Application of compound as CYP2E1 inhibitor

A CYP2E1, Compound Technology

Pending Publication Date: 2022-03-01
上海灵希生物科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compounds or drugs with inhibitory effects on CYP2E1 reported in current studies include 4-methylpyrazole, disulfiram, diethyldithiocarbamate, isothiocyanate, o-tolylamine, and clomethiazole, etc. Most of them have poor selection specificity for CYP2E1 inhibition and high toxicity, so they are mostly used in basic research
There are currently no specific inhibitors of CYP2E1 for clinical use

Method used

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  • Application of compound as CYP2E1 inhibitor
  • Application of compound as CYP2E1 inhibitor
  • Application of compound as CYP2E1 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0199] Example 1 Preparation of human liver microsomes

[0200] Using differential centrifugation, the liver samples were taken out, thawed, and weighed. Add 50mM Tris-HCl (pH=7.0) (containing 150mM KCl, 2mM EDTA) buffer at a ratio of 1:4 (W / V), grind with a glass homogenizer to make liver homogenate. Centrifuge at 9000×g at 4°C for 20 minutes, take the supernatant and centrifuge at 100,000×g at 4°C for 60 minutes; resuspend the obtained pellet in 4 mL of 0.15M Tris-HCl (pH=7.6), and centrifuge at 100,000 g at 4°C for 60 minutes; take the precipitate Add 0.25M sucrose resuspension at a ratio of 1:2 (W / V), and finally prepare 2 mL of microsomal suspension per gram of liver tissue, store in liquid nitrogen overnight after aliquoting, and transfer to -80°C for a long-term Save for later. All the above operations were carried out in an ice bath. Microsomal protein content (mg / mL) was determined by Bradford method.

[0201] This method is used for liver microsomes of patients w...

Embodiment 2

[0202] The synthesis of embodiment 2 SMIO

[0203] Ethyl 4-methylthiazole-5-carboxylate (1mol) and NaOH (1.6mol), the solvent is a mixed solution of ethanol and water, react overnight at room temperature, TLC detection (pure ethyl acetate), after the reaction is complete, ethanol Evaporate to dryness under reduced pressure, adjust the pH to 2-3 with concentrated sulfuric acid, obtain a solid after suction filtration, wash and dry. 4-methylthiazole-5-carboxylic acid (1mol) and DDC (1mol) were stirred in anhydrous tetrahydrofuran at room temperature. After activation for 2-3h, dimethylhydroxylamine hydrochloride (1.2mol) was added, and triethylamine (1.5 mol) stirred at room temperature overnight, and detected by TLC (PE:EA=3:1). After the reaction was complete, tetrahydrofuran was evaporated to dryness under reduced pressure, extracted three times with ethyl acetate, both sides were washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfa...

Embodiment 3

[0205] The synthesis of embodiment 3 compound SMI7

[0206] Take hydroxylamine hydrochloride (3mmol) in a round-bottomed flask, add 3mL of ethanol, stir at room temperature 25°C for 10min, add 3mL of 1M NaOH solution, then add SMI0 (3mmol), reflux in an oil bath at 80°C, after TLC monitors that the reaction is complete, add 10% dilute hydrochloric acid Neutralize the reaction solution, extract with water and ethyl acetate, combine the organic phases, dry over anhydrous magnesium sulfate, remove the magnesium sulfate by suction filtration, concentrate the filtrate under vacuum, separate by silica gel column chromatography, the eluent and its ratio are petroleum ether: Ethyl acetate=1:2, obtain compound SMI7, the nuclear magnetic detection data of product are as follows (as figure 2 shown): 1 H NMR(400MHz,DMSO)δ11.50(s,2 / 3H),11.48(s,1 / 3H),9.09(s,1 / 3H),8.95(s,2 / 3H),2.57(s,2 / 3H),2.53(s,1 / 3H),2.28(s,1 / 3H),2.26(s,2 / 3H).

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Abstract

The invention discloses an application of a compound as a CYP2E1 inhibitor, which is characterized in that the compound or a salt thereof as an inhibitor takes CYP2E1 as a target spot and is combined with the CYP2E1, and the CYP2E1 inhibitor has an inhibition effect on CYP2E1. The inhibitor can be used for preventing and treating tumors such as liver cancer, glioma, ovarian cancer, bladder cancer and gallbladder cancer. Similarly, the inhibitor can also be used for preventing and treating other inflammation-related diseases such as liver injury, fatty liver, hepatitis, hepatic fibrosis, rheumatic and rheumatoid arthritis, sepsis, Alzheimer's disease, ischemic cerebral apoplexy, Parkinson's disease, hyperlipidemia, atherosclerosis, coronary heart disease, diabetes mellitus and the like.

Description

technical field [0001] The invention relates to the fields of targets and drugs for the prevention and treatment of inflammation-related diseases, in particular to the application of a compound as a CYP2E1 inhibitor. Background technique [0002] It has been recognized that the occurrence of many diseases is related to inflammation, such as tumors (liver cancer, cervical cancer, nasopharyngeal cancer, colorectal cancer, glioma, etc.) Stroke, arteriosclerosis, diabetes, etc.), the above-mentioned inflammation-related diseases can be collectively referred to as inflammation-mediated diseases (IMD). It is generally believed that the long-term uncontrollable inflammatory microenvironment is related to the occurrence of inflammation-related diseases. [0003] The tumor microenvironment plays an important role in the development of tumors. In the past 10 years, the research on tumor microenvironment (tumour microenvironment, TME) has developed rapidly. In 2010, Professor Karin M...

Claims

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Application Information

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IPC IPC(8): A61K31/426A61K31/427A61K31/4439A61K31/497A61K31/5377A61P1/16A61P35/00A61P29/00A61P19/02A61P31/04A61P25/28A61P25/16A61P9/10A61P3/10A61P3/06
CPCA61K31/426A61K31/427A61K31/4439A61K31/497A61K31/5377A61P1/16A61P35/00A61P29/00A61P19/02A61P31/04A61P25/28A61P25/16A61P9/10A61P3/10A61P3/06A61P11/00
Inventor 乔海灵徐海伟方艳郜娜温强李书峰
Owner 上海灵希生物科技发展有限公司
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