Nanomolar small molecule inhibitors for ανβ6, ανβ5, and ανβ3 integrins

Simon L. Goodman, Günter Hölzemann, Gäbor A.G. Sulyok, Horst Kessler

Research output: Contribution to journalArticlepeer-review

185 Scopus citations


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 ανβ6 integrin, a fibronectin/tenascin receptor. As of yet, no nonpeptidic inhibitor of ανβ6 was known. New peptidomimetic and nonpeptidic compounds were examined in isolated integrin binding assays and in cell adhesion assays for their ability to block ανβ6, ανβ3, ανβ5, and αIIbβ3 integrins. The compounds are based on an aromatically substituted β 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 αν-integrins ανβ6 and ανβ3, and nanomolar activity. Furthermore, nearly all compounds are inactive on αIIbβ3. Compound 11 is the first specific, peptidomimetic inhibitor of the ανβ6 integrin receptor.

Original languageEnglish
Pages (from-to)1045-1051
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number5
StatePublished - 28 Feb 2002


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