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Application of ethanone compound in preparation of medicine for treating inflammation

A technology of acetone and drugs, applied in the field of PI3Kγ-specific inhibitors, can solve problems such as limited effects of drugs for inflammatory diseases

Active Publication Date: 2020-09-08
CF PHARMTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In summary, traditional drugs for the treatment of inflammatory diseases have limited effects, and rational drug design based on PI3Kγ targets can provide new and efficient drugs for the treatment of inflammatory diseases

Method used

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  • Application of ethanone compound in preparation of medicine for treating inflammation
  • Application of ethanone compound in preparation of medicine for treating inflammation
  • Application of ethanone compound in preparation of medicine for treating inflammation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: The specific inhibitory effect of compounds on PI3Kγ

[0026] In vitro enzymatic experiments, using the broad-spectrum inhibitor PI-103 as a control, using the ADP-Glo ​​kit to detect the compound 1-(5-(3-((4-chlorobenzyl)amino)-2-hydroxypropoxy)- Inhibitory activity of 2-methyl-1-(p-tolyl)-1hydro-indol-3-yl)ethanone on PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, respectively.

[0027] PI3Kγ blank group: use a 384-well plate to set up 3 parallel experimental groups. Prepare 5 μL of PI3K reaction system, each well contains 2.5 μL of PI3Kγ protein, add 2.5 μL of reaction substrate PIP2 and ATP to start the reaction, incubate at room temperature for 1 hour, use 5 μL of MgCl 2 The reagent terminated the reaction, and after incubation for 2 hours, 10 μL of ADP-Glo ​​detection reagent was added, and after incubation for 45 minutes, the fluorescence value of the reaction solution was detected by a microplate reader.

[0028]Use the same operation to prepare PI3Kα, PI3Kβ, PI3Kδ bl...

Embodiment 2

[0035] Example 2: Detection of specific inhibitory effect of compounds on PI3K pathway in inflammatory cells

[0036] Using RAW264.7 cells under the action of chemokine C5a as a cell model for specific activation of the PI3Kγ pathway, the compound 1-(5-(3-((4-chlorobenzyl)amino)-2-hydroxypropoxy)- Inhibitory effect of 2-methyl-1-(p-tolyl)-1hydro-indol-3-yl)ethanone on phosphorylation of the PI3K downstream effector molecule Akt.

[0037] The specific steps are as follows: the RAW264.7 cells in the logarithmic growth phase were plated on a 96-well plate at 200,000 per well, and 200 μL per well was used in serum-free DMEM medium. Place in a cell culture incubator at 37°C, 5% carbon dioxide overnight. Add the compound for 30 minutes before adding C5a stimulation, and the DMSO content does not exceed 5 / 1000. Then add 25 nM C5a for 3 minutes, remove the medium, add 50 μL of cell lysate to each well, place on ice, and then centrifuge at 3000 rpm at 4°C for 5 minutes. Perform an E...

Embodiment 3

[0039] Example 3: Inhibitory Effect of Compounds on Inflammatory Cell Chemotaxis

[0040] Under the action of chemokines such as C5a, fMLP, CCL3, CXCL1–3 (KC), leukocytes, especially neutrophils and monocytes, stretch out pseudopodia and move along the low concentration gradient to the site of high concentration, Gather to the site where chemokines are produced to produce chemotaxis. Chemotaxis experiments were performed using Transwell technology. Motile cells will slowly migrate from low concentration to high concentration under the action of chemokines, that is, the cells inside the Transwell chamber will move to the outside of the chamber through the filter membrane.

[0041] The experiment was divided into control group and treatment group. First, put the inner side of the Transwell chamber into a 24-well plate, add DMEM serum-free medium to infiltrate the inner chamber, and take it out after 30 minutes. At the same time, the RAW264. (3-((4-chlorobenzyl)amino)-2-hydrox...

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Abstract

The invention discloses an application of 1-(5-(3-((4-chlorobenzyl)amino)-2-hydroxypropoxy)-2-methyl-1-(p-tolyl)-1H-indol-3-yl) ethanone in treatment or prevention of inflammatory diseases. The compound is used for preventing and / or relieving and / or adjunctively treating and / or treating inflammatory diseases such as bronchitis, pneumonia, hepatitis, rhinitis, enterogastritis, gastritis, nephritis,dermatitis, prostatitis, vaginitis, rheumatism and the like. The 1-(5-(3-((4-chlorobenzyl)amino)-2-hydroxypropoxy)-2-methyl-1-(p-tolyl)-1H-indol-3-yl) ethanone has a specific inhibition effect on PI3K gamma and has an inhibition effect on inflammatory cell proliferation and chemotaxis. The compound can inhibit inflammatory response by inhibiting the PI3K gamma.

Description

technical field [0001] The present invention relates to the technical field of biomedicine, in particular to a specific inhibitor of PI3Kγ, which has the effect of relieving and / or adjuvant therapy and / or treating inflammation, such as bronchitis, pneumonia, hepatitis, rhinitis, enteritis, gastritis, Nephritis, dermatitis, prostatitis, vaginitis, rheumatism, etc. Background technique [0002] PI3Ks are a class of lipases that catalyze the phosphorylation of the inositol ring of phosphoinositides and transduce signals as second messengers. PI3K is a complex large family, which can be divided into types I, II, and III according to its structure and substrate specificity. At present, the most widely studied type I PI3K protein receives signals from tyrosine kinase-like receptors and G protein-coupled receptors, and converts PI(4,5)P2 into PI(3,4,5)P3, Thereby, PDK1, Akt and other molecules are recruited and phosphorylated, and the activation signal is transmitted downward, th...

Claims

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Application Information

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IPC IPC(8): A61K31/4045A61P29/00A61P11/00A61P1/16A61P11/02A61P1/00A61P1/04A61P13/12A61P17/00A61P13/08A61P15/02A61P19/02
CPCA61K31/4045A61P29/00A61P11/00A61P1/16A61P11/02A61P1/00A61P1/04A61P13/12A61P17/00A61P13/08A61P15/02A61P19/02
Inventor 金坚朱景宇陈蕴杨兆琪蔡燕飞
Owner CF PHARMTECH
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