title: Discovery of 1,7-cyclized indoles as a new class of potent and highly selective human beta3-adrenergic receptor agonists with high cell permeability.
abstract: The synthesis and evaluation of a novel series of 1,7-cyclized indole-based human adrenergic receptor (beta3-AR) agonists are reported. The synthesis of a variety of 1,7-cyclized indole part was accomplished by the Mitsunobu reaction or a ring closing metathesis (RCM) reaction. SAR studies revealed that expansion of the ring size resulted in considerable selectivity against the beta1- and beta2-ARs. Compound 26, an eight-membered ring analogue with a double bond on its 1,7-linker portion, was found to be a potent beta3-AR agonist (EC50 = 0.75 nM, IA = 90%) with extremely high selectivity for the beta3-AR over the beta1- and beta2-ARs.
authors.affiliation: Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd, 33-94, Enoki, Suita 564-0053, Japan. kazuhiro-mizuno@dainippon-pharm.co.jp
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mizuno
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.forename: Ikuko
authors.initials: I
authors.lastname: Taoka
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Yamashita
authors.forename: Mayumi
authors.initials: M
authors.lastname: Oue
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsujiuchi
authors.forename: Yukiyo
authors.initials: Y
authors.lastname: Arai
authors.forename: Shinya
authors.initials: S
authors.lastname: Suzuki
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Furutani
authors.forename: Shiro
authors.initials: S
authors.lastname: Kato
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D011869:Radioligand Assay; D013329:Structure-Activity Relationship
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D007211:Indoles