TY - JOUR T1 - Nonpeptide glycoprotein IIb/IIIa inhibitors. 8. Antiplatelet activity and oral antithrombotic efficacy of L-734,217. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 62 LP - 73 VL - 278 IS - 1 AU - J J Cook AU - M A Holahan AU - E A Lyle AU - D R Ramjit AU - G R Sitko AU - M T Stranieri AU - R F Stupienski, 3rd AU - A A Wallace AU - E L Hand AU - J R Gehret AU - T Kothstein AU - M D Drag AU - G Y McCormick AU - J J Perkins AU - N C Ihle AU - M E Duggan AU - G D Hartman AU - R J Gould AU - J J Lynch, Jr Y1 - 1996/07/01 UR - http://jpet.aspetjournals.org/content/278/1/62.abstract N2 - 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. ER -