ANTIPLATELET AND ANTITHROMBOTIC EFFICACY OF SR-121787, A NONPEPTIDE ORALLY-ACTIVE GP IIB IIIA ANTAGONIST, IN RABBITS - COMPARISON WITH CLOPIDOGREL AND ASPIRIN/

Precious reports indicate that rabbits are not an appropriate species for testing glycoprotein (GP) IIb/IIIa antagonists because tested comp ounds caused only a weak inhibitory action on aggregation of rabbit pl atelets. SR 121566 is a novel low-molecular-weight antiplatelet agent with high affinity and specificity for the GP IIb/IIIa complex. In thi s study, SR 121566 exhibited a potent dose-dependent inhibition of ade nosine diphosphate (ADP)-induced aggregation of rabbit platelets in vi tro [median inhibitory concentration (IC50), 0.8 +/- 0.04 mu M], where as the GP IIb/IIIa antagonists SC 52012A and GR 144053F were devoid of antiplatelet activity. After oral administration of SR 121787, the pr odrug of SR 121566, rabbit platelet aggregation ex vivo was inhibited in a dose-dependent maimer [median effective dose (ED50) for ADP-, ara chidonic acid (AA)- and collagen-induced aggregation 2 h after gavage, 2.3 +/- 0.3, 6.1 +/- 0.9, and 2.5 +/- 0.4 mg/kg], a 58% inhibition of ADP-induced platelet aggregation being still observed 6 h after singl e oral treatment with 20 mg/kg. In an arteriovenous-shunt model, oral administration of SR 121787 resulted in a dose-dependent inhibition of thrombus growth (ED50, 10.4 +/- 0.8 mg/kg). Clopidogrel revealed a ma ximal inhibitory efficacy of 40% at 20 mg/kg p.o., and aspirin, at 100 mg/kg p.o., was without effect in this model. SR 121787 at oral doses less than or equal to 10 mg/kg, did not cause an increase in blood lo ss after incision of the rabbit ear. In conclusion, SR 121787 is the f irst GP IIb/IIIa antagonist with oral antiplatelet and antithrombotic activity in rabbits.