Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms

We describe the research that led
to the discovery of compound 40 (ruzasvir, MK-8408),
a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with
a “flat” GT1 mutant profile. This NS5A inhibitor contains
a unique tetracyclic indole core while maintaining the imidazole–proline–valine
Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as
part of an all-oral DAA regimen for the treatment of chronic HCV infection.