SC-49992 - A POTENT AND SPECIFIC INHIBITOR OF PLATELET-AGGREGATION

Fibrinogen binding is required for platelet aggregation and subsequent thrombus formation. SC-49992 (SC), an RODE mimetic, is a potent and s pecific inhibitor of the binding of fibrinogen to its receptor on acti vated platelets, glycoprotein IIb/IIIa (IC50 0.7 mu M). SC was more po tent (1-5 mu M) than either RGDS, RGDF or the gamma chain dodecapeptid e in blocking platelet aggregation to a variety of agonists,in both do g and human platelet rich plasma. SC was more potent as an inhibitor o f GP IIb/IIIa on platelets than it was against other integrin and non- integrin receptors, including the RGD-dependent vitronectin receptor a nd other non-RGD-dependent integrins such as CDII/CD18. SC had little effect on ristocetin induced agglutination. SC blocked ex vivo collage n induced aggregation in dogs and collagen induced thrombocytopenia in rats. These data suggest that elimination of the Arg-NH2 and the Arg- Gly amide bond of RGDF provided increased inhibitory potency and speci ficity. This structural modification may be of value in the developmen t of other more potent RGDF mimetics for the inhibition of platelet ag gregation.