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.
Subject(s)
Antiviral Agents/pharmacology , Carbamates/pharmacology , Drug Discovery , Hepacivirus/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Carbamates/chemical synthesis , Carbamates/chemistry , Dose-Response Relationship, Drug , Drug Combinations , Genotype , Hepacivirus/genetics , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Humans , Macrocyclic Compounds/chemistry , Microbial Sensitivity Tests , Molecular Structure , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Sofosbuvir/chemistry , Structure-Activity Relationship , Sulfonamides/chemistry , Tablets/chemistry , Tablets/pharmacology , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolismABSTRACT
[reaction: see text] A highly convergent synthesis of the angiogenesis inhibitor luminacin D has been achieved in 13 linear steps (19 steps total, 5.3% overall yield) utilizing a samarium(II) iodide-mediated mixed tandem aldol/Evans-Tishchenko reaction to construct the carbohydrate precursor. The modular synthetic design will allow derivatization at key positions necessary for biochemical mode of action studies.
