title: Discovery of a novel series of benzoic acid derivatives as potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. 3. Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety.
abstract: We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds ( 10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC50 = 0.38 nM) for beta3, high selectivity over beta1 and beta2, and good pharmacokinetic properties in rats, dogs, and monkeys.
authors.affiliation: Chemistry Research Laboratories, Pharmacological Research Laboratories, Applied Pharmacology Research Laboratories, Astellas Pharma Inc, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Imanishi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Tomishima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hamashima
authors.forename: Kenichi
authors.initials: K
authors.lastname: Washizuka
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
authors.forename: Kouji
authors.initials: K
authors.lastname: Hattori
mesh_terms: D015078:2-Hydroxyphenethylamine / Q000031:analogs & derivatives* / Q000737:chemistry; D000284:Administration, Oral; D000322:Adrenergic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D058667:Adrenergic beta-3 Receptor Agonists; D000818:Animals; D019817:Benzoic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry*; D001897:Boronic Acids / Q000737:chemistry; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000737:chemistry; D004986:Ether / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry*
chemical_list: D000322:Adrenergic Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D001713:Biphenyl Compounds; D001897:Boronic Acids; D004852:Epoxy Compounds; D022702:Receptors, Adrenergic, beta-3; D013764:Tetrahydronaphthalenes; D004986:Ether; D015078:2-Hydroxyphenethylamine; D019817:Benzoic Acid