Discovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Substitutions

We describe the discovery of MK-6169, a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (<b>21</b>) was discovered as a preclinical candidate for further development

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 <b>40</b> (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 <b>40</b> 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