Discovery Of Hepatitis C Virus Ns3-Ns4a Complex Inhibitors

Hepatitis C virus (HCV) infection is a serious global health problem because of its high prevalence, chronic nature and significant morbidity of the resulting diseases. The current standard of care (peginterferon-alpha 2a/b and ribavirin combination) is limited by numerous side-effects and suboptimal efficacy in genotype-1 HCV-infected patients underscoring the unmet medical need for new therapies. Here we describe our efforts in discovery and optimization of a novel series of specific inhibitors leading to the nomination of ACH-806 (or GS-9132) for clinical development. These inhibitors interrupt the functions of HCV NS3-NS4A complex likely by binding to NS4A. We have summarized our studies on antiviral activity; resistance induction, mechanism of action, and pharmacokinetics with selected inhibitors including ACH-806. Finally, we present the data on a proof-of-concept clinical trial with ACH-806 that validates this novel mechanism of action.