Design and structure-activity relationships of potent and selective inhibitors of blood coagulation factor Xa

…, HW Pauls, H Mason, YM Choi-Sledeski…

Index: Ewing, William R.; Becker, Michael R.; Manetta, Vincent E.; Davis, Roderick S.; Pauls, Henry W.; Mason, Helen; Choi-Sledeski, Yong Mi; Green, Daniel; Cha, Don; Spada, Alfred P.; Cheney, Daniel L.; Mason, Jonathan S.; Maignan, Sebastien; Guilloteau, Jean-Pierre; Brown, Karen; Colussi, Dennis; Bentley, Ross; Bostwick, Jeff; Kasiewski, Charles J.; Morgan, Suzanne R.; Leadley, Robert J.; Dunwiddie, Christopher T.; Perrone, Mark H.; Chu, Valeria Journal of Medicinal Chemistry, 1999 , vol. 42, # 18 p. 3557 - 3571

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Citation Number: 40

Abstract

The discovery of a series of non-peptide factor Xa (FXa) inhibitors incorporating 3-(S)-amino- 2-pyrrolidinone as a central template is described. After identifying compound 4, improvements in in vitro potency involved modifications of the liphophilic group and optimizing the angle of presentation of the amidine group to the S1 pocket of FXa. These studies ultimately led to compound RPR120844, a potent inhibitor of FXa (K i= 7 nM) ...