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.
John O Link  1 ,  James G Taylor ,  Lianhong Xu ,  Michael Mitchell ,  Hongyan Guo ,  Hongtao Liu ,  Darryl Kato ,  Thorsten Kirschberg ,  Jianyu Sun ,  Neil Squires ,  Jay Parrish ,  Terry Kellar ,  Zheng-Yu Yang ,  Chris Yang ,  Mike Matles ,  Yujin Wang ,  Kelly Wang ,  Guofeng Cheng ,  Yang Tian ,  Erik Mogalian ,  Elsa Mondou ,  Melanie Cornpropst ,  Jason Perry ,  Manoj C Desai
Affiliations
  • 1. Medicinal Chemistry, ‡Drug Metabolism, §Biology, ±Formulation and Process Development, ∥Clinical Research, and ⊥Structural Chemistry, Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
PMID: 24320933 DOI: 10.1021/jm401499g
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.

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