2013
DOI: 10.1016/j.bmcl.2013.09.020
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2-(2-Phenylmorpholin-4-yl)pyrimidin-4(3H)-ones; A new class of potent, selective and orally active glycogen synthase kinase-3β inhibitors

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Cited by 32 publications
(15 citation statements)
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“…The kinase induces hyperphosphorylation of tau at several primed (e.g., Tyr231) and non-primed (e.g., S 396 ) phosphorylation sites in cellular neurodegeneration assays, indicating that GSK3 is a key tau kinase in the formation of neurofibrillary tangles (NFT) and ultimately neuronal death 8 . Consistent with these findings, conditional transgenic mice overexpressing GSK3 display tau hyperphosphorylation and neurodegeneration 41 , while pharmacological inhibition of the kinase prevents tau hyperphosphorylation in normal mice or in a transgenic model of AD 28,29,4245 . In line with these findings are the present data with SAR502250 demonstrating that oral administration of the drug decreased hyperphosphorylation on S 396 in the spinal cord and cortex in P301L human tau transgenic mice.…”
Section: Discussionsupporting
confidence: 58%
See 1 more Smart Citation
“…The kinase induces hyperphosphorylation of tau at several primed (e.g., Tyr231) and non-primed (e.g., S 396 ) phosphorylation sites in cellular neurodegeneration assays, indicating that GSK3 is a key tau kinase in the formation of neurofibrillary tangles (NFT) and ultimately neuronal death 8 . Consistent with these findings, conditional transgenic mice overexpressing GSK3 display tau hyperphosphorylation and neurodegeneration 41 , while pharmacological inhibition of the kinase prevents tau hyperphosphorylation in normal mice or in a transgenic model of AD 28,29,4245 . In line with these findings are the present data with SAR502250 demonstrating that oral administration of the drug decreased hyperphosphorylation on S 396 in the spinal cord and cortex in P301L human tau transgenic mice.…”
Section: Discussionsupporting
confidence: 58%
“…The compound was additionally tested for its neuroprotective potential in in vitro/vivo assays of cell death and tau hyperphosphorylation. SAR502250 was described previously as a potent, selective and competitive inhibitor of mouse and human GSK3 (IC 50 = 12 nM in both species), with excellent brain permeability in the mouse (brain/plasma ratio: 2.7 after 2 hours) 28,29 .
Figure 1Chemical structure of SAR502250.
…”
Section: Introductionmentioning
confidence: 98%
“…3b ). 12 Another deprotected product 3l bearing an electron-donating 3-methoxy substituent can be further converted to a dopamine 3 receptor agonist 4l via reductive amination to 3l′ in 75% yield and 88% ee and further demethylation ( Fig. 3c ).…”
Section: Resultsmentioning
confidence: 99%
“…Mitsubishi Tanabe Pharma (Osaka; Fig. 12) is investigating GSK-3␤ inhibitors from a series of 2-(2phenylmorpholin-4-yl) pyrimidin-4(3H)-ones [459,460]. The most potent compound had an IC 50 value 12 nM and clearance value of 0.06 ml/min/mg in a human liver microsome assay.…”
Section: Drugs Interacting With Glycogen Synthase Kinase-3β (Gsk-3β)mentioning
confidence: 99%