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Heterocycle inhibitor for glycogen synthase kinase gsk-3

A compound and general formula technology, applied in the field of glycogen synthase kinase 3β, can solve the problems of activity upregulation and unclear exact function

Inactive Publication Date: 2007-10-03
CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS (CSIC)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in AD, the exact role of any of these kinases in the aberrant hyperphosphorylation of tau remains unclear, and to date, no activity of these enzymes has been found to be upregulated

Method used

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  • Heterocycle inhibitor for glycogen synthase kinase gsk-3
  • Heterocycle inhibitor for glycogen synthase kinase gsk-3
  • Heterocycle inhibitor for glycogen synthase kinase gsk-3

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1 - Enzyme Inhibition of Compositions of the Invention

[0084] GSK-3β inhibition: in the presence or absence of the corresponding test compound, by incubating a mixture of GSK-3 enzyme (Sigma), phosphate (ester) source and GSK-3 substrate, and by measuring the GSK of the mixture -3 activity to determine GSK-3 activity.

[0085] Specifically, in supplementation with 15 µM (final concentration) of synthetic peptide GS 1 as a substrate [Woodgett, J.R. "Use of peptides for affinity purification of protein-serine kinases", Anal. Biochem., 1989, 180, 237-241], 15 μM ATP, 0.2 μC j [ -32 P]ATP and different concentrations of test compounds in a final volume of 12 μl buffer (50 mM tris, pH=7.5, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 10 mM Cl 2 Mg), GSK-3 activity was determined by incubating the enzyme at 37°C for 20 minutes. Reactions were terminated by adding an aliquot of the reaction mixture to phosphocellulose p81 paper. The papers were washed three times with 1% pho...

Embodiment 2

[0101] Example 2 - Analysis of neurite outgrowth after drug treatment

[0102] Cells were maintained in Dulbecco's medium (DEMEM) containing 10% fetal bovine serum, glutamine (2 mM) and antibiotics. To analyze potential GSK-3 inhibitory effects in vivo, mouse neuroblastoma (neuroblastoms) N 2 A culture (Garcia-Perez, J.; Avila, J.; Diaz-Nido, J. "Lithium induces morphological differentiation of mouse neuroblastoma", J. Neurol. Res., 1999, 57, 261-270). Test compounds are added to these cell cultures. This cell line was characterized to express a certain neuronal phenotype (neuritic elongation) after addition of lithium chloride (10 mM), a known GSK-3 inhibitor. After 2-3 days of incubation, the effects of those tested compounds collected in Table 1 were examined. It was found that axonal elongation was produced more than when lithium was added. This fact confirms the inhibitory effect of the compounds of the present invention on GSK-3 in vivo.

Embodiment 3

[0103] Example 3. Cell cycle arrest

[0104] in parallel, at N 2 Potential disruption of the cell cycle by these compounds was studied in A cells. The cell culture was maintained in Dulbecco's medium (DEMEM) containing 10% fetal bovine serum, glutamine (2 mM) and antibiotics.

[0105] The first 4 compounds of general formula (I) collected in Table 3 were analyzed under the conditions described and showed the ability to inhibit the cell cycle at inhibitor concentrations of 100 nM and 1 μM. Cellular blockade was initially observed at concentrations of 100-200 nM and was fully effective at a concentration of 1 μM.

[0106] The compounds tested were not toxic in the resting fibroblast culture MRC-5 after 10 days of continuous exposure to the inhibitor.

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Abstract

Compounds of formula (I) where A, E, G, X, Y, and the bond --- take various meanings are of use in the preparation of a pharmaceutical formulation, for example in the treatment of a disease in which GSK-3 is involved, including Alzheimer's disease or the non-dependent insulin diabetes mellitus, or hyperproliferative disease such as cancer, displasias or metaplasias of tissue, psoriasis, arterosclerosis or restenosis.

Description

field of invention [0001] The present invention relates to enzyme inhibitors, more particularly to heterocyclic inhibitors of glycogen synthase kinase 3β, GSK-3. Background of the invention [0002] Alzheimer's disease (AD) is a neurodegenerative process characterized by cognitive disturbances associated with progressive deterioration of cholinergic function, and neuropathological lesions such as senile plaques formed by fibrillar β-amyloid, and by Neurofibrillary tangles formed by vascular bundles of paired helical filaments. Generally speaking, AD is restricted to the age group of 60 years or older, and is usually the most common cause of dementia in the elderly population. Today, AD affects 23 million people worldwide. As life expectancy increases, it is estimated that by 2050, the number of AD patients will more than triple from today. [Amaduci, L.; Fratiglioni, L. "Epidemiology of AD: Impact on the treatment", in Alzheimer Disease: Therapeutic Strategies, E. Giacobin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D285/08C07C49/395C07C49/597C07D207/44C07D209/48C07D249/12C07D277/36C07D417/12A61K31/433A61P25/28A61K31/122A61K31/4015A61K31/4035A61K31/4196A61K31/426A61K31/4439A61P3/10A61P9/10A61P17/06A61P31/00A61P35/00A61P43/00C07D207/448C07D207/456C07D277/20
CPCC07C49/395C07C49/597C07D207/456C07D209/48C07D249/12C07D277/36C07D285/08C07D417/12
Inventor 阿纳・马丁内斯希尔阿纳・卡斯特罗莫雷尔马里亚・康塞普西翁・佩雷斯马丁梅塞德斯・阿隆索・卡斯科伊莎贝尔・多龙索罗・迪亚斯弗朗西斯科・何塞・莫雷尼奥穆尼奥斯弗朗西斯科・万德奥塞尔胡拉多
Owner CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS (CSIC)
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