Discovery of velpatasvir (GS-5816): A potent pan-genotypic HCV NS5A inhibitor in the single-tablet regimens Vosevi® and Epclusa®

John O Link; James G Taylor; Alejandra Trejo-Martin; Darryl Kato; Ashley A Katana; Evan S Krygowski; Zheng-Yu Yang; Sheila Zipfel; Jeromy J Cottell; Elizabeth M Bacon; Chinh V Tran; Cheng Y Yang; Yujin Wang; Kelly W Wang; Guangyu Zhao; Guofeng Cheng; Yang Tian; Ruoyu Gong; Yu-Jen Lee; Mei Yu; Eric Gorman; Erik Mogalian; Jason K Perry

doi:10.1016/j.bmcl.2019.04.027

Discovery of velpatasvir (GS-5816): A potent pan-genotypic HCV NS5A inhibitor in the single-tablet regimens Vosevi^® and Epclusa^®

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2415-2427. doi: 10.1016/j.bmcl.2019.04.027. Epub 2019 May 4.

Authors

John O Link¹, James G Taylor², Alejandra Trejo-Martin², Darryl Kato², Ashley A Katana², Evan S Krygowski², Zheng-Yu Yang², Sheila Zipfel², Jeromy J Cottell², Elizabeth M Bacon², Chinh V Tran², Cheng Y Yang³, Yujin Wang³, Kelly W Wang³, Guangyu Zhao³, Guofeng Cheng⁴, Yang Tian⁴, Ruoyu Gong⁴, Yu-Jen Lee⁴, Mei Yu⁴, Eric Gorman⁵, Erik Mogalian⁵, Jason K Perry⁶

Affiliations

¹ Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, United States. Electronic address: [email protected].
² Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, United States.
³ Drug Metabolism, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, United States.
⁴ Biology, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, United States.
⁵ Formulation and Process Development, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, United States.
⁶ Structural Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, United States.

PMID: 31230974
DOI: 10.1016/j.bmcl.2019.04.027

Abstract

Direct-acting antiviral inhibitors have revolutionized the treatment of hepatitis C virus (HCV) infected patients. Herein is described the discovery of velpatasvir (VEL, GS-5816), a potent pan-genotypic HCV NS5A inhibitor that is a component of the only approved pan-genotypic single-tablet regimens (STRs) for the cure of HCV infection. VEL combined with sofosbuvir (SOF) is Epclusa^®, an STR with 98% cure-rates for genotype 1-6 HCV infected patients. Addition of the pan-genotypic HCV NS3/4A protease inhibitor voxilaprevir to SOF/VEL is the STR Vosevi^®, which affords 97% cure-rates for genotype 1-6 HCV patients who have previously failed another treatment regimen.

Keywords: DAA; Direct-acting-antiviral; Epclusa(®); GS-5816; HCV; Hepatitis C Virus; NS5A; Non-structural protein 5A; Rule-of-five; SVR; Single-tablet regimen; Sofosbuvir; Sustained viral response; Velpatasvir.

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Carbamates / chemical synthesis
Carbamates / chemistry
Carbamates / pharmacology*
Dose-Response Relationship, Drug
Drug Combinations
Drug Discovery*
Genotype
Hepacivirus / drug effects*
Hepacivirus / genetics
Heterocyclic Compounds, 4 or More Rings / chemical synthesis
Heterocyclic Compounds, 4 or More Rings / chemistry
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Humans
Macrocyclic Compounds / chemistry
Microbial Sensitivity Tests
Molecular Structure
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Sofosbuvir / chemistry
Structure-Activity Relationship
Sulfonamides / chemistry
Tablets / chemistry
Tablets / pharmacology
Viral Nonstructural Proteins / antagonists & inhibitors*
Viral Nonstructural Proteins / genetics
Viral Nonstructural Proteins / metabolism

Substances

Antiviral Agents
Carbamates
Drug Combinations
Heterocyclic Compounds, 4 or More Rings
Macrocyclic Compounds
Protease Inhibitors
Sulfonamides
Tablets
Viral Nonstructural Proteins
sofosbuvir velpatasvir voxilaprevir drug combination
sofosbuvir-velpatasvir drug combination
NS-5 protein, hepatitis C virus
velpatasvir
Sofosbuvir