THE IN-VITRO AND IN-VIVO PHARMACOLOGICAL PROFILES OF A PLATELET GLYCOPROTEIN IIB IIIA ANTAGONIST, NSL-9403/

The in vitro and in vivo pharmacological profiles of NSL-9403 [orotyl- seryl -arginyl-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 va lues of 4.3 +/- 0.4 mu M (collagen) and 18 +/- 0.3 mu M (ADP), which w as about 100 times more potent than RGDS. It also inhibited the bindin g of fibrinogen to activated platelets. Ex vivo collagen and ADP-induc ed platelet aggregation in a guinea pig was inhibited after a bolus in travenous 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 plat elet agonist-induced pulmonary embolic sudden death model, where a bol us injection of collagen and epinephrine induced sudden death in mice, intravenous administration of NSL-9403 before an injection of collage n and epinephrine inhibited this platelet-agonist induced death in a d ose 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 plat elet-dependent arterial thrombosis in a dog femoral arterial thrombosi s model. Thus NSL-9403 is a potent inhibitor or platelet aggregation i n vitro and a potent anti-thrombotic agent in vivo with a relatively s hort duration of action. (C) 1997 Elsevier Science Ltd.