Discovery of Boceprevir, a Ketoamide-Derived HCV NS3 Protease Inhibitor, for Treatment of Genotype 1 Infections

Abstract

Blood-borne hepatitis C infections are the primary cause for liver cirrhosis and hepatocellular carcinoma. Prior to the discovery of direct-acting antiviral agents, the only treatment option was a regimen of interferon and ribavirin. It was modestly effective with only ~40% of genotype 1 patients demonstrating sustained virologic response. It was also accompanied with severe side effects with flu-like symptoms and increased suicidal tendencies during treatment. Advances in understanding the life cycle of the virus identified many potential novel drug targets that could be inhibited with small-molecule inhibitors. HCV NS3 protease, a serine enzyme, was identified as an important target for development of inhibitors because it was involved in processing of HCV-encoded polypeptide at multiple sites. The team resorted to a structure-based design because high-throughput screening with multiple compound libraries did not result in any starting point for SAR optimization. Introduction of electrophilic traps to natural substrate of the enzyme identified a ketoamide-derived undecapeptide lead. It was optimized to identify the first ketoamide-derived direct-acting antiviral agent for the treatment of HCV gt-1 infections approved by FDA. The following chapter describes the discovery of the undecapeptide lead and optimization of the scaffold to discover boceprevir for the treatment of HCV gt-1 infections.