Application of MASH treatment active component in preparation of medicine for preventing and / or treating metabolic dysfunction related steatohepatitis

Abstract

The invention belongs to the field of medicine treatment, and particularly relates to application of an MASH treatment active ingredient in preparation of a medicine for preventing and / or treating metabolic dysfunction related steatohepatitis, and the MASH treatment active ingredient is used as a pharmacodynamic active ingredient to be used for preparing the medicine for preventing and / or treating the metabolic dysfunction related steatohepatitis. The MASH treatment active component is a compound with a structure shown in a formula 1. Researches show that the formula 1 is innovatively used as an active ingredient, and the formula 1 can be used for preventing and treating MASH and can relieve further progress of MASH.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to the field of prevention and treatment of metabolic dysfunction-associated steatohepatitis. BACKGROUND

[0002] Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease in the world, with an incidence rate of up to 25.2%, and metabolic dysfunction-associated steatohepatitis (MASH) is a further development form of MASLD.

[0003] MASH is a complex liver disease caused by obesity and diabetes, which can lead to liver fibrosis, liver failure and even liver cancer. According to the latest epidemiological research, about 5% of adults worldwide are affected by MASH, and this number is even higher in some high-risk groups. However, there are still very limited effective treatment methods for MASH in clinical practice. Therefore, exploring effective treatment targets and treatment regimens for MASH is still a hot issue of concern. With the continuous development of technology, there are some non-specific treatment methods for MASH in the prior art. For example, US12030861A1 discloses an L-lysine salt of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-1-yl]-1-benzofuran-2-carboxylic acid and various forms thereof In addition, CN118304292A discloses a use of a silybum marianum medicinal composition in the preparation of a drug for treating fatty liver disease.

[0004] Although the treatment of MASLD has achieved certain results with the development of technology, the existing treatment regimens have high costs, and the efficacy and safety need to be further verified. SUMMARY

[0005] In view of the complex pathogenesis of MASH and the lack of prevention and / or treatment drugs, the present application aims to provide a use of a MASH treatment active ingredient in the preparation of a drug for preventing and / or treating metabolic dysfunction-associated steatohepatitis, and to provide a safe MASH treatment method with excellent efficacy.

[0006] The second object of the present application is to provide a drug for preventing and / or treating MASH.

[0007] In view of the problems of unclear pathogenesis, uncertain efficacy and safety of MASH, the present application provides the following scheme after in-depth research:

[0008] The application of MASH therapeutic active ingredient in the preparation of a medicine for preventing and / or treating metabolic dysfunction related fatty hepatitis, the MASH therapeutic active ingredient is used as a pharmacodynamic active ingredient for preparing a medicine for preventing and / or treating metabolic dysfunction related fatty hepatitis;

[0009] The MASH therapeutic active ingredient is a compound with the structure of formula 1.

[0010]

[0011] The present application shows that the formula 1 is innovatively used as an active ingredient, which can be used for MASH prevention and treatment, and can alleviate further progression.

[0012] The application, the MASH therapeutic active ingredient and the pharmaceutically acceptable excipient are combined to prepare the medicine for preventing and / or treating metabolic dysfunction related fatty hepatitis.

[0013] The application, the MASH therapeutic active ingredient and the pharmaceutically acceptable excipient are combined to prepare the medicine for preventing and / or treating metabolic dysfunction related fatty hepatitis.

[0014] The application, the preparation is an oral or injection preparation. The oral preparation is, for example, a tablet, a capsule, a powder, etc. The injection preparation is, for example, an injection solution, an injection powder, etc.

[0015] In the present application, the preparation of formula 1 can be prepared in a dose of 50-100 mg / kg.

[0016] In the present application, the use cycle can be more than 20 days, and further can be 25-35 days. In the present application, the administration method includes subcutaneous injection, intradermal injection, intramuscular injection, intraperitoneal injection, intravenous injection, oral method, gavage method; preferably, the administration method is gavage method.

