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.
Subject(s)
Amino Acids/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Integrin alphaVbeta3/antagonists & inhibitors , Molecular Mimicry , Oligopeptides/chemistry , Oligopeptides/pharmacology , 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 AssaysABSTRACT
The integrin alpha(v)beta(3) is expressed in a number of cell types and is thought to play a major role in several pathological conditions. Various small molecules that inhibit the integrin have been shown to suppress tumor growth and retinal angiogenesis. The tripeptide Arg-Gly-Asp (RGD), a common binding motif in several ligands that bind to alpha(v)beta(3), has been depeptidized and optimized in our efforts toward discovering a small molecule inhibitor. We recently disclosed the synthesis and biological activity of several small molecules that did not contain any peptide bond and mimic the tripeptide RGD. The phenethyl group in one of the lead compounds was successfully replaced with a cyclopropyl moiety. The new lead compound was optimized for potency, selectivity, and for its ADME properties. We describe herein the discovery, synthesis, and optimization of cyclopropyl containing analogs that are potent and selective inhibitors of alpha(v)beta(3).
Subject(s)
Acetates/chemical synthesis , Acetates/pharmacology , Integrin alphaVbeta3/antagonists & inhibitors , Naphthyridines/chemical synthesis , Naphthyridines/pharmacology , Animals , Area Under Curve , Cell Line , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Drug Design , Half-Life , Humans , Indicators and Reagents , Male , Mice , Rats , Rats, Sprague-Dawley , Spectrophotometry, Ultraviolet , Structure-Activity Relationship , TransfectionABSTRACT
A peptidomimetic inhibitor of the integrin alpha(v)beta(3) has been substantially modified to produce several new nonpeptidic antagonists. These inhibitors are simpler to synthesize and belong to new classes of scaffolds. Some of the compounds served as the initial lead for further optimization, which led to the discovery of potent and selective inhibitors of the integrin alpha(v)beta(3).
