POTENT IN-VITRO AND IN-VIVO INHIBITORS OF PLATELET-AGGREGATION BASED UPON THE ARG-GLY-ASP-PHE SEQUENCE OF FIBRINOGEN - A PROPOSAL ON THE NATURE OF THE BINDING INTERACTION BETWEEN THE ARG-GUANIDINE OF RGDX MIMETICS AND THE PLATELET GP IIB-IIIA RECEPTOR

Peptide mimetics of the RGDF sequence in which Arg-Gly has been replac ed with 5-(4-amidinophenyl)pentanoyl mimetic has led to a 1000-fold in crease in inhibitory potency over the natural RGDF ligand. The guanidi ne residue of the arginine may be involved in a reinforced ionic inter action with a carboxylate of the receptor which could explain the dram atic increase in potency upon replacement with benzamidine. This hypot hesis is supported by the observation of low inhibitory potency of the corresponding benzylamine (18) and no activity with the corresponding imidazoline derivative (19); plus, ab initio calculations on the resp ective complexes suggest that the benzamidine-carboxylate is more favo rable than the guanidine-carboxylate interaction. The ED50 for the inh ibition of ex vivo collagen induced platelet aggregation in the dog fo r SC-52012 (1) was 0.32 mug/kg/min by iv infusion with a pharmacodynam ic half-life for recovery of approximately 40 min.