Nonpeptide glycoprotein IIb/IIIa inhibitors. 8. Antiplatelet activity and oral antithrombotic efficacy of L-734,217.
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.
Cook
J J
JJ
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
Holahan
M A
MA
Lyle
E A
EA
Ramjit
D R
DR
Sitko
G R
GR
Stranieri
M T
MT
Stupienski
R F
RF
Wallace
A A
AA
Hand
E L
EL
Gehret
J R
JR
Kothstein
T
T
Drag
M D
MD
McCormick
G Y
GY
Perkins
J J
JJ
Ihle
N C
NC
Duggan
M E
ME
Hartman
G D
GD
Gould
R J
RJ
Lynch
J J
JJ
D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000187:drug effects*; D006168:Guinea Pigs; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D006023:Glycoproteins; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D015091:beta-Alanine; C095356:L 734217