Abstract
A series of 2-(2-phenylmorpholin-4-yl)pyrimidin-4(3H)-ones was synthesized and examined for their inhibitory activity against glycogen synthase kinase-3β (GSK-3β). We found 21, 29 and 30 to possess potent in vitro GSK-3β inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.
Keywords:
Alzheimer’s disease; Glycogen synthase kinase-3β; Hyperphosphorylation; Tau protein.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
-
Administration, Oral
-
Animals
-
Binding Sites
-
Cytochrome P-450 Enzyme Inhibitors
-
Cytochrome P-450 Enzyme System / metabolism
-
Enzyme Activation / drug effects
-
Female
-
Glycogen Synthase Kinase 3 / antagonists & inhibitors*
-
Glycogen Synthase Kinase 3 / metabolism
-
Glycogen Synthase Kinase 3 beta
-
Half-Life
-
Humans
-
Male
-
Mice
-
Microsomes, Liver / drug effects
-
Microsomes, Liver / metabolism
-
Molecular Docking Simulation
-
Morpholines / chemical synthesis*
-
Morpholines / pharmacokinetics
-
Morpholines / pharmacology*
-
Phosphorylation / drug effects
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / pharmacokinetics
-
Protein Kinase Inhibitors / pharmacology
-
Protein Structure, Tertiary
-
Pyrimidinones / chemical synthesis
-
Pyrimidinones / chemistry*
-
Pyrimidinones / pharmacokinetics
-
Pyrimidinones / pharmacology*
-
Rats
-
Rats, Sprague-Dawley
-
Stereoisomerism
-
tau Proteins / metabolism
Substances
-
Cytochrome P-450 Enzyme Inhibitors
-
Morpholines
-
Protein Kinase Inhibitors
-
Pyrimidinones
-
tau Proteins
-
Cytochrome P-450 Enzyme System
-
GSK3B protein, human
-
Glycogen Synthase Kinase 3 beta
-
Gsk3b protein, mouse
-
Gsk3b protein, rat
-
Glycogen Synthase Kinase 3