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

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...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-12, Vol.23 (24), p.6933-6937
Hauptverfasser:	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
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Alzheimer’s disease Animals Binding Sites Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - metabolism Enzyme Activation - drug effects Female Glycogen Synthase Kinase 3 - antagonists & inhibitors Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta Glycogen synthase kinase-3β Half-Life Humans Hyperphosphorylation Male Mice Microsomes, Liver - drug effects Microsomes, Liver - metabolism Molecular Docking Simulation Morpholines - chemical synthesis Morpholines - pharmacokinetics Morpholines - pharmacology 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 - chemistry Pyrimidinones - pharmacokinetics Pyrimidinones - pharmacology Rats Rats, Sprague-Dawley Stereoisomerism Tau protein tau Proteins - metabolism
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.09.020