Toward the Back-Up of Boceprevir (SCH 503034): Discovery of New Extended P4-Capped Ketoamide Inhibitors of Hepatitis C Virus NS3 Serine Protease with Improved Potency and Pharmacokinetic Profiles

• Published in: Journal of medicinal chemistry 2009-06, Vol.52 (12), p.3679-3688
• Main Authors: Bogen, Stéphane L, Pan, Weidong, Ruan, Sumei, Nair, Latha G, Arasappan, Ashok, Bennett, Frank, Chen, Kevin X, Jao, Edwin, Venkatraman, Srikanth, Vibulbhan, Bancha, Liu, Rong, Cheng, Kuo-Chi, Guo, Zhuyan, Tong, Xiao, Saksena, Anil K, Girijavallabhan, Viyyoor, Njoroge, F. George
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites; Biological and medical sciences; Drug Discovery; Genome, Viral - drug effects; Hepacivirus - drug effects; Hepacivirus - enzymology; Hepacivirus - genetics; Medical sciences; Models, Molecular; Molecular Conformation; Pharmacology. Drug treatments; Proline - analogs & derivatives; Proline - chemistry; Proline - pharmacology; Rats; RNA, Viral - drug effects; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacokinetics; Serine Proteinase Inhibitors - pharmacology; Stereoisomerism; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; Virus Replication - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801632a

Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P4 pocket and optimization of the P1′ capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P4-capped inhibitors were also found to have improved PK profile.