HCV nonstructural protein 5A (NS5A) is essential for HCV viral replication; thus makes HCV NS5A inhibitor an important component in the combo therapy for HCV infection. The discovery of potent and pan-genotypic HCV NS5A inhibitors faces multiple challenges, such as the significant diversity among genotypes and mutants, substantial potency shift conferred on some key resistance-associated variants (RAVs), inconsistent SARs between different genotypes and mutants, and the lacking of X-ray structures of the inhibitor/protein complexes for rational inhibitor design. Research effort in Merck on HCV NS5A inhibition has led to the discovery of a tetracyclic-indole based inhibitor Elbasvir (MK-8742), one of the two components in ZEPATIERTM which were approved for the treatment of chronic HCV genotype 1 or 4 infections in adults. Herein we present our continued effort on HCV NS5A inhibition and the discovery of a 2nd generation NS5A inhibitor Ruzasvir (MK-8408). Key SARs identified for the discovery of Ruzasvir include multiple structure modifications that could significantly improve the potency against the key RAVs, such as GT2b and GT1a_Y93H simultaneously, and maintain a good potency against the other genotypes and mutants. These structure modifications include the introduction of a relatively large substituent, such as a cyclopropyl or a phenyl group, to the para position of the phenyl “Z” group on the aminal carbon, the introduction of a C1-fluoro substitution on the tetracyclic indole core, and the replacement of the phenyl “Z” group with a thiophene or thiazole moiety. Ruzasvir is a very potent and pan-genotypic NS5A inhibitor which has a “flat” potency profile, with the “flat” been defined by minimum potency shift (&lt;10-fold) from GT1a to other genotypes and RAVs. Ruzasvir is currently in clinical development as a part of an all-oral regimen for the treatment of chronic HCV infection.

Discovery of ruzasvir (MK-8408), a 2nd generation HCV NS5A inhibitor

253rd National Meeting (2017)

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