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

Autor:	Jun-ichi Eguchi, Shinsuke Hiki, Masatake Fujimura, Satoshi Yuki, Shinji Sunada, Tokushi Hanano, Masahiro Okuyama, Fumiaki Uehara, Toshiyuki Kohara, Hiroshi Tanaka, Keiichi Aritomo, Susumu Tsuchiya, Ken-Ichi Saito, Kenji Fukunaga, Kazutoshi Watanabe, Shoichi Asano, Koichi Yamakoshi, Hiroshi Baba, Shinji Tanaka, Takashi Horikawa, Yoshihiro Usui, Aya Shoda, Akiko Mori, Keiji Yamagami
Rok vydání:	2013
Předmět:	Male Morpholines Clinical Biochemistry Tau protein Administration Oral Pharmaceutical Science Hyperphosphorylation tau Proteins Pyrimidinones macromolecular substances Inhibitory postsynaptic potential Biochemistry Rats Sprague-Dawley Glycogen Synthase Kinase 3 Mice Cytochrome P-450 Enzyme System Oral administration GSK-3 Drug Discovery Animals Cytochrome P-450 Enzyme Inhibitors Humans Phosphorylation Glycogen synthase Protein Kinase Inhibitors Molecular Biology Binding Sites Glycogen Synthase Kinase 3 beta biology Chemistry Organic Chemistry Stereoisomerism In vitro Protein Structure Tertiary Rats Enzyme Activation Molecular Docking Simulation Orally active Microsomes Liver biology.protein Molecular Medicine Female Half-Life
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 23:6933-6937
ISSN:	0960-894X
DOI:	10.1016/j.bmcl.2013.09.020
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8a885218d2050bd32f637b9c4aaa1822 https://doi.org/10.1016/j.bmcl.2013.09.020 Zobrazit plný text záznamu Full Text from ScienceDirect