Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577

Abstract We report the design and synthesis of a novel class of N , N ′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure–activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine22 as a potent FXa inhibitor (FXa IC 50 = 4 nM, EC 2×PT = 7 μM). However, the potent CYP3A4inhibition activity (IC 50 = 0.3 μM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidinesresulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine36 (BMS-344577, IC 50 = 9 nM, EC 2×PT = 2.5 μM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.