Compound, preparation method and application in preparation of GSK-3beta inhibitor

A compound and composition technology, applied in the field of medicine, can solve the problems of limited drug effect, lack of Aβ aggregation and depolymerization, complex pathogenesis, etc., and achieve the effect of novel structure, reducing toxic side effects, and promoting depolymerization

Active Publication Date: 2019-11-22
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The inventors of the present disclosure have found that the pathogenesis of AD is complicated, and the mechanisms are interconnected and interact with each other. The effect of drugs with a single target and a single mechanism of action is limited. This may be an important reason for the lack of effective drugs to reverse the progress of AD; the current GSK-3β inhibitors lack direct effects on Aβ aggregation and disaggregation

Method used

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  • Compound, preparation method and application in preparation of GSK-3beta inhibitor
  • Compound, preparation method and application in preparation of GSK-3beta inhibitor
  • Compound, preparation method and application in preparation of GSK-3beta inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Embodiment 1: Synthesis of the compound of formula I.

[0070] (1) Dissolve compound 1 (5.56g, 12mmol) and compound 2 (4.11g, 14.4mmol) in dioxane (16mL) and water (0.8mL), add Pd(dppf)Cl 2 (0.35g, 0.48mmol), and K 2 CO 3 (4.38g, 36mmol), under the protection of nitrogen, stirred at 100°C for 2.5h. Filter while hot and concentrate under reduced pressure. A small amount of water was added to the residue and extracted with dichloromethane. After the organic phases were combined, they were washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the crude product as off-white solid.

[0071] The above crude product was dissolved in 60 mL of methanol, 20 mL of potassium hydroxide (6.8 g, 120 mmol) aqueous solution was added, and the reaction was stirred at 60° C. for 1.5 h. Cool to room temperature, adjust pH to neutral with saturated potassium bisulfate solution, and extract with ethyl ac...

Embodiment 2

[0076] Example 2: GSK-3 inhibitory activity experiment.

[0077] 1. Test method:

[0078] Incubate the FAM-labeled substrate with kinase, ATP and a certain concentration of compound (from Example 1) solution at 28°C for 1 h. After quenching with a quencher, use a Caliper instrument to measure the conversion rate of the substrate. The better the inhibition, the lower the conversion value. The results are shown in Table 1.

[0079] 2. Test results:

[0080] The compound of formula I prepared in Table 1 Example 1 has inhibitory activity on GSK-3β

[0081] compound GSK-3β% inhibition rate a

[0082] a Indicates the inhibition rate of different subtypes of GSK-3 when the concentration is 1 μM; b half effective inhibitory concentration.

Embodiment 3

[0083] Example 3: Aβ aggregation inhibition experiment.

[0084] 1. Test method:

[0085] 0.5 mg of hexafluoroisopropanol-treated Aβ 1-42 Dissolved in dimethyl sulfoxide (DMSO) to make 2mM stock solution, aliquoted and stored at -20°C for future use. The stock solution was diluted to 40 μM with 50 mM PBS buffer (pH=7.4, 100 mM NaCl). The compound of formula I (B10) and the positive control drug Curcumin (Curcumin) were each dissolved in DMSO to form a 2mM stock solution, and the stock solution was diluted to a concentration of 40 μM with 50 mM PBS buffer (pH=7.4, 100 mM NaCl) for use. Aβ 1-42 (20 μL, 40 μM) and 20 μL PBS buffer, Aβ 1-42 (20 μ L, 40 μ M) and formula I compound (20 μ L, 40 μ M), Aβ 1-42 (20 μL, 40 μM) and Curcumin (20 μL, 40 μM) were respectively placed in a 96-well black plate and incubated at 37° C. for 24 h. Add 160 μL of thioflavin T glycine-sodium hydroxide (50 mM, pH=8.0) buffer solution with a concentration of 5 μM into the reaction well, place it i...

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Abstract

The invention provides a compound, a preparation method and application of the compound in preparation of a GSK-3 beta inhibitor. The chemical structure of the compound is shown as a formula I shown in the specification. The compound provided by the invention has GSK-3beta inhibition activity, can directly act on A[beta], can inhibit the aggregation of A[beta] and promote depolymerization of A[beta] aggregate, and is a novel GSK-3beta inhibitor. The compound can also inhibit Cu<2+>-induced A[beta] aggregation and depolymerize Cu<2+>-induced A[beta] aggregate, and can act on multiple aspects related to AD pathogenesis in a multi-targeting manner.

Description

technical field [0001] The disclosure belongs to the field of medicine, and relates to compounds, preparation methods and applications in the preparation of GSK-3β inhibitors. Background technique [0002] The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art. [0003] Alzheimer's disease (AD) is a common chronic neurodegenerative disease, clinically manifested as memory impairment, aphasia, apraxia, agnosia, impairment of visuospatial skills, executive dysfunction, and personality and behavioral changes Wait. The pathological features of AD are senile plaques formed by aggregation of β-amyloid (Aβ) protein in the brain, neurofibrillary tangles (NFTs) formed by aggregation of hyperphosphorylated tau protein, chronic inflammation, and degeneration of cholinergic neurons Wait. In addition to aging and genetic factors, the etiology of AD is very complex, and multiple factors interact. The a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4709A61P25/28
CPCA61P25/28C07D471/04Y02P20/55
Inventor 刘兆鹏石小龙严宁刘萍
Owner SHANDONG UNIV
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