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Structure-activity study on a novel series of macrocyclic inhibitors of the hepatitis C virus NS3 protease leading to the discovery of BILN 2061.

Llinàs-Brunet M, Bailey MD, Bolger G, Brochu C, Faucher AM, Ferland JM, Garneau M, Ghiro E, Gorys V, Grand-Maître C, Halmos T, Lapeyre-Paquette N, Liard F, Poirier M, Rhéaume M, Tsantrizos YS, Lamarre D

Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.

From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.

J. Med. Chem. 2004;47(7):1605-8.

Pubmed ID: 15027850

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