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Novel application of 2-(4-(benzo[d]thiazole-2-yl)-2-bromo-6-methoxyphenoxyl) acetic acid

A technology of methoxyphenoxy and thiazole, applied in the field of medicine

Inactive Publication Date: 2015-11-11
ZHANGJIAGANG INST OF IND TECH SOOCHOW UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In terms of research on anti-inflammatory drugs related to MIF, many foreign pharmaceutical companies and scientific research institutions are developing new MIF inhibitors with anti-inflammatory effects, but there is no MIF inhibitor that has been successfully marketed yet.

Method used

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  • Novel application of 2-(4-(benzo[d]thiazole-2-yl)-2-bromo-6-methoxyphenoxyl) acetic acid
  • Novel application of 2-(4-(benzo[d]thiazole-2-yl)-2-bromo-6-methoxyphenoxyl) acetic acid
  • Novel application of 2-(4-(benzo[d]thiazole-2-yl)-2-bromo-6-methoxyphenoxyl) acetic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1: Experiment of compound's enzyme inhibitory activity on MIF.

[0018] Experimental principle: MIF has dopachrome tautomerase activity, which can convert orange D and L-type dopachrome methyl esters into colorless indole derivatives. minute absorbance test.

[0019] Preparation of experimental reagents: lipopolysaccharide (Escherichia coli serotype 055:B5), (L)-3,4-dihydroxyphenylpyruvate methyl ester and sodium periodate were purchased from Sigma-Aldrich (St. Louis, Eastern City, Missouri, USA) ); (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole methyl acetate (ISO-1) is a typical inhibitor of MIF, purchased from Merck, Germany Calbiochem, a subsidiary of its biochemical reagent brand, is used here as a positive control; the compound is dissolved in 10mM DMSO stock solution, and finally the RAW264.7 macrophages are incubated at 37°C when the concentration of DMSO in the buffer is lower than 0.25%. Add 5% heat-inactivated fetal bovine serum (Fetalbovineserum...

Embodiment 2

[0022] Example 2: Effect of compounds on MIF-induced chemotaxis and migration of macrophages.

[0023] Experimental principle: MIF has a chemotaxis and migration effect on macrophages, and inhibitors acting on MIF can inhibit the chemotaxis and migration of macrophages caused by MIF to a certain extent.

[0024] Experimental procedure: Recombinant human MIF was placed in the lower chamber of the CIM-16 plate with or without MIF tautomerase inhibitors, and then RAW264.7 macrophages were inoculated in the upper chamber containing 20,000 cells in serum-free medium. Then the CIM-16-well plate was transferred to xCELLigenceRTCA-DP (Roche Diagnostics, Mannheim, Germany), and the data was collected every 15 minutes during the 4-hour detection cycle, and finally the data was analyzed by RTCA1.2 software.

[0025] Experimental results: HitMIF means Heat-inactivated MIF, which is used as a negative control here, figure 2 The histogram in the first column on the left in the center ind...

Embodiment 3

[0026] Example 3: Cell Sensitivity Experiment.

[0027] Experimental principle: The MTT analysis method is based on the living cell metabolite reducing agent MTT thiazole blue, and uses a microplate reader to measure the optical density OD value at 490nm to reflect the number of living cells, so as to determine the killing effect of the compound on the cultured cells.

[0028] Experimental procedure: cell viability was determined by MTT assay, BV-2 microglial cells, THP-1 cells or RAW264.7 macrophages were inoculated in triplicate at a density of 5×10 4 cells / plate, cells were treated in glycocalyixns and LPS for 24 hours, MTT was added to each plate and incubated at 37°C for 4 hours, after the medium was discarded, DMSO was added to the dissolved formazan dye, The optical density was tested at 540nm, and all experimental results were expressed as M±S.D. All data were analyzed using SPSS program (version 14.0) for one-way analysis of variance and StudentNewmanKeul's analysis, ...

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Abstract

The invention discloses a novel application of 2-(4-(benzo[d]thiazole-2-yl)-2-bromo-6-methoxyphenoxyl) acetic acid. Specifically speaking, the 2-(4-(benzo[d]thiazole-2-yl)-2-bromo-6-methoxyphenoxyl) acetic acid in the novel application has a function of an MIF (macrophage migration inhibition factor) inhibitor and can be used for remarkably inhibiting release of inflammatory factors (TNF (Tumor Necrosis Factor)-alpha and NO) induced by LPS (Lipopolysaccharide), inhibiting chemotactic migration of macrophage caused by MIF, inhibiting phosphorylation of ERK (extracellular signal-regulated kinase) 1 / 2 and preparing MIF-related anti-inflammatory medicaments.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to the medical application of a small molecular compound, in particular to 2-(4-(benzo[d]thiazol-2-yl)-2-bromo-6-methoxyphenoxy) Use of acetic acid or a pharmaceutically acceptable salt thereof in the preparation of medicines for treating inflammatory diseases related to MIF, especially MIF inhibitors. Background technique [0002] Macrophage migration inhibitory factor (MIF) is a multifunctional protein that integrates cytokines, enzyme activities, and neuroendocrine hormones. As a cytokine, MIF is involved in almost all inflammatory disease processes, it promotes innate and acquired immune responses by activating macrophages and T cells, is an important regulator of the innate immune system, and is considered to link the endocrine system and mediators of the immune system. MIF is closely related to the pathogenesis of various immune and inflammatory diseases, such as the role of ...

Claims

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Application Information

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IPC IPC(8): A61K31/428A61P29/00A61P7/00A61P31/04A61P19/02A61P9/10
Inventor 镇学初侯廷军许磊张瑜郑龙太
Owner ZHANGJIAGANG INST OF IND TECH SOOCHOW UNIV
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