Discovery of GS-9451: an acid inhibitor of the hepatitis C virus NS3/4A protease

Bioorg Med Chem Lett. 2012 Apr 1;22(7):2629-34. doi: 10.1016/j.bmcl.2012.01.017. Epub 2012 Feb 1.

Abstract

The discovery of GS-9451 is reported. Modification of the P3 cap and P2 quinoline with a series of solubilizing groups led to the identification of potent HCV NS3 protease inhibitors with greatly improved pharmacokinetic properties in rats, dogs and monkeys.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology
  • Biological Availability
  • Caco-2 Cells
  • Carboxylic Acids / chemical synthesis*
  • Carboxylic Acids / pharmacokinetics
  • Carboxylic Acids / pharmacology
  • Crystallography, X-Ray
  • Dogs
  • Hepacivirus / chemistry
  • Hepacivirus / drug effects*
  • Hepacivirus / enzymology
  • Hepatitis C / drug therapy
  • Hepatitis C / virology
  • Humans
  • Macaca fascicularis
  • Models, Molecular
  • Quinolines / chemical synthesis*
  • Quinolines / pharmacokinetics
  • Quinolines / pharmacology
  • Rats
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / pharmacokinetics
  • Serine Proteinase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry

Substances

  • Antiviral Agents
  • Carboxylic Acids
  • GS-9451
  • NS3 protein, hepatitis C virus
  • Quinolines
  • Serine Proteinase Inhibitors
  • Viral Nonstructural Proteins