Glycine α-Ketoamides as HCV NS3 Protease Inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 6; pp. 1111 - 1114
• Main Authors: Han, Wei, Hu, Zilun, Jiang, Xiangjun, Wasserman, Zelda R., Decicco, Carl P.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 24.03.2003; Elsevier
• Subjects: Amides - chemical synthesis; Amides - pharmacology; Amines - chemistry; Amino Acids - chemistry; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites; Biological and medical sciences; Glycine - analogs & derivatives; Glycine - chemical synthesis; Glycine - pharmacology; Hepacivirus - enzymology; Medical sciences; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Structure-Activity Relationship; Viral Nonstructural Proteins - metabolism; Ketoamide; Peptides; Serine endopeptidases; Enzyme; Active site; Enzyme inhibitor; Pyrazine derivatives; Inhibitor enzyme complex; In vitro; Modeling; Virus; Peptidases; Tetrapeptide; Molecular model; Hydrolases; Antiviral; Carboxamide; Flaviviridae; Hepatitis C virus; Hepacivirus; Protease inhibitor; Pentapeptide
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00031-3

Using a tetrapeptide-based α-ketoamide template, various amines and amino acids were incorporated to explore the prime side of the HCV NS3 protease catalytic site. Glycine carboxylic acid was found to be the most effective prime group. Further optimization yielded an inhibitor with IC 50 of 0.060 μM. A series of tetrapeptide-based α-ketoamides was designed, synthesized, and evaluated as HCV NS3 protease inhibitors. Glycine α-ketoamide I was identified as a potent inhibitor with an IC 50 of 0.060 μM.