3knx

Publication Abstract from PubMed

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, and affects more than 200 million people worldwide. Although combination therapy of interferon-alpha and ribavirin is reasonably successful in treating majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of a series of ketoamide derived P(1)-P(3) macrocyclic inhibitors that are more potent than the first generation clinical candidate, boceprevir (1, Sch 503034), is discussed. The optimization of these macrocyclic inhibitors identified a P(3) imide capped analogue 52 that was 20 times more potent than 1 and demonstrated good oral pharmacokinetics in rats. X-ray structure of 52 bound to NS3 protease and biological data are also discussed.

Discovery and structure-activity relationship of P1-P3 ketoamide derived macrocyclic inhibitors of hepatitis C virus NS3 protease.,Venkatraman S, Velazquez F, Wu W, Blackman M, Chen KX, Bogen S, Nair L, Tong X, Chase R, Hart A, Agrawal S, Pichardo J, Prongay A, Cheng KC, Girijavallabhan V, Piwinski J, Shih NY, Njoroge FG J Med Chem. 2009 Jan 22;52(2):336-46. PMID:19102654^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.