title: Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3β (GSK-3β) inhibitors for type 2 diabetics.
abstract: The design, synthesis, and evaluation of 6-6-7 tricyclic quinolones containing the strained spirocycle moiety aiming at the GSK-3β inhibitor were described. Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3β inhibitory activity in both cell-free and cell-based assays (IC(50) = 36nM, EC(50) = 3.2μM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. shigeki.seto@mb.kyorin-pharm.co.jp
authors.forename: Shigeki
authors.initials: S
authors.lastname: Seto
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yumoto
authors.forename: Kyoko
authors.initials: K
authors.lastname: Okada
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Asahina
authors.forename: Aya
authors.initials: A
authors.lastname: Iwane
authors.forename: Maki
authors.initials: M
authors.lastname: Iwago
authors.forename: Reiko
authors.initials: R
authors.lastname: Terasawa
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Shreder
authors.forename: Koji
authors.initials: K
authors.lastname: Murakami
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kohno
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology; D015195:Drug Design; D005951:Glucose Tolerance Test; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D015363:Quinolones; D013141:Spiro Compounds; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3