The anti-platelet and anti-thrombotic effects of FK633, a peptide-mimetic GPIIB/IIIA antagonist.
The anti-platelet and anti-thrombotic properties of FK633, a peptide mimetic GPIIb/IIIa antagonist were studied. In human platelet rich plasma, FK633 inhibited ADP-, collagen-, thrombin-, and PAF-induced platelet aggregation with IC50 values of 103, 87, 98, and 239 nM, respectively. RGDS acted similarly, but it's potency was about 1,000 times weaker than FK633, FK633 inhibited 125I-fibrinogen binding to human washed platelet with an IC50 of 88 nM. FK633 did not inhibit alphavbeta3, alpha5beta1, and alphavbeta1 integrin-mediated cellular adhesion up to 1.0mM, while RGDS inhibited all these interactions. In dogs, bolus injection of FK633 at 0.1 mg/kg significantly suppressed ex vivo ADP-induced platelet aggregation (>40% inhibition) and thrombus formation at stenosed and injured coronary artery, but did not prolong template bleeding time. However, FK633 inhibited >90% ADP-induced aggregation at 0.32 mg/kg, causing significant prolongation of the bleeding time. Thus, FK633 is a specific GPIIb/IIIa antagonist with potent anti-thrombotic effect in vivo, but careful dosing study might be necessary to avoid the bleeding complications in the clinic.
Department of Pharmacology, New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
T
T
Aoki
D
D
Cox
K
K
Senzaki
J
J
Seki
A
A
Tanaka
H
H
Takasugi
Y
Y
Motoyama
D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000166:cytology; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*
D004151:Dipeptides; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; C103087:((4-(4-amidinophenoxy)butanoyl)aspartyl)valine; D005340:Fibrinogen