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

• Published in: Bioorganic & medicinal chemistry letters Vol. 29; no. 16; pp. 2415 - 2427
• Main Authors: Link, John O., Taylor, James G., Trejo-Martin, Alejandra, Kato, Darryl, Katana, Ashley A., Krygowski, Evan S., Yang, Zheng-Yu, Zipfel, Sheila, Cottell, Jeromy J., Bacon, Elizabeth M., Tran, Chinh V., Yang, Cheng Y., Wang, Yujin, Wang, Kelly W., Zhao, Guangyu, Cheng, Guofeng, Tian, Yang, Gong, Ruoyu, Lee, Yu-Jen, Yu, Mei, Gorman, Eric, Mogalian, Erik, Perry, Jason K.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-08-2019
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; DAA; Direct-acting-antiviral; Dose-Response Relationship, Drug; Drug Combinations; Drug Discovery; Epclusa; Genotype; GS-5816; HCV; Hepacivirus - drug effects; Hepacivirus - genetics; Hepatitis C Virus; 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; Non-structural protein 5A; NS5A; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Rule-of-five; Single-tablet regimen; Sofosbuvir; Sofosbuvir - chemistry; Structure-Activity Relationship; Sulfonamides - chemistry; Sustained viral response; SVR; Tablets - chemistry; Tablets - pharmacology; Velpatasvir; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Single-tablet regimen; DAA; GS-5816; Velpatasvir; Sustained viral response; SVR; NS5A; HCV; Direct-acting-antiviral; Epclusa; Rule-of-five; Sofosbuvir; Hepatitis C Virus; Non-structural protein 5A; Epclusa(®)
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.04.027

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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.