Poncioni, Bernard, Rösel, Johannes, Tintelnot-Blomley, Marina, Lang, Marc
• Format: Article
• Language: English
• Subjects: Administration, Oral; AIDS/HIV; Amino Acid Sequence; Amino Acids - administration & dosage; Amino Acids - chemical synthesis; Amino Acids - pharmacokinetics; Amino Acids - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - administration & dosage; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Biological and medical sciences; Biological Availability; Cells, Cultured; Female; HIV Protease - metabolism; HIV Protease Inhibitors - administration & dosage; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - pharmacokinetics; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; human immunodeficiency virus 1; Hydrazines - administration & dosage; Hydrazines - chemical synthesis; Hydrazines - pharmacokinetics; Hydrazines - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Molecular Structure; Pharmacology. Drug treatments; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960022p

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.