The Invention of Grazoprevir: An HCV NS3/4a Protease Inhibitor

The development of highly potent and efficacious HCV NS3/4a protease inhibitors has been a key factor in the recent evolution of all-oral HCV infection therapies. While many different 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 >90%. The path to the invention of grazoprevir was ultimately successful due to a number of key medicinal chemistry decisions and strategies. Molecular modeling inspired the original P2–P4 macrocyclic design, and the flexibility and reliability of the ring-closing metathesis reaction proved instrumental in the rapid synthesis of diverse analogs. The identification of the P2 heterocycle present in grazoprevir was discovered through exploration of novel chemical space enabled by a key synthesis-inspired design strategy. This chapter details the design and synthesis elements of the program in addition to the optimization for broad genotype and mutant enzyme potency, cellular activity, and liver exposure in preclinical species which ultimately led to the invention of grazoprevir.