Nonstructural protein 5A (NS5A) inhibitors are potent direct-acting antiviral agents (DAA) for Hepatitis C (HCV) infection. Initial clinical experience with NS5A inhibitors indicated that they suffered from a low genetic barrier to resistance and demonstrate weak activity against non-GT1 and GT1a mutants. This made necessary the identification of NS5A inhibitors with increased potency against a wider variety of genotypes as well as NS5A resistance mutations. We hypothesized that changes to our NS5A molecular scaffolds may be able to influence mutant profile and developed SAR that led to the discovery of the novel NS5A inhibitor, MK-8742 (elbasvir). MK-8742 is a tetracyclic indole-based NS5A inhibitor which shows broad genotype activity and was submitted for FDA approval as part of an all-oral, interferon-free regimen for the treatment of HCV infection. The SAR studies that led to the discovery of MK-8742, some of its activity of MK-8742 and its synergistic antiviral affect with HCV Protease inhibitor MK-5172 is discussed in this presentation.

Alternative core development around HCV NS5A inhibitor MK-8742 scaffold

251st National Meeting (2016)

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