In vitro, antithrombotic and bleeding time studies of BMS-654457, a small-molecule, reversible and direct inhibitor of factor XIa.

摘要: BMS-654457 ((+) 3′-(6-carbamimidoyl-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-2-yl)-4-carbamoyl-5′-(3-methyl-butyrylamino)-biphenyl-2-carboxylic acid) is a small-molecule factor XIa (FXIa) inhibitor. We evaluated the in vitro properties of and its vivo activities rabbit models electrolytic-induced carotid arterial thrombosis cuticle bleeding time (BT). Kinetic studies conducted with chromogenic substrate demonstrated that reversible competitive inhibitor for FXIa. increased activated partial thromboplastin (aPTT) without changing prothrombin time. It was equipotent prolonging plasma aPTT human rabbit, less potent rat dog. did not alter platelet aggregation to ADP, arachidonic acid collagen. In vivo, or vehicle given IV prior initiation transection. Preservation integrated blood flow over 90 min (iCBF, % control) used as marker antithrombotic efficacy. at 0.37 mg/kg + 0.27 mg/kg/h produced almost 90 % preservation iCBF compared (87 ± 10 16 ± 3 %, respectively, n = 6 per group) BT by 1.2 ± 0.04-fold (P < 0.05). At higher dose (1.1 mg/kg + 0.8 mg/kg/h), 1.33 ± 0.08-fold. This compares favorably equivalent doses reference anticoagulants (warfarin dabigatran) antiplatelet agents (clopidogrel prasugrel) which four- six-fold increases same model. summary, effective prevention rabbits limited effects on BT. study supports inhibition FXIa, small-molecule, direct promising therapy wide therapeutic window.