Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection

J Med Chem. 2014 Mar 13;57(5):2033-46. doi: 10.1021/jm401499g. Epub 2014 Jan 10.

Abstract

A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Administration, Oral
  • Animals
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / therapeutic use*
  • Base Sequence
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use*
  • DNA Primers
  • Double-Blind Method
  • Fluorenes / pharmacokinetics
  • Fluorenes / pharmacology
  • Fluorenes / therapeutic use*
  • Half-Life
  • Hepatitis C / drug therapy*
  • Humans
  • Macaca fascicularis
  • Male
  • Placebos
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • Benzimidazoles
  • DNA Primers
  • Fluorenes
  • Placebos
  • Viral Nonstructural Proteins
  • ledipasvir
  • NS-5 protein, hepatitis C virus