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.
John O Link  1 ,  James G Taylor  2 ,  Alejandra Trejo-Martin  2 ,  Darryl Kato  2 ,  Ashley A Katana  2 ,  Evan S Krygowski  2 ,  Zheng-Yu Yang  2 ,  Sheila Zipfel  2 ,  Jeromy J Cottell  2 ,  Elizabeth M Bacon  2 ,  Chinh V Tran  2 ,  Cheng Y Yang  3 ,  Yujin Wang  3 ,  Kelly W Wang  3 ,  Guangyu Zhao  3 ,  Guofeng Cheng  4 ,  Yang Tian  4 ,  Ruoyu Gong  4 ,  Yu-Jen Lee  4 ,  Mei Yu  4 ,  Eric Gorman  5 ,  Erik Mogalian  5 ,  Jason K Perry  6
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.