Nonpeptide Glycoprotein IIb/IIIa Inhibitors. 15. Antithrombotic Efficacy of L-738,167, a Long-Acting GPIIb/IIIa Antagonist, Correlates with Inhibition of Adenosine Diphosphate-Induced Platelet Aggregation but not with Bleeding Time Prolongation

Abstract

The nonpeptide platelet glycoprotein IIb/IIIa antagonist, L-738,167, was characterized in dog and nonhuman primate. In an anesthetized canine model of coronary artery electrolytic lesion, L-738,167 elicited dose-dependent (3, 4, 4.5 and 5 μg/kg i.v.) decreases in incidence of occlusion, reductions in thrombus mass and elevations in bleeding time. Antithrombotic efficacy correlated with inhibition of adenosine diphosphate-induced platelet aggregation but was dissociated from marked bleeding time elevation. Similarly, suppression of platelet-dependent cyclic flow reductions with L-738,167 in the canine coronary artery (5 μg/kg i.v.) and African green monkey carotid artery (10 μg/kg i.v.) correlated with inhibition of adenosine diphosphate-induced platelet aggregation but not with inhibition of thrombin-induced platelet aggregation or significant prolongation of bleeding time. In conscious dogs and sedated chimpanzees, single dose intravenous bolus (5–20 μg/kg) and oral (25–200 μg/kg) administration of L-738,167 exhibited long duration (≥8 hr) inhibition of ex vivo platelet aggregation. Once daily oral administration to conscious dogs (10–30 μg/kg/day for 15 days) and rhesus monkeys (200–250 μg/kg/day for 11 days) maintained significant but submaximal (50–90% inhibition) trough levels of inhibition of adenosine diphosphate-induced ex vivo platelet aggregation. Platelet sensitivity to adenosine diphosphate after multiple days of oral dosing in dogs was similar to pretreatment sensitivity. L-738,167 showed characteristics suitable for chronic oral therapy with a glycoprotein IIb/IIIa inhibitor.