CN113082033A

CN113082033A - Application of FR180204 in preparation of medicine for preventing and/or treating non-alcoholic fatty liver disease or hepatitis

Info

Publication number: CN113082033A
Application number: CN202110463477.3A
Authority: CN
Inventors: 王靖翔; 刘祖瑞; 高明景; 谢正伟
Original assignee: Beijing Yiyao Technology Co ltd
Current assignee: Beijing Yiyao Technology Co ltd
Priority date: 2021-04-26
Filing date: 2021-04-26
Publication date: 2021-07-09

Abstract

The invention discloses an application of FR180204 in preparing a medicament for preventing and/or treating non-alcoholic fatty liver disease or hepatitis. Compared with the prior art, the invention discloses a novel medical application of FR180204, which is found to have excellent effects of preventing and/or treating non-alcoholic fatty liver disease or hepatitis. According to the invention, research shows that FR180204 can obviously reduce ALT, AST, CHO and TG values in an MCD model, and can obviously improve hepatic steatosis, inflammatory state and liver injury.

Description

Application of FR180204 in preparation of medicine for preventing and/or treating non-alcoholic fatty liver disease or hepatitis

Technical Field

The invention belongs to the technical field of new medical application of FR180204, and particularly relates to application of FR180204 in preparation of a medicament for preventing and/or treating non-alcoholic fatty liver disease or hepatitis.

Background

Non-alcoholic fatty liver disease (NAFLD) affects the health of more and more people as the standard of living increases. Non-alcoholic fatty liver disease (NAFLD) refers to the condition of excess fat in the liver of a human who has little or no alcohol consumption. The most common NAFLD is a non-severe disease known as hepatic steatosis (fatty liver), where fat accumulates in hepatocytes: although this is not normal, it may not itself damage the liver. NAFLD is most commonly found in individuals with a series of risk factors known as metabolic syndrome, characterized by elevated fasting blood glucose, or postprandial glucose intolerance, overweight or obesity, hyperlipidemia (e.g., cholesterol and triglycerides and low high density lipids, protein cholesterol (HDL-C) levels, and hypertension); not all patients have all manifestations of the metabolic syndrome.

Some nonalcoholic steatohepatitis (NAFLD) patients may develop a more severe disease-nonalcoholic steatohepatitis (NASH): about 2-5% of adults and up to 20% of obese people are likely to suffer from NASH. In NASH, fat accumulation in the liver is associated with inflammation and scarring to varying degrees. NASH is a potentially serious disease with a great risk of developing end-stage liver disease, cirrhosis and hepatocellular carcinoma. Some patients with cirrhosis are at risk of liver failure and may eventually require liver transplantation.

NAFLD can be distinguished from NASH by NAFLD Activity Score (NAS): histopathological score for fatty liver biopsy (0-3), lobular inflammation (0-2), and hepatocyte swelling (0-2). NAS less than 3 corresponds to NAFLD, 3-4 corresponds to critical NASH, NAS greater than 5 corresponds to NASH. Biopsies were also scored as fibrosis (0 to 4).

The incidence of global obesity, metabolic syndrome, pre-diabetes and diabetes is high, and is expected to double to 3.66 billion by 2030. It is estimated that 2540 million (11.5%) of 2011 american diabetics develop diabetes, 3770 million (14.5%) by 2031, and 20.2% of hispanic adults suffer from diabetes. Since about 70% of patients with T2DM have fatty liver and necrosis and fibrosis (i.e., NASH) are more severe in diabetic patients, diabetes epidemiology indicates a significant increase in the incidence of NASH and chronic liver disease. Noninvasive evaluation of liver steatosis using nuclear magnetic resonance imaging, NAFLD prevalence was estimated to be 34% in the united states or approximately 8000 million, and greater than 5% in two-thirds of obese subjects. However, this prevalence is considered to be much higher in T2 DM. MRI showed a prevalence of NAFLD of 76% in 107 unselected T2DM patients, similar to the recent studies in italy and brazil. Recent studies have shown that the prevalence of NAFLD is rapidly increasing in obese children and adolescents, particularly in children of hispanic lineage.

There is currently no approved drug for the prevention or treatment of NAFLD or NASH. Many pharmaceutical interventions have been tried in NAFLD/NASH, but the overall effect is limited. Despite the reports of the primary benefits of GFT505 and OCA, there remains an important unmet clinical need for an effective and well-tolerated drug that can prevent or slow the progression of NAFLD and NASH.

Disclosure of Invention

The purpose of the invention is as follows: aiming at the defects in the prior art, the invention provides an application of FR180204 in preparing a medicament for preventing and/or treating non-alcoholic fatty liver disease or hepatitis.

The technical scheme is as follows: in order to achieve the purpose, the invention adopts the following technical scheme:

FR180204, CAS:865362-74-9, molecular formula: c₁₈H₁₃N₇Molecular weight: 327.34.

application of FR180204 in preparing a medicament for preventing and/or treating non-alcoholic fatty liver disease.

Application of FR180204 in preparation of a medicament for preventing and/or treating non-alcoholic steatohepatitis.

A composition for preventing and/or treating non-alcoholic fatty liver disease, comprising FR180204 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant.

