Vol. 281, Issue 2, 677-689, 1997

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

Jacquelynn J. Cook, Gary R. Sitko, Marie A. Holahan, Maria T. Stranieri, Joan D. Glass, Ben C. Askew, Charles J. McIntyre, David A. Claremon, John J. Baldwin, George D. Hartman, Robert J. Gould and Joseph J. Lynch, Jr.

Departments of Pharmacology (J.J.C., G.R.S., M.A.H., M.T.S., J.D.G., R.J.G., J.J.L.) and Medicinal Chemistry (B.C.A., C.J.M., D.A.C., J.J.B., G.D.H.), Merck Research Laboratories, West Point, Pennsylvania

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.