Nonpeptide glycoprotein IIb/IIIa inhibitors. 8. Antiplatelet activity and oral antithrombotic efficacy of L-734,217.

Abstract

The antiplatelet activity of L-734,217, a nonpeptide platelet GPIIb/IIIa antagonist, was evaluated in the rat, guinea pig and dog. IC50 for inhibition of in vitro platelet aggregation for these species (agonists: adenosine diphosphate, collagen) were rat, 838,000 and > 1,100,000 nM; guinea pig, 124 and 156 nM; dog, 42 and 50 nM. In an in vivo rat/in vitro dog platelet aggregation assay, effective antiaggregatory plasma concentrations of L-734,217 were achieved after 8.0 to 16.0 mg/kg p.o. vs. 0.3 to 1.0 mg/kg i.v. to rats. Delays in platelet-dependent hemostatic plug formation in severed mesenteric arteries were observed after 2.0 to 5.0 mg/kg p.o. vs. 0.1 to 0.2 mg/kg i.v. to guinea pigs. Dose-dependent inhibitions of ex vivo platelet aggregation after 0.3 to 3.0 mg/kg p.o. and 0.03 to 0.3 mg/kg i.v. L-734,217 to conscious dogs yielded estimates of 8 to 16% oral bioavailability. The antiplatelet activity of 3.0 mg/kg p.o. L-734,217 in dogs was unaffected by dosage form or food. In a conscious dog model of left circumflex coronary artery electrolytic lesion, 3.0 mg/kg p.o. L-734,217 q4 to 8 hr reduced thrombus mass, prevented occlusive coronary artery thrombosis and reduced or prevented myocardial infarction and ventricular ectopy. In anesthetized dogs, a dissociation between inhibition of ex vivo platelet aggregation and template bleeding time prolongation was observed with i.v. L-734,217. The results of the coadministration of heparin, aspirin and L-734,217 to anesthetized dogs suggested a synergistic effect on template bleeding time with no effect on plasma L-734,217 concentrations. These findings indicate L-734,217 to be an important lead structure for the development of therapeutically useful oral antiplatelet agents.

• Authors: J J Cook, M A Holahan, E A Lyle, D R Ramjit, G R Sitko, M T Stranieri, R F Stupienski 3rd, A A Wallace, E L Hand, J R Gehret, T Kothstein, M D Drag, G Y McCormick, J J Perkins, N C Ihle, M E Duggan, G D Hartman, R J Gould, J J Lynch Jr
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 278 Issue 1 Pg. 62-73 (Jul 1996) ISSN: 0022-3565 [Print] United States
• PMID: 8764336 (Publication Type: Journal Article)

Chemical References

• Glycoproteins
• Piperidines
• Platelet Aggregation Inhibitors
• beta-Alanine
• L 734217

Topics

• Animals
• Dogs
• Dose-Response Relationship, Drug
• Glycoproteins (drug effects)
• Guinea Pigs
• Male
• Piperidines (pharmacology)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• beta-Alanine (analogs & derivatives, pharmacology)