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

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. (C) 2017 Elsevier Ltd. All rights reserved.