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Multifunctional acetylcholinesterase inhibitor and its application

A technology of acetylcholinesterase and inhibitors, applied in the field of new multifunctional acetylcholinesterase inhibitors, can solve the problems of poor therapeutic effect of AChE inhibitors, achieve obvious neuroprotective effects, and inhibit Aβ aggregation

Active Publication Date: 2020-05-12
山东泰合医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the therapeutic effects of these AChE inhibitors are not good, and they can only provide limited remission or stabilization of the disease at a specific stage of disease development and are accompanied by severe side effects.

Method used

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  • Multifunctional acetylcholinesterase inhibitor and its application
  • Multifunctional acetylcholinesterase inhibitor and its application
  • Multifunctional acetylcholinesterase inhibitor and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Effect of compound on AChE enzyme activity

[0025] Acetylcholinesterase (AChE), acetylthiocholine iodide (ATC) as a substrate and 5,5-dithiobis(2-nitrobenzoic acid) (DTNB) as a developer were all purchased from Sigma. The AChE inhibitory activity was determined with reference to the method reported by Ellan et al. (Ellman, G. L. et al. Biochem. Pharmacol. 1961, 7, 88.). Add 40 μL of phosphate buffer (pH = 8.0) to each well of a 96-well plate, and then add 0.39, 0.78, 1.56, 3.125, 6.25, 12.5, 25, 50 and 100 μM of 10 μL of the test compound solution or blank control to the corresponding Then add 10 μL of AChE and incubate in a shaker at 37°C for 5 min. Add 20 μL of DTNB solution, then place it in a 37°C shaker and incubate for 5 min, then add 10 μL of substrate ATC, place it in a 37°C shaker and incubate for 3 min, and then measure the absorbance at 412 nm with a microplate reader and calculate Inhibition rate of the test compound to AChE. Calculate the IC of...

Embodiment 2

[0028] Example 2 Effect of compound on Aβ aggregation

[0029] Use DMSO (Sigma) to combine Aβ 1-42 (Gill Biochemical Co., Ltd., Shanghai, China) was dissolved and prepared into a 200 μM stock solution. The stock solution was centrifuged at 13,500 rpm for 10 minutes, and the supernatant of the stock solution was used for the experiment. Dissolve the test compound to 0.8 mM with DMSO. The ability of the compound to inhibit Aβ aggregation was indirectly tested by measuring the fluorescence emission of ThT. First add 76μL of phosphate buffered saline (pH 7.4 PBS) to the 96-well plate, then add 2μL of 0.8 mM compound and 2μL of 200μM Aβ 1-42 After incubating for 24 hours at room temperature, add 80 μL of 5 μM ThT solution (dissolve THT with 50 mM glycine-NaOH buffer pH 8.5) to the reaction solution. The fluorescence emission was measured at 490 nm of the microplate reader, and the excitation wavelength was 390 nm. The same spectrum was recorded by performing three independent exper...

Embodiment 3

[0033] Example 3 Compound vs. Aβ 1-42 The protective effect of inducing SH-SY5Y nerve cell damage

[0034] SH-SY5Y was purchased from the National Cell Bank of the United States, using DMEM medium containing 10% fetal bovine serum, and routinely cultured in an incubator at 37°C and 5% CO2 saturated humidity. Take 2-2.5×10 5 The density of cells / mL was seeded in 96-well plates, and the experiment was carried out after 24 hours of culture. Replace with fresh culture medium and divide the cells into normal group, Aβ 1-42 Damage model group and test compound pretreatment group. Compounds of formula I (10 µM) were added to the test compound treatment group, EGCG (tea polyphenol) was added to the EGCG positive control group, and the Aβ group and the normal group were not added. After culturing for 2 hours, add Aβ at a final concentration of 10 µM to all groups except the normal group 1-42 , Continue to incubate for 24 hours, add MTT (final concentration 0.5 mg / ml), after incubating fo...

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Abstract

The invention discloses a novel multifunctional acetylcholin esterase inhibitor, 2-(5-((4-methylpiperidin-1-yl)methyl)-1,3,4-oxadiazol-2-mercapto)-1-p-methylacetophenone and application thereof in preparing a drug for preventing and / or treating a disease related to AChE, preparing a drug for preventing and / or treating a disease related to A beta aggregation and preparing a drug for preventing and / or treating a disease caused by A beta induced nerve injury. The compound provided by the invention can inhibit the AChE, can effectively inhibit A beta aggregation, has obvious neuroprotection to theA beta induced nerve injury and can be used for preparing a drug for preventing and / or treating relevant neurodegenerative diseases such as AD.

Description

Technical field [0001] The invention relates to a novel multifunctional acetylcholinesterase inhibitor and its application, 2-(5-((4-methylpiperidin-1-yl)methyl)-1,3,4-oxadiazole-2 -Mercapto)-1-p-methylacetophenone as an acetylcholinesterase inhibitor. Background technique [0002] Alzheimer’s Disease (AD) is a progressive, multifactorial, and fatal neurodegenerative disease. The clinical manifestations are cognitive impairment and abnormal patient behavior. According to the World Alzheimer's Disease Report, the number of AD patients worldwide in 2015 was 46 million, and it is expected that the number of patients will reach 130 million by 2050. [0003] The etiology and pathogenesis of AD are still unclear, and choline dysfunction, amyloid-β (Aβ) aggregation and tau protein phosphorylation are thought to play an important role in the development of AD. However, clinical trials of drugs targeting Aβ and tau protein all ended in failure. At present, increasing the level of acetylc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/06A61K31/454A61P25/28A61P25/00
CPCA61P25/00A61P25/28C07D413/06
Inventor 朱孔凯江成世张华张娟成志强宋佳丽葛永喜
Owner 山东泰合医药科技有限公司
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