In vitro and in vivo studies of AT-1362, a newly synthesized and orally active inhibitor of thrombin

AT-1362 was found to be a potent, selective, and competitive inhibitor of thrombin, with a Ki value of 6.7 nM. In a rat model of venous thrombosis induced by partial stasis and endothelial disruption, the ID₅₀ values (a dose required to obtain 50% inhibition of thrombus formation over each vehicle group) of AT-1362 and argatroban were 0.03 mg/kg i.v. plus 0.5 μg/kg/minute and 0.13 mg/kg i.v. plus 8.7 μg/kg/minute, respectively, and the antithrombotic effect of AT-1362 without prolongation of bleeding time lasted for 2 hours and disappeared 4 hours after oral administration of 30 mg/kg. In the rat tail transection model, the BT₂ values (a dose causing two-fold prolongation of the bleeding time over each vehicle group) of AT-1362 and argatroban were 0.56 mg/kg i.v. plus 9.3 μg/kg/minute and 1.1 mg/kg i.v. plus 73.3 μg/kg/minute, respectively. The reduction of thrombus formation and the prolongation of bleeding time were correlated with an ex vivo activated partial thromboplastin time (APTT) for both drugs. AT-1362 at 0.3 mg/kg i.v. plus 5 μg/kg/minute and argatroban at 0.6 mg/kg i.v. plus 40 μg/kg/minute significantly (p < 0.05 and p < 0.01, respectively) improved the vessel patency in a FeCl₂-induced carotid artery thrombosis model in rats. These results suggest that AT-1362 may be a potent antithrombotic agent for the treatment of thrombotic diseases. (C) 2000 Elsevier Science Ltd.