Discovery of piperazinylimidazo[1,2-a]pyridines as novel S4 binding elements for orally active Factor Xa inhibitors

Abstract We have recently reported the discovery of orally active sulfonylalkylamide Factor Xa (FXa) inhibitors, as typified by compound 1 (FXa IC 50  = 0.061 μM). Since the pyridylpiperidine moiety was not investigated in our previous study, we conducted detailed structure–activity relationship studies on this S4 binding element. This investigation led to the discovery of piperazinylimidazo[1,2- a ]pyridine 2b as a novel and potent FXa inhibitor (FXa IC 50  = 0.021 μM). Further modification resulted in the discovery of 2-hydroxymethylimidazo[1,2- a ]pyridine 2e (FXa IC 50  = 0.0090 μM), which was found to be a selective and orally bioavailable FXa inhibitor with reduced CYP3A4 inhibition.