Design and synthesis of novel cyclic RGD-containing peptides as highly potent and selective integrin alpha IIb beta 3...

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-G-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.