ANTITHROMBOTIC EFFECTS IN A RAT MODEL OF ASPIRIN-INSENSITIVE ARTERIALTHROMBOSIS OF DESETHYL KBT-3022, THE MAIN ACTIVE METABOLITE OF A NEW ANTIPLATELET AGENT, KBT-3022

The antithrombotic effect of desethyl KBT-3022, which is the main acti ve metabolite of the new antiplatelet agent, KBT-3022 (ethyl 2-[4,5-bi s(4-methoxyphenyl)thiazol-2-yl] pyrrol-1-ylacetate; a cyclooxygenase i nhibitor), was determined using a photochemically induced arterial thr ombosis model in the rat femoral artery. Pretreatment with desethyl KB T-3022 (0.1, 0.3 and 1 mg/kg, i.v.) prolonged the time required to ach ieve thrombotic occlusion in the femoral artery and inhibited collagen -induced platelet aggregation in whole blood ex vivo, each in a dose-d ependent manner. In all 6 rats used, particularly at the highest dose (1 mg/kg, i.v.) tested, cyclic variations in blood flow were hardly ev er observed and complete cessation of blood flow did not occur during the 30-min observation time. BM-13505 (I, 3 and 10 mg/kg, i.v.), a thr omboxane A(2) receptor antagonist, also prolonged the time to occlusio n, but cyclic variations in blood flow did occur. On the other hand, a spirin (10 and 30 mg/kg, i.v.) had little effect in terms of preventin g thrombosis, although it inhibited collagen-induced platelet aggregat ion to the same extent as did desethyl KBT-3022. Desethyl KBT-3022 inh ibited the thrombin-induced aggregation of washed platelets in a conce ntration-dependent manner (1-40 mu M), whereas aspirin and BM-13505 di d not. These findings suggest that the potent antithrombotic effect of desethyl KBT-3022 may be attributable in part to its additional abili ty to inhibit thrombin-induced platelet aggregation. Accordingly, thro mboxane A(2) and thrombin may be important thrombotic mediators in thi s rat model.