288078-72-8Relevant articles and documents
Aroylguanidine-based factor Xa inhibitors: The discovery of BMS-344577
Shi, Yan,Li, Chi,O'Connor, Stephen P.,Zhang, Jing,Shi, Mengxiao,Bisaha, Sharon N.,Wang, Ying,Sitkoff, Doree,Pudzianowski, Andrew T.,Huang, Christine,Klei, Herbert E.,Kish, Kevin,Yanchunas Jr., Joseph,Liu, Eddie C.-K.,Hartl, Karen S.,Seiler, Steve M.,Steinbacher, Thomas E.,Schumacher, William A.,Atwal, Karnail S.,Stein, Philip D.
scheme or table, p. 6882 - 6889 (2010/07/03)
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 guanidine 22 as a potent FXa inhibitor (FXa IC50 = 4 nM, EC2×PT = 7 μM). However, the potent CYP3A4 inhibition activity (IC50 = 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 guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC50 = 9 nM, EC2×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.
