The antithrombotic effect of
desethyl KBT-3022, which is the main active metabolite of the new
antiplatelet agent,
KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl] pyrrol-1-ylacetate; a
cyclooxygenase inhibitor), was determined using a photochemically induced arterial
thrombosis model in the rat femoral artery. Pretreatment with
desethyl KBT-3022 (0.1, 0.3 and 1 mg/kg, i.v.) prolonged the time required to achieve thrombotic occlusion in the femoral artery and inhibited
collagen-induced platelet aggregation in whole blood ex vivo, each in a dose-dependent manner. In all 6 rats used, particularly at the highest dose (1 mg/kg, i.v.) tested, cyclic variations in blood flow were hardly ever observed and complete cessation of blood flow did not occur during the 30-min observation time.
BM-13505 (1, 3 and 10 mg/kg, i.v.), a
thromboxane A2 receptor antagonist, also prolonged the time to occlusion, but cyclic variations in blood flow did occur. On the other hand,
aspirin (10 and 30 mg/kg, i.v.) had little effect in terms of preventing
thrombosis, although it inhibited
collagen-induced platelet aggregation to the same extent as did
desethyl KBT-3022.
Desethyl KBT-3022 inhibited the
thrombin-induced aggregation of washed platelets in a concentration-dependent manner (1-40 microM), whereas
aspirin and
BM-13505 did not. These findings suggest that the potent antithrombotic effect of
desethyl KBT-3022 may be attributable in part to its additional ability to inhibit
thrombin-induced platelet aggregation. Accordingly,
thromboxane A2 and
thrombin may be important thrombotic mediators in this rat model.