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Acid sphingomyelinase inhibitor and application thereof in related diseases

A technology for acid sphingomyelinase and inhibitors, which is applied in the field of preparation of acid sphingomyelinase inhibitors, and can solve problems such as poor selectivity, poor stability of phosphatase, and inability to apply

Active Publication Date: 2018-07-06
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the reported direct inhibitors of aSMase are only substrate analogs, diphosphates, 3,5-bisphosphate inositols and a few natural products.
Moreover, the reported molecules have defects such as poor selectivity, poor stability to phosphatases, and poor membrane penetration ability, so they cannot be applied to the development of drugs for related diseases (Cell Physiol.Biochem.2010, 26:01-08)

Method used

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  • Acid sphingomyelinase inhibitor and application thereof in related diseases
  • Acid sphingomyelinase inhibitor and application thereof in related diseases
  • Acid sphingomyelinase inhibitor and application thereof in related diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 Synthesis of some compounds of the present invention, including Ia-Ie and IIa-IIf, taking compound Ia as an example

[0030] Preparation of 4-methoxy-3-octyloxybenzoic acid:

[0031]

[0032] Dissolve 1 g (5.49 mmol) of methyl 3-hydroxy-4-methoxybenzoate in 20 mL of acetone, add 2.27 g (16.4 mmol) of potassium carbonate, 91 mg (0.549 mmol) of potassium iodide, and 1.27 g (6.59 mmol) of bromooctane ), warming up to reflux reaction 10h, cooled to room temperature. The reaction solution was filtered, the filter cake was washed 3 times with dichloromethane, the organic phases were combined, and the solvent was spin-dried to obtain a white solid, which was dissolved in 10 mL of methanol, 10 mL of water and 2.20 g (54.9 mmol) of sodium hydroxide were added, After refluxing for 1 h, cool to room temperature, add 15% HCl aqueous solution to adjust to acidity, and the product 4-methoxy-3-octyloxybenzoic acid is precipitated as white solid 1.43 g, yield 94.2%. 1 H-...

Embodiment 2

[0066] Example 2 Compounds Ia-Ig, IIa-IIf inhibit acid sphingomyelinase activity experiment.

[0067] Acid sphingomyelinase can hydrolyze sphingomyelin in cells to generate ceramide. For a certain amount of fluorescently labeled reaction substrates, different enzyme activities catalyze and generate different amounts of products. By detecting the content of products, the level of enzyme activity can be investigated. The present invention carries out experimental design according to this principle. Extract the protein in the cultured cells, add buffer, fluorescently labeled reaction substrate, and then add different concentrations of compounds Ia-Ie, IIa-IIf, set up a blank control group, perform fluorescence analysis after the reaction, and finally calculate Compound IC 50 value.

[0068] The specific results are shown in the table:

[0069] Table: the acid sphingomyelinase inhibitory activity of some compounds of the present invention

[0070]

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PUM

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Abstract

Belonging to the field of medicinal chemistry, the invention in particular relates to acid sphingomyelinase. The acid sphingomyelinase inhibitor provided by the invention has a specific structure shown as formula I. The invention also provides a synthesis method of the compound shown as formula I and application of the compound in apoptosis and inflammation related diseases including atherosclerosis (AS), diabetes, emphysema, pulmonary edema, pulmonary fibrosis, cystic fibrosis, nonalcoholic fatty liver, Alzheimer's disease (AD), multiple sclerosis (AD), cerebral stroke and depression.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a preparation method of an acid sphingomyelinase inhibitor represented by formula I and its application in diseases related to cell apoptosis and inflammation. [0002] Background technique [0003] Sphingomyelinase (SMase) hydrolyzes sphingomyelin (SM) in mammals to generate ceramide and phosphorylcholine. There are three main forms of expression: acid sphingomyelinase (aSMase), neutral sphingomyelinase (nSMase) and alkaline sphingomyelinase (Alk-SMase). Studies have shown that the biological activity of acid sphingomyelinase accounts for 90% of the total activity of SMase, and it is the fastest and most direct way for ceramide generation in mammals (foreign medicine. Radiation Medicine Nuclear Medicine Volume, 2005, 29 (1 ), 44-47). [0004] Ceramide is an important second messenger that can play a role in the signal transduction process and participate in a v...

Claims

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Application Information

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IPC IPC(8): C07C259/10A61K31/16A61P9/10A61P3/10A61P11/00A61P1/16A61P25/28A61P25/00A61P25/24
CPCC07C259/10
Inventor 王进欣杨侃董继斌尤启冬
Owner CHINA PHARM UNIV
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