“…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 28,29,42–45 . 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.…”
Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer’s disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aβ25–35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aβ25–35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.
“…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 28,29,42–45 . 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.…”
Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer’s disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aβ25–35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aβ25–35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.
“…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 ).…”
2-Substituted chiral morpholines were synthesized via a newly developed asymmetric hydrogenation of dehydromorpholines catalyzed by a bisphosphine–rhodium complex bearing a large bite angle.
“…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
Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers are very productive. The review on Drugs interacting with Enzymes was accepted in August 2012. However, this field is very dynamic. New potential targets for the treatment of Alzheimer's disease were identified. This update describes drugs interacting with 60 enzymes versus 43 enzymes in the first paper. Some compounds progressed in their development, while many others were discontinued. The present review covers the evolution of research in this field through April 2014.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
