DESIGN AND SYNTHESIS OF NOVEL CYCLIC RGD-CONTAINING PEPTIDES AS HIGHLY POTENT AND SELECTIVE INTEGRIN ALPHA(IIB)BETA(3) ANTAGONISTS

Utilizing conformational constraints in conjunction with various structural considerations, we have synthesized a series of cyclic disulfide peptides that are highly potent and selective antagonists for the platelet integrin alpha(IIb)beta(3) (GPIIb/IIIa). The affinities of the peptides for alpha(IIb)beta(3) were determined by platelet aggregation assays and an alpha(IIb)beta(3) ELISA. Their affinities for alpha(5) beta(1) and alpha(V) beta(5) integrins were also determined in respective ELISA assays. Structure-activity relationship studies suggest that R-C-D-Ar-R (Ar = hydrophobic residue) is the essential pharmacophore that is responsible for their high alpha(IIb)beta(3) binding affinity, very high selectivity, and distinct biological properties. One of these analogues, TP9201, has been shown to inhibit platelet-mediated thrombus formation without associated prolongation of template bleeding time. The arginine residue adjacent the carboxy terminus of the R-G-D-Ar sequence could function as the biological effector element that determines this distinct and unexpected biological property.