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  • Title: Design and synthesis of novel cyclic RGD-containing peptides as highly potent and selective integrin alpha IIb beta 3 antagonists.
    Author: Cheng S, Craig WS, Mullen D, Tschopp JF, Dixon D, Pierschbacher MD.
    Journal: J Med Chem; 1994 Jan 07; 37(1):1-8. PubMed ID: 7507165.
    Abstract:
    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.
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