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

We have recently reported the discovery of orally active sulfonylalkylamide Factor Xa (FXa) inhibitors, as typified by compound 1 (FXa IC50 = 0.061 mu M). 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 IC50 = 0.021 mu M). Further modification resulted in the discovery of 2-hydroxymethylimidazo[1,2-a]pyridine 2e (FXa IC50 = 0.0090 mu M), which was found to be a selective and orally bioavailable FXa inhibitor with reduced CYP3A4 inhibition. (C) 2007 Elsevier Ltd. All rights reserved.