title: Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection.
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.
authors: 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.
authors: John O
authors: JO
authors: Link
authors: James G
authors: JG
authors: Taylor
authors: Lianhong
authors: L
authors: Xu
authors: Michael
authors: M
authors: Mitchell
authors: Hongyan
authors: H
authors: Guo
authors: Hongtao
authors: H
authors: Liu
authors: Darryl
authors: D
authors: Kato
authors: Thorsten
authors: T
authors: Kirschberg
authors: Jianyu
authors: J
authors: Sun
authors: Neil
authors: N
authors: Squires
authors: Jay
authors: J
authors: Parrish
authors: Terry
authors: T
authors: Kellar
authors: Zheng-Yu
authors: ZY
authors: Yang
authors: Chris
authors: C
authors: Yang
authors: Mike
authors: M
authors: Matles
authors: Yujin
authors: Y
authors: Wang
authors: Kelly
authors: K
authors: Wang
authors: Guofeng
authors: G
authors: Cheng
authors: Yang
authors: Y
authors: Tian
authors: Erik
authors: E
authors: Mogalian
authors: Elsa
authors: E
authors: Mondou
authors: Melanie
authors: M
authors: Cornpropst
authors: Jason
authors: J
authors: Perry
authors: Manoj C
authors: MC
authors: Desai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001483:Base Sequence; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017931:DNA Primers; D004311:Double-Blind Method; D005449:Fluorenes / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006207:Half-Life; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D010919:Placebos; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D017931:DNA Primers; D005449:Fluorenes; D010919:Placebos; D017361:Viral Nonstructural Proteins; C586541:ledipasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase