1. R-isomers of Arg-Gly-Asp (RGD) mimics as potent alphavbeta3 inhibitors.
- Author
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Nagarajan SR, Devadas B, Malecha JW, Lu HF, Ruminski PG, Rico JG, Rogers TE, Marrufo LD, Collins JT, Kleine HP, Lantz MK, Zhu J, Green NF, Russell MA, Landis BH, Miller LM, Meyer DM, Duffin TD, Engleman VW, Finn MB, Freeman SK, Griggs DW, Williams ML, Nickols MA, Pegg JA, Shannon KE, Steininger C, Westlin MM, Nickols GA, and Keene JL
- Subjects
- Amino Acids chemical synthesis, Animals, Antineoplastic Agents pharmacokinetics, Colonic Neoplasms, Hypercalcemia chemically induced, Isomerism, Melanoma, Mice, Mice, Inbred Strains, Oligopeptides pharmacokinetics, Skin Neoplasms, Xenograft Model Antitumor Assays, Amino Acids chemistry, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Integrin alphaVbeta3 antagonists & inhibitors, Molecular Mimicry, Oligopeptides chemistry, Oligopeptides pharmacology
- Abstract
The integrin alpha(v)beta(3), 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 alpha(v)beta(3) 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 beta-amino acids have been shown to be potent. We were surprised to find the potencies of analogs containing enantiomerically pure S-isomers of beta-amino acids which were only marginally better than the corresponding racemic mixtures. We therefore synthesized RGD mimics containing R-isomers of beta-amino acids and found them to be relatively potent inhibitors of alpha(v)beta(3). 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.
- Published
- 2007
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