Discovery and Development of the Next-Generation HCV NS3 Protease Inhibitor Glecaprevir

Abstract

The early collaboration between Enanta and Abbott/AbbVie on HCV NS3 protease inhibitor program led to the discovery of ABT-450 (paritaprevir), which is a component of two FDA-approved IFN-free DAA combination therapies (Viekira Pak™ and Technivie™) with approval to treat genotypes 1 and 4, respectively. However, its activity against some key resistant mutants and other HCV genotypes was limited. This chapter reviews our further effort to identify a next-generation HCV protease inhibitor with pan-genotypic activity, excellent activity against resistant mutants, and favorable pharmacokinetic (PK) properties, which included the identification of the first proof-of-concept (PoC) compound in P2-P4 macrocyclic series by evaluation of different core structures and the discovery of the candidate compound ABT-493 through extensive SAR studies at P*, P1, and P1’ positions and particularly on the linker. In combination with the HCV NS5A inhibitor pibrentasvir, ABT-493 (glecaprevir) was approved by the FDA in August 2017 for treatment of hepatitis C and is marketed by AbbVie as Mavyret™/Maviret™ in multiple countries.