Abstract 9916: Potent Antithrombotic Effect of a Small-molecule, Reversible and Direct Inhibitor of Factor XIa With Minimum Bleeding Time Effect In Rabbit Models of Arterial Thrombosis and Hemostasis
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 potent, reversible and direct factor XIa (FXIa) inhibitor. It inhibits human FXIa with Ki of 0.2 nM and with >1000 fold selectivity over most of the relevant serine proteases. We conducted an in vivo proof of concept study and characterized the antithrombotic and bleeding time (BT) effects of BMS-654457 in rabbits. The direct thrombin inhibitor melagatran was included as a reference agent. BMS-654457 and melagatran were studied in rabbit models of electrically-induced carotid arterial thrombosis and cuticle bleeding. Compounds were given as an IV bolus plus infusion 30 min or IV infusion 60 min before the initiation of thrombosis or cuticle transection. Integrated carotid blood flow over 90 min (iCBF, % control) was used as a marker of the antithrombotic effect. Ex vivo clotting times were measured by using a commercial hemostasis analyzer. BMS-654457 at 0.011+0.008, 0.037+0.027, 0.11+0.08, 0.37+0.27 and 1.1+0.8 mg/kg+mg/kg/h IV increased iCBF to 17±3, 46±6*, 48±9*, 87±10* and 96±5%*, respectively, vs. 16 ± 3% in the vehicle-treated group (n=6 per group, *P<0.05, vs. vehicle). The antithrombotic EC50 (concentration that increased iCBF by 50% of the control, μM) was 0.28 for BMS-654457 and 0.15 for melagatran. At their top equivalent antithrombotic doses, BMS-654457 and melagatran increased BT by 1.33±0.08 and 6.7±0.3-fold, respectively (n=6 per group). As expected for a FXIa inhibitor, BMS-654457 increased ex vivo activated partial thromboplastin time (aPTT) without changing prothrombin time and thrombin time. The antithrombotic effect of BMS-654457 was significantly correlated with its ex vivo aPTT, supporting ex vivo aPTT as a pharmacodynamic biomarker. This study demonstrated that BMS-654457 is as effective as melagatran in the prevention of arterial thrombosis in rabbits, and prolonged BT less than melagatran. These findings suggest that inhibition of FXIa, with a small-molecule, reversible and direct inhibitor, may represent a promising antithrombotic therapy with a wide therapeutic index.
- © 2013 by American Heart Association, Inc.