Development of Low Molecular Weight Ligands for Integrin α_vβ₃

We designed and synthesized non-peptide organic molecular ligands for integrin α_vβ₃. Candidate ligands featured amidino analog and carboxy groups as binding sites on either side of a spacer, which consisted of benzophenone or an analog, such as diphenyl sulfide, diphenyl sulfoxide, diphenyl sulfone, or diphenyl ether. Competitive binding assays to integrin α_vβ₃ with respect to [¹²⁵I]echistatin were used to determine inhibitory activity of the synthetic ligands. Ligands bearing 2-aminobenzimidazoyl and glycyl groups separated by a benzophenone spacer demonstrated more potent binding than did a linear Arg-Gly-Asp (RGD) tripeptide that represents the native integrin α_vβ₃ binding motif. Ligands possessing 2-aminobenzimidazoyl and carboxy groups and diphenyl sulfoxide or diphenyl ether spacers inhibited binding of [¹²⁵I]echistatin with IC₅₀ values similar to that of the linear RGD tripeptide.