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Application of tripdiolide in preparation of medicine for preventing and/or treating NLRP3 inflammasome-mediated inflammatory diseases

An inflammatory disease, triptolide technology, applied in the field of medicine, can solve the problems of liver toxicity, increased activity of liver function-related enzymes, and low activity of NLRP3 inhibitors in vivo, achieving a wide therapeutic window and reducing the level of verification. Effect

Pending Publication Date: 2021-12-10
SHENZHEN XN PHARMATECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Traditional NLRP3 inhibitors have low activity in vivo, at the mg / kg level, such as MCC950 (also known as CP-456,773) and CY-09, both of which have an effective dose of 40mg / kg in the mouse Muckle-Wells syndrome model
In addition, MCC950 can block the activation of NLRP3 inflammasome at nanomolar concentrations. Pfizer took the lead in carrying out the clinical phase II trial of MCC950 in rheumatoid arthritis. discontinued due to hepatotoxicity

Method used

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  • Application of tripdiolide in preparation of medicine for preventing and/or treating NLRP3 inflammasome-mediated inflammatory diseases
  • Application of tripdiolide in preparation of medicine for preventing and/or treating NLRP3 inflammasome-mediated inflammatory diseases
  • Application of tripdiolide in preparation of medicine for preventing and/or treating NLRP3 inflammasome-mediated inflammatory diseases

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The present embodiment provides a kind of synthetic method of triptolide, specifically as follows:

[0054]

[0055] Dissolve triptolide (27mg, 0.07mmol) in anhydrous tetrahydrofuran (4mL), add LiBH successively 4 · THF solution (2N, 84 μL, 0.17 mmol) and BF 3 ·Et 2 O solution (45 μL, 0.35 mmol), stirred at room temperature for 3 h under the protection of argon. After the reaction was completed, dilute hydrochloric acid was added to quench the reaction and continued to stir for 10 min, and dichloromethane was added to extract three times. Column chromatography obtained 7 mg of triptolide white, with a yield of 25.9%.

[0056] The product is characterized by: 1H NMR (500MHz, CDCl3, δ): 4.73(m, 2H), 3.85(d, J=1.5Hz, 1H), 3.83(d, J=3.0Hz, 1H), 3.55(d, J =12.0Hz, 1H), 3.44(dd, J=3.0Hz, J=1.0Hz, 1H), 2.53(m, 2H), 2.29(m, 4H), 1.97(m, 1H), 1.63(m, 2H ), 1.28 (m, 2H), 1.23 (s, 3H), 1.03 (d, J=7.0Hz, 3H), 0.87 (d, J=7.0Hz, 3H).13C NMR (125MHz, CDCl3, δ): 173.9, 162.1, ...

Embodiment 2

[0057] Embodiment 2 biological experiment

[0058] 1. Method

[0059] 1. Animals and reagents

[0060] All animal experiments were approved by the ethics review of the University of Macau. C57BL / 6J mice were provided by the Specific Pathogen Free (SPF) Animal Center of the University of Macau. One week before the experiment, the mice should acclimate to the environment in a 12-h dark / light cycle, with free access to food and water, and the temperature should be controlled between 22.5±0.5°C. Tumor necrosis factor-α (TNF-α) was purchased from PeproTech. Lipopolysaccharide (LPS) and Gram-positive bacteria Bacillus subtilis flagellin (FLA-BS) were purchased from InvivoGen. MCC950 was purchased from Cayman Chemical. All other materials and reagents were purchased from Thermo Fisher Scientific and Sigma-Aldrich or otherwise indicated.

[0061] 2. Cell culture

[0062] AD-293 cell line was purchased from Strategene (La Jolla, CA, USA). AD-293 cells were maintained in DMED hi...

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Abstract

The invention provides an application of tripdiolide in preparation of a medicine for preventing and / or treating NLRP3 inflammasome mediated inflammatory diseases. The structure of the tripdiolideis shown in the specification. The tripdiolide can effectively inhibit the assembly of the NLRP3 inflammasome so as to inhibit inflammatory reaction and pyroptosis, in addition, the tripdiolide is excellent in activity and low in toxicity, and a new solution is provided for the development of drugs for treating inflammatory diseases mediated by the NLRP3 inflammasome.

Description

technical field [0001] The invention relates to the field of medicine, in particular to the application of triptolide in the preparation of drugs for preventing and / or treating inflammatory diseases mediated by NLRP3 inflammasomes. Background technique [0002] Pyroptosis is a programmed cell death mode discovered in recent years, which can release cell contents and pro-inflammatory mediators, leading to inflammation. The formation of inflammasome is one of the factors that induce pyroptosis, among which NLRP3 (NOD-likereceptor protein 3) inflammasome is the most deeply studied inflammasome. The NLRP3 inflammasome is a large protein complex formed by NEK7, NLRP3, ASC, and procaspase-1 in the form of multimers in the cytoplasm. NLRP3 protein mainly contains N-terminal PYD domain, NACHT domain and C-terminal LRR domain. Normally, when cells are stimulated by etiology-associated molecular patterns and risk-associated molecular patterns, NRLP3 will be activated, and the confor...

Claims

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Application Information

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IPC IPC(8): A61K31/585A61P29/00
CPCA61K31/585A61P29/00
Inventor 徐晶王颖宁澄清丁漠雨
Owner SHENZHEN XN PHARMATECH CO LTD
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