CN116270649A

CN116270649A - Application of GANT61 or its derivative in preparing medicine for treating and/or preventing non-alcoholic fatty liver disease

Info

Publication number: CN116270649A
Application number: CN202310293155.8A
Authority: CN
Inventors: 徐晓军; 张伟涛; 冯连顺; 刘泽禹
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2023-03-23
Filing date: 2023-03-23
Publication date: 2023-06-23

Abstract

The invention relates to the field of new application of medicines, in particular to medical application of GANT61 or derivatives thereof. The invention discloses GANT61 or a derivative thereof, which has the effects of improving non-alcoholic fatty liver, reducing blood fat, improving insulin resistance, and inhibiting liver inflammation and fibrosis. The invention discovers the improvement effect of GANT61 or the derivatives thereof on the non-alcoholic fatty liver disease for the first time, and provides more choices for the treatment of the non-alcoholic fatty liver disease.

Description

Application of GANT61 or its derivative in preparing medicine for treating and/or preventing non-alcoholic fatty liver disease

Technical Field

The invention relates to the field of new application of medicines, in particular to application of GANT61 or derivatives thereof in preparation of medicines for treating and/or preventing nonalcoholic fatty liver diseases.

Background

Nonalcoholic steatohepatitis (nonalcoholic fatty liver, NASH), a potentially progressive liver disease, can lead to cirrhosis, hepatocellular carcinoma and death. NASH brings a huge economic burden and reduces the quality of life. However, the pathogenesis of NASH has not been fully elucidated. The most popular, i.e. "double hit", hypothesis is currently considered the best representation of progression from steatosis to NASH. The first hit steatosis is caused by unhealthy lifestyle, obesity, insulin resistance or type 2 diabetes. The second stroke, caused by oxidative stress, lipid peroxidation or other deleterious damage, subsequently causes liver injury and inflammation. Knowledge of the key molecular mechanisms of NASH process can provide theoretical support for the development of safe and effective therapeutic drugs. NASH develops when lipid accumulates in hepatocytes for long periods of time to form lipotoxicity, which can lead to tissue damage and associated pro-inflammatory, pro-fibrotic and pro-cancerous responses.

GANT61 has formula C ₂₇ H ₃₅ N ₅ The molecular weight is 429.60, the white crystalline powder has the following chemical structural formula:

disclosure of Invention

The invention aims to: the invention aims to provide an application of GANT61 or a derivative thereof for improving non-alcoholic fatty liver, reducing blood fat, improving insulin resistance, inhibiting liver inflammation and fibrosis in preparing a medicine for treating and/or preventing non-alcoholic fatty liver diseases.

The technical scheme is as follows: the GANT61 or a derivative thereof of the invention is applied to the preparation of a medicament for treating and/or preventing nonalcoholic fatty liver disease.

In the pharmacological activity study of 6ANT61, the inventors found that GANT61 is effective in reducing the weight, serum cholesterol and triglyceride levels in high fat diet-induced mice, improving insulin resistance and inhibiting liver inflammation and fibrosis.

Further, derivatives include isomers, diastereomers, enantiomers, tautomers, solvates, salts of solvates, or pharmaceutically acceptable salts of GANT 61.

The invention relates to application of a composition containing GANT61 or a derivative thereof in preparing a medicine for treating and/or preventing non-alcoholic fatty liver disease.

Further, the composition is a pharmaceutical preparation prepared by taking GANT61 or a derivative thereof as an active ingredient and adding a pharmaceutically acceptable carrier or auxiliary material. The pharmaceutical preparation is tablet, capsule, syrup, suspension or injection. The adjuvants are perfume, sweetener, liquid/solid filler or diluent.

The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:

(1) GANT61 and its derivatives and pharmaceutical compositions are effective in reducing blood lipid, total cholesterol by 28.0%, and triglyceride by 40.0%; GANT61 and its derivatives and pharmaceutical compositions can also effectively improve glucose tolerance and insulin resistance of the body by 23.7% and 35.1%, respectively;

GANT61 and its derivatives and pharmaceutical compositions can also improve inflammation and fibrosis index, and reduce liver injury index ALT and AST by 55.0% and 30.4%, respectively.

(2) GANT61 and its derivatives and pharmaceutical compositions are widely used and can be prepared into medicines for treating and/or preventing alcoholic fatty liver; the medicine has more excellent treatment effect, and the optimal weight improvement can reach 8.6%.

