Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 27, Issue 16, Pages 3733-3738Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.06.077
Keywords
Glycogen synthase kinase-3; Alzheimer's disease; Alkylpiperazine
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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.
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