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 replaced with 5-(4-amidinophenyl)pentanoyl mimetic has led to a 1000-fold increase in inhibitory potency over the natural RGDF ligand. The guanidine residue of the arginine may be involved in a reinforced ionic interaction with a carboxylate of the receptor which could explain the dramatic increase in potency upon replacement with benzamidine. This hypothesis 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 respective complexes suggest that the benzamidine-carboxylate is more favorable than the guanidine-carboxylate interaction. The ED50 for the inhibition of ex vivo collagen induced platelet aggregation in the dog for SC-52012 (1) was 0.32 microgram/kg/min by iv infusion with a pharmacodynamic half-life for recovery of approximately 40 min.