Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors
Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors
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DOI：
10.1016/j.bmcl.2017.06.077
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发表时间：
2017-08-15
影响因子：
2.7
通讯作者：
Horikawa, Takashi
中科院分区：
文献类型：
--
作者：
Kohara, Toshiyuki;Nakayama, Kazuki;Horikawa, Takashi
我们在此描述了糖原合成酶激酶(GSK)-3 β抑制剂的进一步进化的结果，这些化合物含有3-甲基吗啡啉片段。morpholine部分转化为哌嗪部分产生了有效的GSK-3p抑制剂。对哌嗪部分氮原子的SAR研究表明，苯基对GSK-3 β具有有效的抑制活性。对接研究表明，哌嗪氮原子上的苯基和哌嗪上的甲基分别与GSK-3 β发生阳离子- π和ch - π相互作用。4-甲氧基苯基类似物29对GSK-3 β表现出最有效的抑制活性，具有良好的体外和体内药代动力学特征，并且29在小鼠口服后显着降低tau磷酸化。(C) 2017 Elsevier Ltd.版权所有。
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3 beta inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3p inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3 beta. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-pi and CH-pi interactions with GSK-3 beta respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3 beta with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice. (C) 2017 Elsevier Ltd. All rights reserved.