Discovery and Structure-Activity Relationship of P-1-P-3 Ketoamide Derived Macrocyclic Inhibitors of Hepatitis C Virus NS3 Protease

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 genoty...

Full description

Saved in:
Bibliographic Details
Published inJournal of medicinal chemistry Vol. 52; no. 2; pp. 336 - 346
Main Authors Venkatraman, Srikanth, Velazquez, Francisco, Wu, Wanli, Blackman, Melissa, Chen, Kevin X., Bogen, Stephane, Nair, Latha, Tong, Xiao, Chase, Robert, Hart, Andrea, Agrawal, Sony, Pichardo, John, Prongay, Andrew, Cheng, Kuo-Chi, Girijavallabhan, Viyyoor, Piwinski, John, Shih, Neng-Yang, Njoroge, F. George
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 22.01.2009
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
INTERFERON-ALPHA-2B
DESIGN
PEGINTERFERON ALPHA-2A
METATHESIS CATALYSTS
CRYSTAL-STRUCTURE
INITIAL TREATMENT
SERINE-PROTEASE
RIBAVIRIN
COMBINATION
PROTEINASE
Online AccessGet full text

Cover

More Information
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm800940u