Preferably, the auxiliary material is selected from one or more of a carrier, a diluent, an excipient or an adjuvant.

Application of a composition containing FR180204 in preparation of a medicament for preventing and/or treating non-alcoholic fatty liver disease.

A composition for preventing and/or treating non-alcoholic steatohepatitis, comprising FR180204 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant.

Use of a composition comprising FR180204 in the preparation of a medicament for the prevention and/or treatment of non-alcoholic steatohepatitis.

By "pharmaceutically acceptable" is meant that the molecule itself and the combination drug do not produce adverse, allergic, or other untoward reactions when properly administered to an animal or human.

Said "pharmaceutically acceptable auxiliary materials" should be compatible with FR180204, i.e. capable of being blended therewith without substantially reducing the effectiveness of the pharmaceutical composition in the usual case. Specific examples of some substances that can be used as pharmaceutically acceptable excipients are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium methylcellulose, ethylcellulose and methylcellulose; gelatin; talc; a solid lubricant; a polyol; an emulsifier; a colorant; a flavoring agent; tabletting agents, stabilizers; an antioxidant; a preservative; pyrogen-free water; isotonic saline solution. These materials are used as needed to aid in the stability of the formulation or to aid in the enhancement of the activity or its bioavailability or to produce an acceptable mouthfeel or odor upon oral administration.

In the present invention, unless otherwise specified, the dosage form of the drug is not particularly limited, and may be prepared into injection, oral liquid, tablet, capsule, dripping pill, spray, etc. by a conventional method, and the dosage form of the drug should be selected to match the administration mode.

Has the advantages that: compared with the prior art, the invention discloses a novel medical application of FR180204, which is found to have excellent effects of preventing and/or treating non-alcoholic fatty liver disease or hepatitis. According to the invention, research shows that FR180204 can obviously reduce ALT, AST, CHO and TG values in an MCD model, and can obviously improve hepatic steatosis, inflammatory state and liver injury.

Drawings

FIG. 1 is a graph of ALT levels in a mouse MCD model drug activity assay.

FIG. 2 is a graph of AST levels in a mouse MCD model drug activity assay experiment.

FIG. 3 is a graph of CHO levels in a mouse MCD model drug activity assay experiment.

FIG. 4 is a graph of TG levels in a mouse MCD model drug activity assay experiment.

FIG. 5 is a schematic sectional view of liver diseases in the normal group (left panel), model group (middle panel) and administration group (right panel) in the experiment of testing the pharmaceutical activity of mouse MCD model by HE staining method.

Detailed Description

The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention. The experimental methods in the examples described below are all conventional methods unless otherwise specified; the materials, reagents, instruments, etc. used are commercially available unless otherwise specified.

Examples

The first experiment method comprises the following steps:

1. the 8-week old C57BL/6 was kept under environmental control and was free to eat standard feed and water. After one week of acclimation, the mice were divided into four groups, normal group mice were fed with normal feed, model group mice and administration group mice were fed with methionine choline deficient feed (MCD, a 02082002B). Two weeks after MCD feeding, mice in the administration group were injected intraperitoneally with vehicle (0.5% sodium carboxymethylcellulose (CMC-Na, Sigma)) containing ERK inhibitor FR180204 once daily for 14 consecutive days, mice in the model group and normal group were injected with vehicle at the same frequency, and mice were sacrificed after 14 days, and their body weights and liver tissues were weighed.

2. Portions of each liver were fixed with 4% paraformaldehyde and analyzed for liver histology by Hematoxylin and Eosin (HE) staining and oil red staining. Other tissues were collected and frozen in liquid nitrogen for use, and serum was collected to measure metabolite parameters.

Second, experimental results

1. As shown in fig. 1, FR180204 is effective in reducing ALT values in the MCD model.

2. As shown in fig. 2, FR180204 can effectively reduce the AST value in the MCD model.

3. As shown in fig. 3, FR180204 can effectively reduce CHO values in the MCD model.

4. As shown in fig. 4, FR180204 can effectively reduce the TG value in the MCD model.

5. As shown in figure 5, the results of HE staining in FR180204 treatment group show that FR180204 can obviously improve hepatic steatosis, inflammatory necrosis and hepatic injury.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the appended claims.

Claims

Application of FR180204 in preparation of a medicament for preventing and/or treating non-alcoholic fatty liver disease.
Application of FR180204 in preparation of a medicament for preventing and/or treating non-alcoholic steatohepatitis.
3. A composition for preventing and/or treating non-alcoholic fatty liver disease, comprising FR180204 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant.
4. The composition according to claim 3, wherein the adjuvant is selected from one or more of a carrier, a diluent, an excipient or an adjuvant.
5. Application of a composition containing FR180204 in preparation of a medicament for preventing and/or treating non-alcoholic fatty liver disease.
6. A composition for preventing and/or treating non-alcoholic steatohepatitis, comprising FR180204 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant.
7. The composition according to claim 6, wherein the adjuvant is selected from one or more of a carrier, a diluent, an excipient or an adjuvant.
8. Use of a composition comprising FR180204 in the preparation of a medicament for the prevention and/or treatment of non-alcoholic steatohepatitis.