Discovery of novel 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3 beta inhibitors

作者：Usui Yoshihiro; Uehara Fumiaki; Hiki Shinsuke; Watanabe Kazutoshi^*; Tanaka Hiroshi; Shouda Aya; Yokoshima Satoshi; Aritomo Keiichi; Adachi Takashi; Fukunaga Kenji; Sunada Shinji; Nabeno Mika; Saito Ken Ichi; Eguchi Jun ichi; Yamagami Keiji; Asano Shouichi; Tanaka Shinji; Yuki Satoshi; Yoshii Narihiko; Fujimura Masatake; Horikawa Takashi

来源：Bioorganic & Medicinal Chemistry Letters, 2017, 27(16): 3726-3732.

DOI：10.1016/j.bmcl.2017.06.078

• glycogen synthase kinase-3
• Alzheimer's disease
• phenylpiperazine

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3 beta inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3 beta inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3 beta. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Glnl 85 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed.

• 出版日期2017-8-15