Nanomolar small molecule inhibitors for αvβ6, αvβ5, and αvβ3 integrins

Integrin adhesion receptors frequently recognize a core amino acid sequence, Arg-Gly-Asp, in their target ligands. Inhibitors with the ability to inhibit one or a small subset of such RGD-dependent integrins have been invaluable in defining their biological function. Here, we have characterized low molecular weight inhibitors for their ability to specifically inhibit alphavbeta6 integrin, a fibronectin/tenascin receptor. As of yet, no nonpeptidic inhibitor of alphavbeta6 was known. New peptidomimetic and nonpeptidic compounds were examined in isolated integrin binding assays and in cell adhesion assays for their ability to block alphavbeta6, alphavbeta3, alphavbeta5, and alpha1Ibbeta3 integrins. The compounds are based on an aromatically substituted beta amino acid or glutaric acid derivative as an acidic center and an aminopyridyl or guanidyl residue as a basic mimetic. We found several classes of inhibitors with different selectivities, especially mono- or biselectivity on the alphav-integrins alphavbeta6 and alphavbeta3, and nanomolar activity. Furthermore, nearly all compounds are inactive on alphaIIbbeta3. Compound 11 is the first specific, peptidomimetic inhibitor of the alphavbeta6 integrin receptor.