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NLRP3 inhibitor and application thereof

A technology of inhibitors and drugs, applied in the direction of anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve the problems of large side effects, poor effect, high cost, etc., to achieve effective treatment, good The effect of the treatment effect

Active Publication Date: 2021-05-25
THE THIRD XIANGYA HOSPITAL OF CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Traditional drugs for IBD treatment at home and abroad include: aminosalicylic acid preparations, glucocorticoids, immunosuppressants, etc. These drugs have shortcomings such as poor efficacy and large side effects. In recent years, biological agents and small molecule drugs have emerged continuously, but due to cost High cost, easy to produce drug resistance and other limitations, which limit its wide clinical application

Method used

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  • NLRP3 inhibitor and application thereof
  • NLRP3 inhibitor and application thereof
  • NLRP3 inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 The compound of formula 1 is used to treat DSS-induced colitis in mice.

[0031] The experimental method is as follows: 6-8 weeks old C57 mice are used to construct the DSS-induced enteritis model, that is, the mice are fed with fresh 3% DSS solution, and the compound of formula 1 is formulated with dimethyl sulfoxide (DMSO) and normal saline Solution, administered by intraperitoneal injection. Observe the general condition, body weight and hematochezia of the mice in the healthy control group, DSS model group, and the compound treatment group of formula 1, perform DAI scoring, execute the mice after 9 days, collect colon samples, compare the length of the colon, and perform intestinal histopathological examination .

[0032] The results show that the compound intervention of formula 1 can significantly improve the degree of weight loss in DSS-induced colitis model mice ( figure 1 A, pfigure 1 B, pfigure 1 C) and significantly reduce the shortening of the co...

Embodiment 2

[0033] Example 2 The compound of formula 1 relieves DSS-induced colitis in mice by inhibiting the activation of NLRP3 inflammasome and the maturation and release of IL-1β.

[0034] The experimental method is as follows: the colon tissue in Example 1 was collected, a 1 cm intestinal segment was removed from the distal end of the colon, washed and cultured for 8 hours, and the expression of IL-1β and IL-6 in the supernatant was detected by ELISA.

[0035] The results show that the compound of formula 1 inhibits the increase of IL-1β and IL-6 in mouse colon tissue in the mouse colitis model induced by DSS, and the inhibitory effect on IL-1β is more obvious (results see figure 2 ).

Embodiment 3

[0036] Example 3 The compound of formula 1 is used to inhibit the activation of NLRP3 inflammasome and the maturation and release of IL-1β.

[0037] The experimental method is as follows: First, isolate and culture C57 mouse peritoneal macrophages, stimulate them with 100ng / mL LPS for 3 hours, add different doses of the compound of formula 1 for half an hour, then add 10mM Nigericin to stimulate them for 1 hour, collect the cell supernatant, The content of IL-1β in the cell supernatant was detected by ELISA; then the peritoneal macrophages of C57 mice were extracted and cultured, stimulated by 100ng / mL LPS for 3 hours, treated with the compound of formula 1 for half an hour, then stimulated with 10mM Nigericin for 1 hour, collected Cell lysates and cell supernatants were used to detect the expression of NLRP3 and other proteins and the release of p10 and p17 by Western blot.

[0038] The results showed that after LPS+Nigericin treatment, the release of IL-1β from mouse peritonea...

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Abstract

The invention discloses a brand new application of a compound shown in a formula 1, namely the compound is used for preparing a medicine for treating an inflammatory bowel disease (IBD) by inhibiting activation of NLRP3 inflammasome and maturation and release of IL-1beta. According to the present invention, the research results show that the compound represented by the formula 1 can inhibit the mouse colitis induced by dextran sulfate sodium salt (DSS), and the application mechanism of the compound represented by the formula 1 mainly comprises that the activation of the NLRP3 inflammasome is inhibited so as to reduce the release of IL-1beta so as to inhibit inflammation; by recording and analyzing the weight loss, the disease activity index (DAI) score and the colon shortening condition of a DSS-induced colitis model mouse and the expression condition of IL-1beta and the like in the mouse colon tissue, the inhibition effect of the compound in the formula 1 on the colitis disease of the DSS-induced mouse colitis model is evaluated.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to an NLRP3 inhibitor and its application. Background technique [0002] Clinically, inflammatory bowel disease (Inflammatory bowel disease, IBD), including ulcerative colitis and Crohn's disease, is a group of chronic relapsing non-specific intestinal inflammatory diseases that tend to occur in young adults with rapid progression, It is extremely destructive and requires life-long treatment. IBD has limited drugs and poor curative effect. Patients often suffer from complications such as intestinal obstruction, hemorrhage, and canceration. 70-80% of patients need surgical treatment. The morbidity rate is high, and the prognosis and quality of life are extremely poor. Therefore, IBD is called "green tumor". In recent years, with the changes in living environment and dietary structure, the incidence of IBD in my country has increased exponentially. Traditional drugs for IBD treatm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/496A61P1/00A61P1/04A61P29/00
CPCA61K31/496A61P1/00A61P1/04A61P29/00
Inventor 田力赵锴龙秀艳罗睿恒李静许学明
Owner THE THIRD XIANGYA HOSPITAL OF CENT SOUTH UNIV
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