A novel, potent, and orally bioavailable thiazole HCV NS5A inhibitor for the treatment of hepatitis C virus

Abstract A medicinal chemistry program based on the small-molecule HCV NS5A inhibitor daclatasvir has led to the discovery of dimeric phenylthiazole compound 8 , a novel and potent HCV NS5A inhibitor. The subsequent SAR studies and optimization revealed that the cycloalkyl amide derivatives 27a - 29a exhibited superior potency against GT1b with GT1b EC 50 values at picomolar concentration. Interestingly, high diastereospecificity for HCV inhibition was observed in this class with the (1 R ,2 S ,1′ R ,2′ S ) diastereomer displaying the highest GT1b inhibitory activity. The best inhibitor 27a was found to be 3-fold more potent (GT1b EC 50  = 0.003 nM) than daclatasvir (GT1b EC 50  = 0.009 nM) against GT1b, and no detectable in vitro cytotoxicity was observed (CC 50  > 50 μM). Pharmacokinetic studies demonstrated that compound 27a had an excellent pharmacokinetic profiles with a superior oral exposure and desired bioavailability after oral administration in both rats and dogs, and therefore it was selected as a developmental candidate for the treatment of HCV infection.