NSL-9403

The in vitro and in vivo pharmacological profiles of NSL-9403 [orotyl-serylarginyl-glycyl-asparatyl-tryptophane], a platelet glycoprotein IIb/IIIa (GpIIb/IIIa) antagonist, has been studied. NSL-9403 inhibited platelet aggregation of human platelet-rich plasma (PRP) with IC50 values of 4.3 +/- 0.4 microM (collagen) and 1.8 +/- 0.3 microM (ADP), which was about 100 times more potent than RGDS. It also inhibited the binding of fibrinogen to activated platelets. Ex vivo collagen and ADP-induced platelet aggregation in a guinea pig was inhibited after a bolus intravenous administration of NSL-9403 at 1.25 mg/kg and above. NSL-9403 had an anti-thrombotic effect in in vivo thrombosis models. In a platelet agonist-induced pulmonary embolic sudden death model, where a bolus injection of collagen and epinephrine induced sudden death in mice, intravenous administration of NSL-9403 before an injection of collagen and epinephrine inhibited this platelet-agonist induced death in a dose dependent manner. In an arterio-venous shunt, infusion of NSL-9403 at 3 mg/kg/hour prevented an increase in circulation pressure due to thrombus formation in the shunt circuit and platelet loss. Infusion of NSL-9403 at 1 to 10 mg/kg/hour produced a complete inhibition of platelet-dependent arterial thrombosis in a dog femoral arterial thrombosis model. Thus NSL-9403 is a potent inhibitor or platelet aggregation in vitro and a potent anti-thrombotic agent in vivo with a relatively short duration of action.