T-686, a novel inhibitor of plasminogen activator inhibitor-1, inhibits thrombosis without impairment of hemostasis in rats.
The aim of this study was to evaluate the antithrombotic potential of T-686 ((3E,4E)-3-benzylidene-4-(3,4,5-trimethoxy-benzylidene)-pyrr olidine-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.
Ohtani
A
A
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda-shi, Saitama, Japan.
Murakami
J
J
Hirano-Wakimoto
A
A
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000991:Antithrombins / Q000627:therapeutic use*; D001166:Arteriovenous Shunt, Surgical; D001597:Benzylidene Compounds / Q000627:therapeutic use*; D001760:Bleeding Time; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006487:Hemostasis / Q000187:drug effects*; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013388:Succinimides / Q000627:therapeutic use*; D013924:Thrombophlebitis / Q000517:prevention & control*; D013988:Ticlopidine / Q000494:pharmacology; D014859:Warfarin / Q000494:pharmacology
D000925:Anticoagulants; D000991:Antithrombins; D001597:Benzylidene Compounds; D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; D013388:Succinimides; C104988:T 686; D014859:Warfarin; D013988:Ticlopidine