GSK2818713, a novel biphenylene scaffold-based Hepatitis C NS5A replication complex inhibitor with broad genotype coverage.

Pan-genotype NS5A inhibitors underpin a hugely successful treatment of the Hepatitis C Virus (HCV) infections. Discovery of GSK2818713 (13), an NS5A replication complex inhibitor of hepatitis C virus (HCV) characterized by a significantly improved genotype coverage relative to first-generation NS5A inhibitor daclatasvir (DCV) is detailed herein. The SAR analysis revealed cooperative potency effects of the biphenylene, bicyclic pyrrolidine (Aoc) and methyl-threonine structural motifs. Relative to DCV, 13 improved activity against gt1a and gt1b NS5A variants as well as HCV chimeric replicons containing NS5A fragments from genotypes 2-6. Long term treatment of subgenomic replicons with 13 potently and durably decreased HCV RNA levels for genotype 1a (gt1a), gt2a and gt3a. These properties, as well as the lack of cross-resistance, of antagonism with other HCV agents and suitable pharmacokinetic properties, identified 13 as a preclinical candidate.