Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors
| Autor: | Daiki Sakai, Kazutoshi Watanabe, Mika Nabeno, Hiroshi Tanaka, Shinji Tanaka, Shinji Sunada, Jun-ichi Eguchi, Keiko Takiguchi-Hayashi, Ken-Ichi Saito, Shin-ichi Kusaka, Kazuki Nakayama, Kenji Fukunaga, Toshiyuki Kohara, Tomoko Bessho, Takashi Horikawa, Akiko Mori |
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| Rok vydání: | 2017 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Pharmaceutical Science macromolecular substances Pyrimidinones 010402 general chemistry 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship GSK-3 Morpholine Drug Discovery Moiety Phenyl group Humans Molecular Biology Protein Kinase Inhibitors Glycogen Synthase Kinase 3 beta Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Aryl Organic Chemistry 0104 chemical sciences Molecular Docking Simulation Piperazine chemistry Docking (molecular) Molecular Medicine Methyl group |
| Zdroj: | Bioorganicmedicinal chemistry letters. 27(16) |
| ISSN: | 1464-3405 |
| Popis: | We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3β. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3β respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3β with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice. |
| Databáze: | OpenAIRE |
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