Discovery of Elbasvir

Abstract

On January 28, 2016, the US Food and Drug Administration approved Zepatier™ (a fixed-dose two-drug combination containing the NS5A inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir) for the treatment of adult patients with chronic hepatitis C virus genotype 1 or genotype 4 infection. The discovery of elbasvir (EBR) was the result of a concerted research effort within Merck’s newly formed External Basic Research (also, EBR) group and a team of scientists from WuXi AppTec. Lead ID efforts combined components from both internal and literature compounds to generate a first-generation benzofuran-based NS5A inhibitor (MK-4882) that demonstrated preclinical proof of concept before entering phase 1 clinical trials. Lead optimization efforts and refinement of the core structure ultimately led to the identification of elbasvir, a ring-constrained tetracyclic indole-based analogue of MK-4882 which showed increased potency against clinical resistance variants and an improved resistance profile.