Development of a New Structural Class of Broadly Acting HCV Non-Nucleoside Inhibitors Leading to the Discovery of MK-8876

ChemMedChem. 2017 Sep 7;12(17):1436-1448. doi: 10.1002/cmdc.201700228. Epub 2017 Jul 25.

Abstract

Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palm I and palm II binding regions. An initial candidate was potent in vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, in vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants. Ultimately, a biology and medicinal chemistry collaboration led to the discovery of the development candidate MK-8876. MK-8876 demonstrated a pan-genotypic potency profile and maintained potency against clinically relevant mutants. It demonstrated moderate bioavailability in rats and dogs, but showed low plasma clearance characteristics consistent with once-daily dosing. Herein we describe the efforts which led to the discovery of MK-8876, which advanced into Phase 1 monotherapy studies for evaluation and characterization as a component of an all-oral direct-acting drug regimen for the treatment of chronic HCV infection.

Keywords: MK-8876; NS5B; hepatitis C; inhibitors; non-nucleoside.

MeSH terms

  • Animals
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use*
  • Benzofurans / chemistry*
  • Benzofurans / pharmacokinetics
  • Benzofurans / pharmacology
  • Benzofurans / therapeutic use*
  • Dogs
  • Hepacivirus / drug effects*
  • Hepacivirus / physiology
  • Hepatitis C / drug therapy*
  • Humans
  • Molecular Docking Simulation
  • Pan troglodytes
  • Rats
  • Viral Nonstructural Proteins / metabolism

Substances

  • Antiviral Agents
  • Benzofurans
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus