Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors.

Abstract The N , N ′-disubstituted cyanoguanidine is an excellent bioisostereof the thiourea and keteneaminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K i = 6.5 nM, EC 2xPT = 32 μM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamicsin animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand–protein interactions are discussed.