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Ursolic acid neutral cholesterol ester hydrolase inhibitor and application thereof

A cholesterol lipid and inhibitor technology, applied in the field of biomedicine, can solve the problems of reducing the oral bioavailability of drugs, achieve high inhibitory activity, simple synthesis process, and high yield

Active Publication Date: 2018-04-06
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, most oral prodrugs of carboxylic acid esters, amides, thioesters, and carbamates can be rapidly hydrolyzed by NCEH1 distributed in the gastrointestinal tract and liver, and are hydrolyzed into water-soluble and relatively soluble prodrugs before being absorbed into the blood. Large product, reduces oral bioavailability of drug

Method used

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  • Ursolic acid neutral cholesterol ester hydrolase inhibitor and application thereof
  • Ursolic acid neutral cholesterol ester hydrolase inhibitor and application thereof
  • Ursolic acid neutral cholesterol ester hydrolase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of 3-carboxypropionyl-ursolic acid

[0026] At room temperature, successively add ursolic acid (228.4mg, 0.5mmol), 4-dimethylaminopyridine (122.4mg, 1.0mmol), succinic anhydride (200.2mg, 2mmol) into the dichloromethane (15mL) solution, and add The reaction was stirred at room temperature and the progress of the reaction was monitored. After the reaction is complete, add water (25mL), adjust the pH to 2-3 with 1M HCl solution, extract three times with ethyl acetate (40mL×3), wash the combined organic phase with water (30mL×1), wash with saturated sodium chloride solution (25mL×1 ), dried over anhydrous sodium sulfate, evaporated to remove the solvent, and the crude product was obtained by column chromatography (dichloromethane / methanol=100 / 1-20 / 1 gradient elution) to obtain a white solid with a yield of 60-70%. 1 H-NMR spectrum as figure 1 shown.

[0027] The nuclear magnetic resonance spectrum of product is specifically as follows:

[0028] 1 H NMR (400M...

Embodiment 2

[0031] Synthesis of 3-carbonyl-ursolic acid

[0032] At room temperature, dissolve ursolic acid (456.7mg, 1.0mmol) in acetone (20mL) solution, cool to 0°C, and slowly add the prepared concentrated sulfuric acid solution of chromium trioxide dropwise (chromium trioxide: concentrated sulfuric acid: Water = 1.824g: 1.57mL: 7.6mL), after the addition was completed, the reaction was stirred at 0°C, and the reaction progress was monitored. After the reaction was complete, the reaction was quenched with isopropanol. After acetone was aliquoted, water (30mL) was added to dichloromethane to extract three times (50mL×3), and the combined organic phase was washed with water (30mL×1) and saturated sodium chloride solution (30mL×1 ), dried over anhydrous sodium sulfate, and evaporated to remove the solvent. The crude product was subjected to column chromatography (petroleum ether / ethyl acetate=20 / 1-5 / 1 gradient elution) to obtain a white solid with a yield of 65-75%. 1 H-NMR spectrum as ...

Embodiment 3

[0037] Quantitative evaluation of the inhibitory ability of ursolic acid compounds on neutral cholesterol lipohydrolase (NCEH1)

[0038] Using the hydrolytic metabolism of D-fluorescein methyl ester (DME) as a probe reaction, bioluminescence was used to determine the inhibitory IC of ursolic acid compounds on neutral cholesterol lipohydrolase (NCEH1) with the help of human liver microsome incubation system in vitro 50 :

[0039] a. In 50 microliters of in vitro metabolic reaction system, containing phosphate buffer solution with a pH of 6.5, the concentration of human liver microsomal protein is 2 μg / ml, and the final concentration of inhibitors is in the range of 0.1 μM-80 μM. Pre-incubation with shaking on the instrument for 10 minutes;

[0040] b. Add D-fluorescein methyl ester (DME) substrate (final concentration 3 μM) to the reaction system to initiate the reaction, and incubate the reaction with shaking on a microplate reader for 10 minutes;

[0041] c. Add Luciferin D...

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Abstract

The invention provides an ursolic acid neutral cholesterol ester hydrolase inhibitor and application thereof and belongs to the technical field of biological medicines. The ursolic acid compound can strongly and selectively inhibit activity of NCEH1, and further oral bioavailability of a carboxylic ester exogenous precursor medicine is improved. The inhibitor can inhibit clopidogrel from metabolizing a non-active product and can be taken as a clopidogrel synergist. The inhibitor also can alleviate lipid ectopic deposition-induced insulin resistance and even impaired glucose tolerance by inhibiting NCEH1 from participating in fat metabolism. In vitro activity determination finds that the compound (3-hydropropionyl-ursolic acid) has the NCEH1 inhibition IC50 reaching 12 nanomole, and anotherhuman body carboxylesterase (hCE2) is not obviously inhibited, so that selectivity reaches up to 6919 times. Besides, the compound also has the advantages of good safety, simple preparation technology and high synthesis yield, so that the compound has a good application prospect.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and mainly relates to an ursolic acid neutral cholesterol lipohydrolase (NCEH1) inhibitor and application thereof. Background technique [0002] Neutral Cholesterol Ester Hydrolase 1 (NCEH1) is an important serine hydrolase distributed in the human body. NCEH1 is mainly distributed in fat and liver cells, and it participates in the hydrolysis and metabolism of cholesterol lipids and fatty acid esters in the body, thereby regulating the balance of human lipid metabolism. In recent years, studies at home and abroad have shown that the activity of NCEH1 in the adipose tissue of patients with obesity and type II diabetes is significantly increased, and it is closely related to the pathogenesis of insulin resistance in muscle and liver (Hepatology, 2012; 56:2188-2198; Nat Chem Biol, 2014; 10:113-121). Inhibiting NCEH1 in adipocytes can not only reduce the levels of plasma free cholesterol and fa...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/56A61P5/50A61P3/04A61P3/10
CPCC07J63/008
Inventor 杨凌葛广波邹立伟王平宁静
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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