THE ANTIPLATETLET AND ANTITHROMBOTIC EFFECTS OF FK633, A PEPTIDE-MIMETIC GPIIB IIIA ANTAGONIST/

The anti-platelet and anti-thrombotic properties of FK633, a peptide m imetic GPIIb/IIIa antagonist were studied. In human platelet rich plas ma, FK633 inhibited ADP-, collagen-, thrombin-, and PAF-induced platel et aggregation with IC50 values of 103, 87, 98, and 239 nM, respective ly. RGDS acted similarly, but it's potency was about 1,000 times weake r than FK633. FK633 inhibited I-125-fibrinogen binding to human washed platelet with an IC50 of 88 nM. FK633 did not inhibit alpha(v) beta(3 ), alpha(5) beta(1), and alpha(v) beta(1) integrin-mediated cellular a dhesion up to I.OmM, while RGDS inhibited all these interactions. In d ogs, 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 agg regation at 0.32 mg/kg, causing significant prolongation of the bleedi ng time. Thus, FK633 is a specific GPIIb/IIIa antagonist with potent a nti-thrombotic effect in vivo, but careful dosing study might be neces sary to avoid the bleeding complications in the clinic.