The improvement of non-alcoholic fatty liver activity by GANT61 is further illustrated below in connection with the examples.

Drawings

FIG. 1 is the experimental results of mouse body weight;

FIG. 2 is the experimental results of liver weight/body weight of mice;

FIG. 3 is the experimental results of weight of epididymal white fat/body weight of mice;

FIG. 4 is an Oral Glucose Tolerance Test (OGTT) result;

FIG. 5 is an area under Oral Glucose Tolerance Test (OGTT) curve result

FIG. 6 is an insulin resistance test (ITT) result;

FIG. 7 is an area under insulin resistance test (ITT) curve result;

FIG. 8 is an experimental result of total cholesterol in serum;

FIG. 9 is an experimental result of triglycerides in serum;

FIG. 10 is the experimental results of glutamic pyruvic transaminase (ALT) in serum;

FIG. 11 shows the results of experiments on glutamic-oxaloacetic transaminase (AST) in serum;

FIG. 12 is an mRNA measurement of a gene associated with liver inflammation in mice;

FIG. 13 shows mRNA measurement of a gene related to liver fibrosis in mice.

Detailed Description

The technical scheme of the invention is further described below by referring to examples.

Examples: GANT61 effect on nonalcoholic fatty liver disease

1. Experimental method

Model set (HFFC): male C57BL/6J mice with a 6-week-old period were fed with high-fat, high-fructose and high-cholesterol (high fat, fructose and cholesterol, HFFC) feed and injected intraperitoneally with vehicle once a couple of days for 9 weeks. Body weight was recorded weekly.

GANT61 dosing group: male C57BL/6J mice, 6 weeks old, were fed HFFC high fat diet and injected intraperitoneally with GANT61 (20 mg/kg) once a couple of days for 9 weeks. Body weight was recorded weekly.

2. Experimental results

The body weight of the GANT 61-fed group was reduced by 3.50g (FIG. 1) compared to HFFC-high fat diet-fed mice. In addition, the proportion of liver weight in the GANT 61-administered mice was reduced from 5.23% in the model group to 3.80% in the GANT 61-administered group (FIG. 2). The proportion of epididymal fat weight to the body weight of mice was reduced from 5.00% in the model group to 3.71% in the GANT 61-dosed group (FIG. 3). Glucose tolerance and insulin resistance were significantly improved in the high fat fed mice treated with compound GANT61 (FIGS. 4-7). Furthermore, the serum TC of the GANT61 dosed mice was reduced by 3.26mM compared to the high-fat model group (fig. 8). The serum TG levels of the GANT61 dosed mice were reduced by 1.24mM compared to the mice of the high-fat model group (fig. 9). Subsequently, further examination of common indices ALT and AST for clinical liver injury revealed that ALT and AST were significantly reduced in the GANT 61-dosed group, i.e., GANT61 could alleviate liver injury caused by high-fat diet HFFC (fig. 10-11). Finally, the mRNA levels of the genes related to liver inflammation and fibrosis were measured, and it was verified that the liver inflammation and fibrosis index of mice in the group to which the GANT61 was administered was also significantly reduced (fig. 12-13), which suggests that the GANT61 can also alleviate liver inflammation and fibrosis progression.

Taken together, the compound GANT61 ameliorates the high fat diet induced non-alcoholic fatty liver disease in C57BL/6J mice and has significant efficacy.

Claims

Use of gant61 or a derivative thereof for the preparation of a medicament for the treatment and/or prophylaxis of non-alcoholic fatty liver disease.
2. The use according to claim 1, characterized in that: the derivatives include isomers, diastereomers, enantiomers, tautomers, solvates, salts of solvates, or pharmaceutically acceptable salts of GANT 61.
3. Use of a composition comprising GANT61 or a derivative thereof in the manufacture of a medicament for the treatment and/or prophylaxis of non-alcoholic fatty liver disease.
4. A use according to claim 3, characterized in that: the composition is a pharmaceutical preparation prepared by taking GANT61 or derivatives thereof as an active ingredient and adding pharmaceutically acceptable carriers or auxiliary materials.
5. The use according to claim 4, characterized in that: the pharmaceutical preparation is a tablet, a capsule, syrup, a suspending agent or an injection.
6. The use according to claim 4, characterized in that: the auxiliary materials are spice, sweetener, liquid/solid filler or diluent.