The anti-platelet and anti-thrombotic effects of FK633, a peptide-mimetic [formula omitted] antagonist

Abstract

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 α vβ 3, α 5β 1, and α vβ 1 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.