PREVENTION OF THROMBOSIS AND ENHANCEMENT OF THROMBOLYSIS IN RABBITS BY SR-121787, A GLYCOPROTEIN-II GLYCOPROTEIN-III ANTAGONIST

SR 121566, a novel nonpeptide antiplatelet agent with high affinity an d specificity for the GP IIb/IIIa complex, exhibits potent in vitro an tiaggregating activity in rabbit platelets. This paper reports results from a study in rabbits about the efficacy and tolerability of SR 121 787, the prodrug of SR 121566. After p.o. pretreatment with SR 121787, ADP-, arachidonic acid- and collagen-induced rabbit platelet aggregat ion was inhibited ex vivo in a dose-dependent manner (ED50 between 2.3 and 6.1 mg/kg). Collagen-induced thrombocytopenia was totally abolish ed by SR 121787 at 20 mg/kg p.o. In a carotid artery lesion model of a rterial thrombosis, p.o. administration of SR 121787 resulted in a dos e-dependent inhibition of thrombosis with a maximum effect of 68% (ED5 0 = 16.0 +/- 0.3 mg/kg). Recombinant tissue plasminogen activator-indu ced thrombolysis of a preformed thrombus in the jugular vein was poten tiated by SR 121787 at doses between 1 and 6 mg/kg i.v. In an ear inci sion bleeding model, SR 121787 at doses up to 15 mg/kg p.o. did not ca use an increase in blood loss. These results demonstrate that SR 12178 7 exerts oral antiplatelet, antithrombotic and thrombolysis-enhancing efficacy in rabbits. SR 121787 appears to be a promising compound for evaluation under clinical conditions in the therapy of acute coronary syndromes.