Previous reports indicate that rabbits are not an appropriate species for testing
glycoprotein (
GP) IIb/IIIa antagonists because tested compounds caused only a weak inhibitory action on aggregation of rabbit platelets.
SR 121566 is a novel low-molecular-weight
antiplatelet agent with high affinity and specificity for the
GP IIb/IIIa complex. In this study,
SR 121566 exhibited a potent dose-dependent inhibition of
adenosine diphosphate (
ADP)-induced aggregation of rabbit platelets in vitro [median inhibitory concentration (IC50), 0.8 +/- 0.04 microM], whereas the
GP IIb/IIIa antagonists SC 52012A and GR 144053F were devoid of antiplatelet activity. After
oral administration of
SR 121787, the
prodrug of
SR 121566, rabbit platelet aggregation ex vivo was inhibited in a dose-dependent manner [median effective dose (ED50) for
ADP-
arachidonic 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 single 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 maximal 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 < or = 10 mg/kg, did not cause an increase in blood loss after incision of the rabbit ear. In conclusion,
SR 121787 is the first
GP IIb/IIIa antagonist with oral antiplatelet and antithrombotic activity in rabbits.