Targeting the GSK3β/β-catenin Signaling to Treat Alzheimer´s Disease: Plausible or Utopic?

Zeidán-Chuliá, Fares; Moreira, José Cláudio Fonseca

doi:10.1016/b978-0-12-803959-5.50014-3

Cited by 3 publications

(1 citation statement)

References 122 publications

(106 reference statements)

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“…Since its discovery in the early 1980s, GSK3’s role in glucose control and various disease states has been extensively studied. − However, the details of the signaling pathway linking insulin to GSK3 and GS activity were not fully understood until the mid-1990s. As a negative regulator among the kinases involved in insulin signaling, GSK3 is an attractive target for small-molecule drug therapy.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3

et al. 2017

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In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine analogues which are inhibitors of human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes to explore a wide variety of substitution patterns and convergently access a diverse array of analogues. Compound 1 (CHIR-911, CT-99021, or CHIR-73911) emerged from an exploration of heterocycles at the C-5 position, phenyl groups at C-4, and a variety of differently substituted linker and aminopyridine moieties attached at the C-2 position. These compounds exhibited GSK3 ICs in the low nanomolar range and excellent selectivity. They activate glycogen synthase in insulin receptor-expressing CHO-IR cells and primary rat hepatocytes. Evaluation of lead compounds 1 and 2 (CHIR-611 or CT-98014) in rodent models of type 2 diabetes revealed that single oral doses lowered hyperglycemia within 60 min, enhanced insulin-stimulated glucose transport, and improved glucose disposal without increasing insulin levels.

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Section: Introductionmentioning

confidence: 99%

Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3

et al. 2017

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Binding and stability of indirubin-3-monoxime in the GSK3β enzyme: a molecular dynamics simulation and binding free energy study

Kandasamy

Hunday

Kumaradhas

2019

Journal of Biomolecular Structure and Dynamics

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Calcium Signalling Toolkits in Astrocytes and Spatio-Temporal Progression of Alzheimer's Disease

Lim¹,

Rodriguez-Arellano²,

Parpura³

et al. 2016

CAR

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Pathological remodelling of astroglia represents an important component of the pathogenesis of Alzheimer's disease (AD). In AD astrocytes undergo both atrophy and reactivity; which may be specific for different stages of the disease evolution. Astroglial reactivity represents the generic defensive mechanism, and inhibition of astrogliotic response exacerbates b-amyloid pathology associated with AD. In animal models of AD astroglial reactivity is different in different brain regions, and the deficits of reactive response observed in entorhinal and prefrontal cortices may be linked to their vulnerability to AD progression. Reactive astrogliosis is linked to astroglial Ca(2+) signalling, this latter being widely regarded as a mechanism of astroglial excitability. The AD pathology evolving in animal models as well as acute or chronic exposure to β-amyloid induce pathological remodelling of Ca(2+) signalling toolkit in astrocytes. This remodelling modifies astroglial Ca(2+) signalling and may be linked to cellular mechanisms of AD pathogenesis.

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Targeting the GSK3β/β-catenin Signaling to Treat Alzheimer´s Disease: Plausible or Utopic?

Cited by 3 publications

References 122 publications

Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3

Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3

Binding and stability of indirubin-3-monoxime in the GSK3β enzyme: a molecular dynamics simulation and binding free energy study

Calcium Signalling Toolkits in Astrocytes and Spatio-Temporal Progression of Alzheimer's Disease

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