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Application of fumarate and pharmaceutically acceptable salt thereof in preparation of medicines for ferroptosis related diseases

A kind of technology of fumarate and dimethyl fumarate, applied in the field of chemical medicine

Inactive Publication Date: 2019-02-22
XIANGYA HOSPITAL CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There are not many strategies for treating ferroptosis-related diseases disclosed in the prior art. Therefore, it is very meaningful to develop a new drug that targets ferroptosis, has strong selectivity and significant efficacy for treating ferroptosis-related diseases of

Method used

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  • Application of fumarate and pharmaceutically acceptable salt thereof in preparation of medicines for ferroptosis related diseases
  • Application of fumarate and pharmaceutically acceptable salt thereof in preparation of medicines for ferroptosis related diseases
  • Application of fumarate and pharmaceutically acceptable salt thereof in preparation of medicines for ferroptosis related diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] In vitro inhibition of hepatic ferroptosis assay:

[0049] (1) GSH and GSSG level determination test:

[0050] The monolayer of adherent HepG2 cells was digested with trypsin to form a single cell suspension, and the cells were plated in 96-well plates at 4000 cells / well. After 4-6 hours of cell attachment, add DMSO, 10 μM dimethyl fumarate, 30 μM dimethyl fumarate, 10 μM monomethyl fumarate, and 30 μM monomethyl fumarate to the cell culture plate. Methyl ester was incubated for 20 h, and the GSH / GSSG-GloTM Assay kit (Promega, V6611) was used to detect the total GSH and GSSH of the cells. The specific operation was performed according to the instructions, and the experiment was repeated three times. The result is as figure 1 and figure 2 shown.

[0051] It can be seen from the results in the figure that dimethyl fumarate and monomethyl fumarate can significantly up-regulate the GSH level and GSSH level of HepG2 cells in a concentration-dependent manner, and the up-...

Embodiment 2

[0062] Inhibition test of hepatic ferroptosis in alcoholic fatty liver disease model mice:

[0063] Twenty-four 8-week-old SPF grade C57BL / 6 male mice were randomly divided into 4 groups, namely blank group, model group, model + low-dose dimethyl fumarate (100mg / Kg) group and model + high-dose fumarate group Acetate dimethyl ester (200mg / Kg) group. The mice initially drank the Lieber-DeCarli control diet freely for 5 days to make them gradually adapt to the liquid diet and tube feeding. Subsequently, the model group was allowed to freely drink the liquid diet containing 5% (volume / volume) Lieber-DeCarli alcohol for 10 days, while the control group The group was given an isocaloric control diet. Starting from the 11th day, the model+administration group was given dimethyl fumarate (100 mg / Kg) and dimethyl fumarate (200 mg / Kg) by intragastric administration once a day, respectively, for 10 consecutive days. Afterwards, mice were anesthetized with 5% chloral hydrate intraperito...

Embodiment 3

[0078] Inhibition test of hepatic ferroptosis in rats with liver fibrosis:

[0079] 36 7-week-old 200-250g SPF grade SD rats were randomly divided into 4 groups, namely control group, model group, model+low dose dimethyl fumarate (15mg / Kg) group and model+high dose Dimethyl fumarate (25mg / Kg) group. The model group was established by subcutaneous injection of 40% CCl4 peanut oil solution 0.3ml / 100g, twice a week. From the second week, the mice were given 10% alcohol as the only drink and fed with cornmeal feed mixed with 0.5% cholesterol, and the models were built continuously for 8 weeks. Simultaneously with modeling, the model + drug administration group were given dimethyl fumarate (15 mg / Kg) and dimethyl fumarate (25 mg / Kg) by intragastric administration once a day, respectively, for 8 consecutive weeks. After the mice were anesthetized intraperitoneally with 5% chloral hydrate, the liver tissues were collected, some were fixed in formalin, and some were preserved in liq...

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Abstract

The invention relates to application of fumarate and pharmaceutically acceptable salt thereof in preparation of medicines for treating ferroptosis related diseases. According to the application, the fumarate comprises dimethyl fumarate and / or monomethyl fumarate. The application has the advantages that the influence of the fumarate and the pharmaceutically acceptable salt thereof on the level of key regulatory gene GPX4 protein for ferroptosis is disclosed for the first time, a theoretical basis is provided for research on a treatment strategy for the ferroptosis diseases, and an insertion site is provided for preparing the new medicines for treating the ferroptosis related diseases.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to the application of fumaric acid esters and pharmaceutically acceptable salts thereof in the preparation of medicines for treating diseases related to ferroptosis. Background technique [0002] Ferroptosis is a type of iron / reactive oxygen species-dependent cell death pathway, which is different from other death pathways such as apoptosis, necrosis and autophagy. Ferroptosis is mainly manifested as lipid peroxidation and accumulation of intracellular reactive oxygen species. Ferrostatin-1 and Erastin are currently recognized ferroptosis inhibitors and activators. Studies have shown that Erastin affects the synthesis of glutathione by inhibiting the cystine / glutamate transporter, hindering the uptake of cystine and reducing it to cysteine. GSH is an essential cofactor for glutathione peroxidase to inhibit the generation of lipid reactive oxygen species. Among them, g...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/225A61P1/16A61P35/00A61P13/12A61P25/00A61P3/00A61P9/10A61P25/28A61P25/16A61P25/14A61P3/10
CPCA61P1/16A61P3/00A61P3/10A61P9/10A61P13/12A61P25/00A61P25/14A61P25/16A61P25/28A61P35/00A61K31/225A61K9/0019
Inventor 陈永恒刘霆张叶赵爽陈主初
Owner XIANGYA HOSPITAL CENT SOUTH UNIV
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