title: Design and synthesis of 1,5- and 2,5-substituted tetrahydrobenzazepinones as novel potent and selective integrin alphaVbeta3 antagonists.
abstract: The design and synthesis of novel integrin alpha(V)beta(3) antagonists based on a 1,5- or 2,5-substituted tetrahydrobenzaezpinone core is described. In vitro activity of respective compounds was determined via alpha(V)beta(3) binding assay, and selected derivatives were submitted to further characterization in functional cellular assays. SAR was obtained by modification of the benzazepinone core, variation of the spacer linking guanidine moiety and core, and modification of the guanidine mimetic. These efforts led to the identification of novel alpha(V)beta(3) inhibitors displaying potency in the subnanomolar range, selectivity versus alpha(IIb)beta(3) and functional efficacy in relevant cellular assays. A method for the preparation of enantiomerically pure derivatives was developed, and respective enantiomers evaluated in vitro. Compounds 31 and 37 were assessed for metabolic stability, resorption in the Caco-2 assay and pharmacokinetics.
authors.affiliation: Neuroscience, Medicinal Chemistry, Abbott GmbH and Co KG, Discovery Research, D-67008, PO Box 210805, Ludwigshafen, Germany
authors.forename: Andreas
authors.initials: A
authors.lastname: Kling
authors.forename: Gisela
authors.initials: G
authors.lastname: Backfisch
authors.forename: Jürgen
authors.initials: J
authors.lastname: Delzer
authors.forename: Hervé
authors.initials: H
authors.lastname: Geneste
authors.forename: Claudia
authors.initials: C
authors.lastname: Graef
authors.forename: Wilfried
authors.initials: W
authors.lastname: Hornberger
authors.forename: Udo E W
authors.initials: UE
authors.lastname: Lange
authors.forename: Arnulf
authors.initials: A
authors.lastname: Lauterbach
authors.forename: Werner
authors.initials: W
authors.lastname: Seitz
authors.forename: Thomas
authors.initials: T
authors.lastname: Subkowski
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D018938:Caco-2 Cells; D002448:Cell Adhesion / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019791:Guanidine / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008968:Molecular Conformation; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001552:Benzazepines; D007202:Indicators and Reagents; D039041:Integrin alpha4beta1; D039302:Integrin alphaVbeta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019791:Guanidine