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2-(2-Phenylmorpholin-4-yl)pyrimidin-4(3H)-ones; a new class of potent, selective and orally active glycogen synthase kinase-3ß inhibitors.

Fukunaga, Kenji; Uehara, Fumiaki; Aritomo, Keiichi; Shoda, Aya; Hiki, Shinsuke; Okuyama, Masahiro; Usui, Yoshihiro; Watanabe, Kazutoshi; Yamakoshi, Koichi; Kohara, Toshiyuki; Hanano, Tokushi; Tanaka, Hiroshi; Tsuchiya, Susumu; Sunada, Shinji; Saito, Ken-Ichi; Eguchi, Jun-ichi; Yuki, Satoshi; Asano, Shoichi; Tanaka, Shinji; Mori, Akiko; Yamagami, Keiji; Baba, Hiroshi; Horikawa, Takashi; Fujimura, Masatake.

Bioorg Med Chem Lett ; 23(24): 6933-7, 2013 Dec 15.

Article in English | MEDLINE | ID: mdl-24176395

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-3ß (GSK-3ß). We found 21, 29 and 30 to possess potent in vitro GSK-3ß inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.

Subject(s)

Glycogen Synthase Kinase 3/antagonists & inhibitors , Morpholines/chemical synthesis , Morpholines/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Administration, Oral , Animals , Binding Sites , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Enzyme Activation/drug effects , Female , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Half-Life , Humans , Male , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Docking Simulation , Morpholines/pharmacokinetics , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Stereoisomerism , tau Proteins/metabolism

ABSTRACT

Subject(s)

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