Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease

HCV serine protease NS3represents an attractive drug target because it is not only essential for viral replicationbut also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug designand optimization, macrocyclic peptidomimeticmolecules bearing both a lipophilic P2 isoindolinecarbamate and a P1/P1′ acylsulfonamide/acylsulfamide carboxylic acid bioisosterewere prepared that possessed subnanomolar potency against the NS3protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir(compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypesand key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevirto HCV NS3protease and proved invalua...