T-686, a novel inhibitor of plasminogen activator inhibitor-1, inhibits thrombosis without impairment of hemostasis in rats

Abstract

The aim of this study was to evaluate the antithrombotic potential of T-686 ((3 E,4 E)-3-benzylidene-4-(3,4,5-trimethoxy-benzylidene)-pyrrolidine-2,5-dione), a novel inhibitor of plasminogen activator inhibitor-1 (PAI-1), in rat thrombosis models. T-686 (0.1–100 mg/kg per day, p.o.) dose dependently decreased the weight of venous thrombi induced by a combination of stasis and hypercoagulability. The antithrombotic effect was enhanced by repeated administration of T-686. Warfarin (0.1 mg/kg per day for 3 days) also prevented thrombus formation. The antithrombotic action by warfarin was accompanied by prolongation of coagulation time, while no effect on coagulation time was observed in T-686-treated rats. T-686 lowered the activity of PAI-1 in plasma. In the arterio-venous shunt model, pretreatment with T-686 (10 mg/kg per day) or ticlopidine (100 mg/kg per day) for 8 days inhibited thrombus formation by 33% and 44%, respectively. T-686 had no effect on collagen-induced platelet aggregation ex vivo, while ticlopidine inhibited platelet aggregation. T-686 did not affect bleeding time at 10–100 times the antithrombotic dose, while warfarin dose dependently prolonged bleeding time at and around the antithrombotic dose. These results suggest that T-686 prevents thrombus formation in rats without impairment of hemostasis.