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

  • J Med Chem. 2004 Mar 25;47(7):1605-8. doi: 10.1021/jm0342414.
Montse Llinàs-Brunet  1 ,  Murray D Bailey ,  Gordon Bolger ,  Christian Brochu ,  Anne-Marie Faucher ,  Jean Marie Ferland ,  Michel Garneau ,  Elise Ghiro ,  Vida Gorys ,  Chantal Grand-Maître ,  Ted Halmos ,  Nicole Lapeyre-Paquette ,  Francine Liard ,  Martin Poirier ,  Manon Rhéaume ,  Youla S Tsantrizos ,  Daniel Lamarre
Affiliations
  • 1. Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Québec H7S 2G5, Canada. [email protected]
PMID: 15027850 DOI: 10.1021/jm0342414
Abstract

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.

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