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Application of CQMU151 in preparation of medicine for treating Th17 cell mediated autoimmune diseases

An autoimmune disease, cell technology, applied in the field of medicine, can solve problems such as carcinogenesis, toxic side effects, etc.

Active Publication Date: 2020-09-15
THE FIRST AFFILIATED HOSPITAL OF CHONGQING MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, digoxin has carcinogenic and toxic side effects; ursolic acid can also act on other targets other than RORγt, such as glucocorticoid receptors, etc.

Method used

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  • Application of CQMU151 in preparation of medicine for treating Th17 cell mediated autoimmune diseases
  • Application of CQMU151 in preparation of medicine for treating Th17 cell mediated autoimmune diseases
  • Application of CQMU151 in preparation of medicine for treating Th17 cell mediated autoimmune diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 N-((1H-benzo[d]imidazol-2-yl)methyl)-3-(morpholinesulfonyl)benzamide inhibits initial CD4 in vitro + Differentiation of T cells into Th17 cells

[0024] 1. Experimental method:

[0025] 1) After the mice were sacrificed, they were soaked in 75% ethanol, and the spleen was dissected and separated into a filter in an ultra-clean bench.

[0026] 2) Rinse and filter with PBS after grinding with the rubber tip of a 5ml syringe. Collect the filtrate into a 15ml centrifuge tube.

[0027] 3) Centrifuge at 4°C for 10 minutes with a centrifugal force of 350*g, discard the supernatant, add red blood cell lysate at a volume 5 times the volume of the cell, blow it gently, let it stand for 2 minutes, and then set it at 4°C with a centrifugal force of 350*g Centrifuge for 5 minutes and discard the supernatant.

[0028] 4) Add the same amount of cold PBS as the erythrocyte lysate, after blowing gently, centrifuge at 4°C for 2 minutes at a centrifugal force of 350*g, disca...

Embodiment 2

[0031] Example 2 The binding test results of N-((1H-benzo[d]imidazol-2-yl)methyl)-3-(morpholinesulfonyl)benzamide and target RORγt

[0032] 1. Experimental method:

[0033] Using the double luciferase method (Yang X O, et al.T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and RORgamma.Immunity 28,29-39(2008)), construct RORγt overexpression plasmid and IL-17 promoter daughter reporter plasmid. Divided into three groups: the blank group without reporter gene, the control group of reporter gene + RORγt overexpression plasmid + DMSO, and the experimental group of reporter gene + RORγt overexpression plasmid + compound interference, and the plasmid was transduced into 293T engineered cells. After 16 hours, the medium was changed and DMSO / compounds were added for interference. Express 2 days.

[0034] After 48 hours, the cells were lysed according to the procedure of Promega's dual-luciferase detection kit, and the fluorescence values ​​of...

Embodiment 3

[0036] Example 3 Effect of N-((1H-benzo[d]imidazol-2-yl)methyl)-3-(morpholinesulfonyl)benzamide on disease severity of EAU in mice in vivo

[0037] 1. Experimental method:

[0038] Antigen preparation: weigh 5 mg of IRBP with a microbalance 651-670 Put the powder in an EP tube, add 1ml of sterile PBS containing 2% DMSO to the EP tube containing IRBP with a pipette, vibrate on a shaker to accelerate dissolution, and then centrifuge at 3000r / min for 30s on a speed centrifuge To discharge the air bubbles in the tube, prepare an IRBP solution with a concentration of 5 mg / ml, and store it at 4°C for later use.

[0039] Anesthetize 20 mice with sodium pentobarbital, connect 100ul (ie 500ng) IRBP solution (5mg / ml) with 100ul complete Freund's adjuvant containing 5mg / ml Mycobacterium tuberculosis through a sterile three-way tube and fully After mixing into a white emulsion, use the above mixed solution with a total volume of 200ul to inject subcutaneously at the back of the neck, bi...

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Abstract

The invention relates to an application of 1H-benzo[d]imidazole-2-yl)methyl)-3-(morpholine sulfonyl) benzamide in the preparation of a medicine for treating Th17 cell mediated autoimmune diseases. Thecompound is obtained by screening from a Chembrige compound library, and experiments show that the compound has the effect of inhibiting Th17 cell differentiation in vitro, can inhibit the differentiation of Th17 cells and the generation of IL-17 in vivo, alleviates clinical symptoms of autoimmune diseases such as Th17 cell mediated experimental autoimmune uveitis (EAU), experimental autoimmune encephalomyelitis (EAE), and type 1 diabetes mellitus, and has good application prospects.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a kind of N-((1H-benzo[d]imidazol-2-yl)methyl)-3-(morpholinesulfonyl)benzamide (named abbreviated as CQMU151) in the preparation of therapeutic Th17 cells mediate the application of autoimmune disease drugs. Background technique [0002] As the third subset discovered by Th cells, Th17 cells are potent tissue inflammation-inducing cells involved in the pathogenesis of many inflammatory and autoimmune diseases. Th17 cells play an important role not only in host defense against bacterial and fungal infections, but also in many immune-related diseases, including uveitis, psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease disease and asthma / airway inflammatory disease. Anti-IL-17 has been proven to have good therapeutic effects on a variety of human diseases. [0003] In Th17 cells, IL-17 transcription is regulated by the Th17-specific transcriptional regulator...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5377A61P37/02A61P27/02A61P25/00A61P3/10
CPCA61K9/0019A61K31/5377A61P3/10A61P25/00A61P27/02A61P37/02
Inventor 侯胜平谭珺刘焕
Owner THE FIRST AFFILIATED HOSPITAL OF CHONGQING MEDICAL UNIVERSITY
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