R-Isomers of Arg-Gly-Asp (RGD) mimics as potent α_vβ₃ inhibitors

The integrin α_vβ₃, vitronectin receptor, is expressed in a number of cell types and has been shown to mediate adhesion of osteoclasts to bone matrix, vascular smooth muscle cell migration, and angiogenesis. We recently disclosed the discovery of a tripeptide Arg-Gly-Asp (RGD) mimic, which has been shown to be a potent inhibitor of the integrin α_vβ₃ and has excellent anti-angiogenic properties including its suppression of tumor growth in animal models. In other investigations involving RGD mimics, only compounds containing the S-isomers of the β-amino acids have been shown to be potent. We were surprised to find the potencies of analogs containing enantiomerically pure S-isomers of β-amino acids which were only marginally better than the corresponding racemic mixtures. We therefore synthesized RGD mimics containing R-isomers of β-amino acids and found them to be relatively potent inhibitors of α_vβ₃. One of the compounds was examined in tumor models in mice and has been shown to significantly reduce the rate of growth and the size of tumors.