Novel non‐nucleoside HCV NS5B inhibitors exhibit low potential for CYP‐mediated drug‐drug interactions

Abstract

INTRODUCTIONHCV RNA‐dependent RNA polymerase (NS5B), essential for viral replication, is an attractive target for HCV drug discovery. We previously disclosed a novel series of potent non‐nucleoside NS5B inhibitors which bind to the "palm" site of the NS5B protein. Here we report the results of in vitro ADME studies with representative NS5B inhibitors aimed at evaluation of their drug‐drug interaction potential.METHODSTest articles were incubated in the presence of human or animal liver microsomes or Cytochrome P450 SupersomesTM (1A2, 1A6, 2C8, 2C9, 2C19, 2D6 and 3A4) and NADPH+ regeneration system and the remaining parent molecules were quantified by LC/MS/MS. CYP inhibition was assessed using Vivid® Cytochrome P450 Screening Kits (1A2, 2C9, 2C19, 2D6 and 3A4) or, for selected compounds, in human liver microsomes.RESULTSTest article stability was assessed in liver microsomes of male and female mice, rats, rabbits, dogs, monkeys and humans. The compounds showed good metabolic stability (t½ > 60 minutes) in liver microsomes of all species tested with the exception of rabbit (both genders) and male rat microsomes. 2C8, 2C9 and 3A4 were identified as CYP isoforms involved in metabolism. CYP inhibition was insignificant for all isoforms tested.CONCLUSIONSThe results suggest that CYP related drug‐drug interaction potential of the compounds evaluated in the current study is minimal.