title: 2-(2-Phenylmorpholin-4-yl)pyrimidin-4(3H)-ones; a new class of potent, selective and orally active glycogen synthase kinase-3β inhibitors.
abstract: A series of 2-(2-phenylmorpholin-4-yl)pyrimidin-4(3H)-ones was synthesized and examined for their inhibitory activity against glycogen synthase kinase-3β (GSK-3β). We found 21, 29 and 30 to possess potent in vitro GSK-3β inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.
authors.affiliation: Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Uehara
authors.forename: Keiichi
authors.initials: K
authors.lastname: Aritomo
authors.forename: Aya
authors.initials: A
authors.lastname: Shoda
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Hiki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okuyama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Usui
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Watanabe
authors.forename: Koichi
authors.initials: K
authors.lastname: Yamakoshi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kohara
authors.forename: Tokushi
authors.initials: T
authors.lastname: Hanano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Susumu
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Shinji
authors.initials: S
authors.lastname: Sunada
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Saito
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Eguchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yuki
authors.forename: Shoichi
authors.initials: S
authors.lastname: Asano
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.forename: Akiko
authors.initials: A
authors.lastname: Mori
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamagami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Baba
authors.forename: Takashi
authors.initials: T
authors.lastname: Horikawa
authors.forename: Masatake
authors.initials: M
authors.lastname: Fujimura
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D009025:Morpholines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D016875:tau Proteins; D003577:Cytochrome P-450 Enzyme System; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer’s disease; Glycogen synthase kinase-3β; Hyperphosphorylation; Tau protein