title: Nanomolar small molecule inhibitors for alphav(beta)6, alphav(beta)5, and alphav(beta)3 integrins.
abstract: 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 alphav(beta)6 integrin, a fibronectin/tenascin receptor. As of yet, no nonpeptidic inhibitor of alphav(beta)6 was known. New peptidomimetic and nonpeptidic compounds were examined in isolated integrin binding assays and in cell adhesion assays for their ability to block alphav(beta)6, alphav(beta)3, alphav(beta)5, and alphalIb(beta)3 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 alpha(v)-integrins alphav(beta)6 and alphav(beta)3, and nanomolar activity. Furthermore, nearly all compounds are inactive on alphaIIb(beta)3. Compound 11 is the first specific, peptidomimetic inhibitor of the alphav(beta)6 integrin receptor.
authors.affiliation: Department of Preclinical Oncology and Medicinal Chemistry, Merck KGaA, Frankfurterstr. 250, 64271 Darmstadt, Germany. Goodman@merck.de
authors.forename: Simon L
authors.initials: SL
authors.lastname: Goodman
authors.forename: Günter
authors.initials: G
authors.lastname: Hölzemann
authors.forename: Gábor A G
authors.initials: GA
authors.lastname: Sulyok
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000951:Antigens, Neoplasm; D002448:Cell Adhesion; D005109:Extracellular Matrix / Q000502:physiology; D005353:Fibronectins / Q000502:physiology; D005977:Glutarates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000502:physiology; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000502:physiology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000596:Amino Acids; D000951:Antigens, Neoplasm; D005353:Fibronectins; D005977:Glutarates; D006146:Guanidines; D016023:Integrins; D010455:Peptides; D011725:Pyridines; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; C073878:integrin alphavbeta6