R-Isomers of Arg-Gly-Asp (RGD) mimics as potent αvβ3 inhibitors

The integrin αvβ3, 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 αvβ3 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 αvβ3. 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.