title: Discovery of novel 2-(alkylmorpholin-4-yl)-6-(3-fluoropyridin-4-yl)-pyrimidin-4(3H)-ones as orally-active GSK-3β inhibitors for Alzheimer's disease.
abstract: We herein describe the results of further evolution of GSK-3β inhibitors for Alzheimer's disease from our promising compounds with in vivo tau phosphorylation inhibitory activity by oral administration. Introduction of a low alkyl group instead of the phenyl group at the 3-position of the morpholine moiety aiming to improve pharmacokinetic profiles resulted in potent low molecular weight GSK-3β inhibitors with good in vitro pharmacokinetic profiles, which also showed in vivo tau phosphorylation inhibitory activity by oral administration. Effect of the stereochemistry of the alkyl moiety is also discussed using docking models.
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Kenji
authors: K
authors: Fukunaga
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Daiki
authors: D
authors: Sakai
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Kazutoshi
authors: K
authors: Watanabe
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Kazuki
authors: K
authors: Nakayama
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Toshiyuki
authors: T
authors: Kohara
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Hiroshi
authors: H
authors: Tanaka
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Shinji
authors: S
authors: Sunada
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Mika
authors: M
authors: Nabeno
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Masako
authors: M
authors: Okamoto
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Ken-Ichi
authors: K
authors: Saito
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Jun-ichi
authors: J
authors: Eguchi
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Akiko
authors: A
authors: Mori
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Shinji
authors: S
authors: Tanaka
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Keiko
authors: K
authors: Inazawa
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors: Takashi
authors: T
authors: Horikawa
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D000818:Animals; D055808:Drug Discovery; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D009025:Morpholines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D009025:Morpholines; D011743:Pyrimidines; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Alkylmorpholine; Alzheimer’s disease; Glycogen synthase kinase 3β