Hepatitis C Virus NS5A Replication Complex Inhibitors:The Discovery of Daclatasvir.

The biphenyl derivatives 2and 3areprototypes of a novel class of NS5A replication complex inhibitorsthat demonstrate high inhibitory potency toward a panel of clinicallyrelevant HCV strains encompassing genotypes 1–6. However, thesecompounds exhibit poor systemic exposure in rat pharmacokinetic studiesafter oral dosing. The structure–activity relationship investigationsthat improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification ofthe highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was therealization that the arylglycine cap of 2could be replacedwith an alkylglycine derivative and still maintain the high inhibitorypotency of the series if accompanied with a stereoinversion, a findingthat enabled a rapid optimization of exposure properties. Compound 33had EC50values of 50 and 9 pM toward genotype-1aand -1b replicons, respectively, and oral bioavailabilities of 38–108%in preclinical species. Compound 33provided clinicalproof-of-concept for the NS5A replication complex inhibitor class,and regulatory approval to market it with the NS3/4A protease inhibitorasunaprevir for the treatment of HCV genotype-1b infection has recentlybeen sought in Japan. [ABSTRACT FROM AUTHOR]