title: Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part 1: design and synthesis of a lead compound exhibiting alpha(v)beta3/alpha(IIb)beta3 dual antagonistic activity.
abstract: In order to generate novel compounds with integrin alpha(v)beta3-antagonistic activity together with antiplatelet activity, tricyclic pharmacophore-based molecules were designed and synthesized. Although piperazine-containing compounds initially prepared were selective alpha(IIb)beta3 antagonists, replacement of piperazine with piperidine furnished a potent alpha(v)beta3/alpha(IIb)beta3 dual antagonist. Structure-activity relationship (SAR) studies provided clues for further development of tricyclic pharmacophore-based integrin antagonists.
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Kubota
authors.forename: Minoru
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Mikio
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Shoichi
authors.initials: S
authors.lastname: Murakami
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Hachisu
authors.forename: Kiyoaki
authors.initials: K
authors.lastname: Katano
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ajito
mesh_terms: D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019096:Vitronectin / Q000737:chemistry
chemical_list: D039302:Integrin alphaVbeta3; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019096:Vitronectin