NONPEPTIDE GLYCOPROTEIN IIB IIIA INHIBITORS .15. ANTITHROMBOTIC EFFICACY OF L-738,167, A LONG-ACTING GPIIB/IIIA ANTAGONIST, CORRELATES WITHINHIBITION OF ADENOSINE DIPHOSPHATE-INDUCED PLATELET-AGGREGATION BUT NOT WITH BLEEDING-TIME PROLONGATION/

The nonpeptide platelet glycoprotein IIb/IIIa antagonist, L-738,167, w as characterized in dog and nonhuman primate. In an anesthetized canin e model of coronary artery electrolytic lesion, L-738,167 elicited dos e-dependent (3, 4, 4.5 and 5 mu g/kg i.v.) decreases in incidence of o cclusion, reductions in thrombus mass and elevations in bleeding time. Antithrombotic efficacy correlated with inhibition of adenosine dipho sphate-induced platelet aggregation but was dissociated from marked bl eeding time elevation. Similarly, suppression of platelet-dependent cy clic flow reductions with L-738,167 in the canine coronary artery (5 m u g/kg i.v.) and African green monkey carotid artery (10 mu g/kg i.v.) correlated with inhibition of adenosine diphosphate-induced platelet aggregation but not with inhibition of thrombin-induced platelet aggre gation or significant prolongation of bleeding time. In conscious dogs and sedated chimpanzees, single dose intravenous bolus (5-20 mu g/kg) and oral (25-200 mu g/kg) administration of L-738,167 exhibited long duration (greater than or equal to 8 hr) inhibition of ex vivo platele t aggregation. Once daily oral administration to conscious dogs (10-30 mu g/kg/day for 15 days) and rhesus monkeys (200-250 mu g/kg/day for 11 days) maintained significant but submaximal (50-90% inhibition) tro ugh levels of inhibition of adenosine diphosphate-induced ex vivo plat elet aggregation. Platelet sensitivity to adenosine diphosphate after multiple days of oral dosing in dogs was similar to pretreatment sensi tivity. L-738,167 showed characteristics suitable for chronic oral the rapy with a glycoprotein IIb/IIIa inhibitor.