Cell experiment:

Platelet aggregation is measured in hirudin-treated rabbit platelet-rich plasma (PRP) with a platelet aggregometer. PRP is mixed with 2.5 μL of vehicle or BMS-654457 at 1 and 10 μM and incubated for 2 min at 37℃. Peak platelet aggregation is determined after the addition of 2.5 μL of the agonist (ADP at 10 μM, arachidonic acid at 250 μM and collagen at 10 μg/mL, final concentration)[1].

Animal experiment:

Rabbits[1][1]BMS-654457 or vehicle (10 % N-N-dimethylacetamide:90 % of 5 % dextrose) is administered as a bolus plus sustaining IV infusion begun 30 min prior to each protocol. Treatment groups include BMS-654457 (mg/kg+mg/kg/h) at 0.011+0.008, 0.037+0.027, 0.11+0.08, 0.37+0.27 and 1.1 +0.8 or vehicle (n=6 per group). The plasma concentration that increased iCBF to EC50 was estimated for BMS654457[1].

BMS-654457 is a small-molecule, reversible inhibitor of factor XIa (FXIa), binding with human and rabbit FXIa with Kis of 0.2 and 0.42 nM, respectively.

BMS-654457 shows comparable in vitro potency against FXIa in humans (Ki=0.2 nM) and in rabbits (Ki =0.42 nM), and was over 500-fold selective against coagulation-related proteases (thrombin, FXa and FVIIa) in these species[1].

BMS-654457 is effective in the prevention of arterial thrombosis in rabbits with limited effects on bleeding time. BMS-654457 is a promising antithrombotic therapy with a wide therapeutic window[1].

[1]. Wong PC, et al. In vitro, antithrombotic and bleeding time studies of BMS-654457, a small-molecule, reversible and direct inhibitor of factor XIa. J Thromb Thrombolysis. 2015 Nov;40(4):416-23.