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.
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 micrograms/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 micrograms/kg i.v.) and African green monkey carotid artery (10 micrograms/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 micrograms/kg) and oral (25-200 micrograms/kg) administration of L-738,167 exhibited long duration (> or = 8 hr) inhibition of ex vivo platelet aggregation. Once daily oral administration to conscious dogs (10-30 micrograms/kg/day for 15 days) and rhesus monkeys (200-250 micrograms/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.
Cook
J J
JJ
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
Sitko
G R
GR
Holahan
M A
MA
Stranieri
M T
MT
Glass
J D
JD
Askew
B C
BC
McIntyre
C J
CJ
Claremon
D A
DA
Baldwin
J J
JJ
Hartman
G D
GD
Gould
R J
RJ
Lynch
J J
JJ
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001760:Bleeding Time; D004195:Disease Models, Animal; D004285:Dogs; D004333:Drug Administration Routes; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008253:Macaca mulatta; D002679:Pan troglodytes; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013927:Thrombosis / Q000517:prevention & control
D001381:Azepines; D005343:Fibrinolytic Agents; C105929:L 738167; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013449:Sulfonamides; D000244:Adenosine Diphosphate