title: Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part 2: synthesis of potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists.
abstract: We synthesized 4-aminopiperidine derivatives of our prototype integrin alpha(v)beta3 antagonist 1 in an attempt to increase the activity and water solubility. Introduction of one or two hydrophilic moieties into the central aromatic ring and/or the benzene ring at the C-terminus of 1 increased water solubility and enhanced inhibition of cell adhesion. The results of a structure-activity relationships (SAR) study indicated that the torsion angle between the central aromatic ring and the piperidine ring, and the acidity at the sulfonamide moiety, might be important for alpha(v)beta3 receptor binding activity. Some of these compounds are novel and potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile.
authors.affiliation: Pharmaceutical Research Department, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Dai
authors.initials: D
authors.lastname: Kubota
authors.forename: Mikio
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Chizuko
authors.initials: C
authors.lastname: Kuroda
authors.forename: Maki
authors.initials: M
authors.lastname: Iguchi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Koyanagi
authors.forename: Shoichi
authors.initials: S
authors.lastname: Murakami
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ajito
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008958:Models, Molecular; 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*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019096:Vitronectin / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: C481395:4-aminopiperidine; D039302:Integrin alphaVbeta3; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019096:Vitronectin; D014867:Water