title: Tricyclic pharmacophore-based molecules as novel integrin alphavbeta3 antagonists. Part IV: preliminary control of alphavbeta3 selectivity by meta-oriented substitution.
abstract: To establish the in vivo efficacy of alphavbeta3/alphaIIbbeta3 dual antagonists possessing a tricyclic pharmacophore, a corresponding alphavbeta3-selective antagonist was required as a control. We initially took two synthetic approaches to obtain alphavbeta3-selective antagonists based on the RGD recognition pattern or on modification of the dihedral angle between the central benzene ring and the adjacent heterocycle, but both proved unsuccessful. However, synthesis of novel antagonists with meta-substitution of the central benzene ring generated weak selectivity for alphavbeta3 over alphaIIbbeta3 for the first time in the family of compounds with the tricyclic pharmacophore. Optimization of meta-oriented antagonists furnished an alphavbeta3-selective antagonist exhibiting inhibitory activity not only in a receptor-binding assay, but also in a cell adhesion assay.
authors.affiliation: Pharmaceutical Research Department, Meiji Seika Kaisha, Ltd, Yokohama 222-8567, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Kubota
authors.forename: Minoru
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Midori
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Naokazu
authors.initials: N
authors.lastname: Yahata
authors.forename: Shoichi
authors.initials: S
authors.lastname: Murakami
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Fujishima
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ajito
mesh_terms: D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019096:Vitronectin / Q000494:pharmacology
chemical_list: D039302:Integrin alphaVbeta3; D010879:Piperazines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019096:Vitronectin