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Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors. 2017
Toshiyuki Kohara, and
Kazuki Nakayama, and
Kazutoshi Watanabe, and
Shin-Ichi Kusaka, and
Daiki Sakai, and
Hiroshi Tanaka, and
Kenji Fukunaga, and
Shinji Sunada, and
Mika Nabeno, and
Ken-Ichi Saito, and
Jun-Ichi Eguchi, and
Akiko Mori, and
Shinji Tanaka, and
Tomoko Bessho, and
Keiko Takiguchi-Hayashi, and
Takashi Horikawa
Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
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.
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