Evolution of HCV NS3/4a Protease Inhibitors

Abstract

HCV NS3/4a protease was identified as a target for drug discovery over 20 years ago. Cleavage products from substrate-based peptides provided the starting point for medicinal chemistry. However, their less-than-ideal properties as leads would make the path to orally bioavailable inhibitors a highly challenging one. Extensive optimization efforts by multiple groups led to inhibitors with reduced peptidic character in both reversible and slowly reversible covalent classes. Ten NS3/4a inhibitors have received regulatory approval to date starting with slowly reversible ketoamides boceprevir and telaprevir in 2011 for use in combination with interferon and ribavirin. Subsequently, reversible inhibitors that advanced into clinical studies from acyclic, P1–P3 macrocyclic, P2–P4 macrocyclic, and P1–P3/P2–P4 bismacrocyclic structural classes yielded seven approved drugs to date. The most recent approvals include multiple third-generation cross-genotype active compounds that also have improved activity against key NS3/4a resistance mutations at A156, R155, and D168. These compounds, including grazoprevir, glecaprevir, and voxilaprevir, can be used in interferon/ribavirin-free, direct-acting antiviral combinations with cure rates approaching 100% coupled with reduced duration of treatment. The evolution of inhibitor design leading to this successful outcome is discussed.