MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease

Antimicrob Agents Chemother. 2010 Jan;54(1):305-11. doi: 10.1128/AAC.00677-09. Epub 2009 Oct 19.

Abstract

The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Area Under Curve
  • Cell Line
  • Cyclopropanes
  • Dogs
  • Genotype
  • Half-Life
  • Hepacivirus / drug effects*
  • Hepacivirus / enzymology
  • Hepacivirus / genetics
  • Humans
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Interferon alpha-2
  • Interferon-alpha / pharmacology
  • Isoindoles
  • Lactams, Macrocyclic
  • Leucine / analogs & derivatives
  • Macaca mulatta
  • Pan troglodytes
  • Proline / analogs & derivatives
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology*
  • Rats
  • Recombinant Proteins
  • Replicon
  • Substrate Specificity
  • Sulfonamides
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / genetics

Substances

  • Antiviral Agents
  • Cyclopropanes
  • Indoles
  • Interferon alpha-2
  • Interferon-alpha
  • Isoindoles
  • Lactams, Macrocyclic
  • NS3 protein, hepatitis C virus
  • Protease Inhibitors
  • Recombinant Proteins
  • Sulfonamides
  • Viral Nonstructural Proteins
  • Proline
  • vaniprevir
  • Leucine