Discovery of Boceprevir and Narlaprevir: The First and Second Generation of HCV NS3 Protease Inhibitors

Synthetic Approaches to New Drugs Approved During 2016

“…Narlaprevir also has demonstrated activity against HCV mutations resistant to other treatments such as boceprevir and telaprevir . The unique activity of this drug can be attributed to a critical electrophilic α-keto-amide “warhead”, which covalently reacts with an HCV NS3 protease active-site serine residue involved in the HCV viral replication process. , Because of their essential roles in viral replication, HCV NS3 and NS5B proteases have recently become key targets for HCV drug development . Strategically, the development of narlaprevir stems specifically from the pursuit of a single-diastereomer, second generation HCV protease inhibitor, which would provide in vitro potency and pharmacokinetic profile improvements over the structurally related antiviral drug boceprevir, which exists as a mixture of diastereomers. , After the R-Pharm pharmaceutical group obtained the license to manufacture narlaprevir from Merck in 2012, further development of the drug was realized through collaborations with Schering-Plough and Texas Liver Institute …”

“…The unique activity of this drug can be attributed to a critical electrophilic α-keto-amide “warhead”, which covalently reacts with an HCV NS3 protease active-site serine residue involved in the HCV viral replication process. , Because of their essential roles in viral replication, HCV NS3 and NS5B proteases have recently become key targets for HCV drug development . Strategically, the development of narlaprevir stems specifically from the pursuit of a single-diastereomer, second generation HCV protease inhibitor, which would provide in vitro potency and pharmacokinetic profile improvements over the structurally related antiviral drug boceprevir, which exists as a mixture of diastereomers. , After the R-Pharm pharmaceutical group obtained the license to manufacture narlaprevir from Merck in 2012, further development of the drug was realized through collaborations with Schering-Plough and Texas Liver Institute …”

“…A final recrystallization from acetone/water completed synthesis of narlaprevir ( IV ) in 83% yield . It is worth noting that this overall route was used to generate >1 kg of narlaprevir and required no chromatographic separation steps. ,, …”

“…15,16 Because of their essential roles in viral replication, HCV NS3 and NS5B proteases have recently become key targets for HCV drug development. 16 Strategically, the development of narlaprevir stems specifically from the pursuit of a single-diastereomer, second generation HCV protease inhibitor, which would provide in vitro potency and pharmacokinetic profile improvements over the structurally related antiviral drug boceprevir, 2j which exists as a mixture of diastereomers. 16,17 After the R-Pharm pharmaceutical group obtained the license to manufacture narlaprevir from Merck in 2012, further development of the drug was realized through collaborations with Schering-Plough and Texas Liver Institute.…”

“…16 Strategically, the development of narlaprevir stems specifically from the pursuit of a single-diastereomer, second generation HCV protease inhibitor, which would provide in vitro potency and pharmacokinetic profile improvements over the structurally related antiviral drug boceprevir, 2j which exists as a mixture of diastereomers. 16,17 After the R-Pharm pharmaceutical group obtained the license to manufacture narlaprevir from Merck in 2012, further development of the drug was realized through collaborations with Schering-Plough and Texas Liver Institute. 18 A kilogram-scale synthetic route to narlaprevir has been reported and proceeds strategically through the union of urea 45, bicyclic amine intermediate 46, and amine salt 48 (Schemes 9 and 10).…”