title: Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and molecular modeling based on the solved X-ray structure of the beta2-adrenergic receptor: part 6.
abstract: As an extension of research, we have investigated modification of left-hand side (LHS) of biphenyl analogues containing an acylsulfonamide moiety in the development of potent and selective human beta(3)-adrenergic receptor (AR) agonists. Result of structure-activity relationships (SAR) and cassette-dosing evaluation in dogs showed that the hydroxynorephedrine analogue 16 had an excellent balance of in vitro and in vivo potency with pharmacokinetic profiles. In addition, to facilitate structure-based drug design (SBDD), we also have performed a docking study of biphenyl analogues based on the X-ray structure of the beta(2)-adrenergic receptor.
authors.affiliation: Chemistry Research Laboratories, Astellas Pharma Inc, Tsukuba-shi, Ibaraki 305-8585, Japan. kouji.hattori@jp.astellas.com
authors.forename: Kouji
authors.initials: K
authors.lastname: Hattori
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Susumu
authors.initials: S
authors.lastname: Toda
authors.forename: Masashi
authors.initials: M
authors.lastname: Imanishi
authors.forename: Shinji
authors.initials: S
authors.lastname: Itou
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tanabe
authors.forename: Kenichi
authors.initials: K
authors.lastname: Washizuka
authors.forename: Takanobu
authors.initials: T
authors.lastname: Araki
authors.forename: Minoru
authors.initials: M
authors.lastname: Sakurai
authors.forename: Shigeo
authors.initials: S
authors.lastname: Matsui
authors.forename: Emiko
authors.initials: E
authors.lastname: Imamura
authors.forename: Koji
authors.initials: K
authors.lastname: Ueshima
authors.forename: Takao
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakano
authors.forename: Naoko
authors.initials: N
authors.lastname: Unami
authors.forename: Kaori
authors.initials: K
authors.lastname: Hamada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Fujiko
authors.initials: F
authors.lastname: Takamura
mesh_terms: D000322:Adrenergic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D058667:Adrenergic beta-3 Receptor Agonists; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D008956:Models, Chemical; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry*; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000322:Adrenergic Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides