Hepatitis C virus (HCV) infection continues to represent a major health issue, with recent estimates of &gt;70 million people infected worldwide. While hepatitis C is slow to progress, the disease ultimately leads to liver damage in many individuals as well as hepatocellular carcinoma in a significant number of cases. HCV was initially treated using a regimen of co-dosed Pegylated IFN-a and ribavirin, but due to severe side-effects and low to moderate efficacy, the utility of this regimen was limited. In recent years, a revolution in the treatment of HCV has been taking place with the standard of care currently focused on all-oral therapies based on a several different combinations of inhibitors of NS5b polymerase, NS3/4a protease and the NS5a replication complex. The development of highly efficacious HCV NS3/4a protease inhibitors has been a key factor in this evolution. While several other NS3/4a inhibitors progressed into clinical development, the P2–P4 macrocycle grazoprevir has proven to be a cornerstone of one of the most effective treatments (ZEPATIER, in combination with NS5a inhibitor elbasvir) leading to sustained virologic response rates of &gt;90%. The utilization of a molecular modeling-based strategy to identify the novel P2-P4 macrocyclic series along with a flexible and reliable synthetic route which enabled rapid synthesis of diverse analogs, was key to the ultimate successful invention of grazoprevir. While the key steps leading to the design of grazoprevir will be the focus, this presentation will also highlight the development of a scalable synthetic route and several of the key clinical studies which demonstrated the robust activity of the fixed-dose combination ZEPATIER.

Invention of grazoprevir: A macrocyclic HCV NS3/4a protease inhibitor for the treatment of the hepatitis C virus infection

ACS Fall 2021

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