[0017] The present application also provides a medicine for preventing and / or treating metabolic dysfunction related fatty hepatitis, which comprises a pharmaceutically effective amount of the active ingredient of formula 1.

[0018] In the present application, the medicine uses formula 1 as an active ingredient. The medicine described in the present application can prevent and / or treat metabolic dysfunction related fatty hepatitis based on the characteristics of the physicochemical structure of formula 1.

[0019] The medicine described in the present application further comprises a pharmaceutically acceptable excipient.

[0020] The medicine described in the present application has a pharmaceutically acceptable administration form.

[0021] The medicine described in the present application has an administration form including oral or injection form.

[0022] Beneficial effects

[0023] The present application shows that the active ingredient of Formula 1 is innovatively used for MASH prevention and treatment, and can alleviate further progression. For example, the active ingredient of Formula 1 described in the present application can significantly improve the metabolic dysfunction-related fatty hepatitis model caused by high-fat high-cholesterol diet. Compared with the conventional drugs commonly used for symptomatic treatment, the compound of Formula 1 not only does not cause any side effects and dependence to the human body, but also has a health care effect on the body. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 The graph of liver weight ratio of two groups of mice.

[0025] Figure 2 The pathological pictures of oil red O, HE and Sirius red staining. Among them, the model group is the MASH mice given normal saline; the treatment group is the MASH mice treated with Formula 1.

[0026] Figure 3 The results of triglyceride content in liver tissue of MASH mice given normal saline or Formula 1 treatment.

[0027] Figure 4 The statistical results of AST and ALT content in serum of MASH mice given normal saline or Formula 1 treatment. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0029] The "metabolic dysfunction-related fatty hepatitis" described in the present application is the conventional metabolic dysfunction-related fatty hepatitis in the art. The metabolic dysfunction-related fatty hepatitis preferably refers to the metabolic dysfunction-related fatty hepatitis caused by various factors, characterized by intraliver fatty degeneration, inflammatory infiltration and different degrees of fibrosis pathological changes. The metabolic dysfunction-related fatty hepatitis preferably refers to the metabolic dysfunction-related fatty hepatitis of human or animal.

[0030] The "treatment" of the present application refers to reducing the degree of fatty degeneration, inflammatory infiltration and fibrosis in the liver, or curing metabolic dysfunction-related fatty hepatitis to normalize it, or slowing down the progression of metabolic dysfunction-related fatty hepatitis.

[0031] In order to make the above objectives, features and advantages of the present application more obvious and easy to understand, the present application will be further described in detail below with reference to the drawings and specific embodiments.

[0032] The reagents and raw materials used in the present application are commercially available.

[0033] Example 1 Preparation of metabolic dysfunction-related fatty hepatitis animal model

[0034] 1.1 Main reagents and experimental animals

[0035] The high-fat high-cholesterol feed used in the experiment was purchased from Nantong Turofei Company.

[0036] The compounds used in the experiment were purchased from Sigma Company unless otherwise specified.

[0037] The SPF C57BL / 6 mice (male, 6-8 weeks old, 16-18 g) used in the experiment were purchased from Hunan Slaik Jingda Experimental Animal Co., Ltd.

[0038] 1.2 Preparation of MASH mouse model

[0039] Male C57BL / 6 (6-8 weeks old) mice were fed with CDHFD feed for 8 weeks.

[0040] 1.3 Formula 1 treatment of MASH mice caused by high-fat high-cholesterol

[0041] The specific scheme is: the animal model prepared in Example 1 is divided into groups for administration after being fed with CDHFD feed for 4 weeks, and the grouping and administration are shown in Table 1:

[0042] Table 1 Grouping and administration of MASH mouse model

[0043]

[0044] Example 2

[0045] After 30 days, the mice were euthanized, and sample collection and body weight and liver weight data recording were performed. The liver weight ratio of mice refers to the ratio of the weight of the liver of mice to their body weight, which is generally used to study the physiological and pathological state of the liver of mice. The liver weight ratio of mice is often used as one of the indicators for evaluating the health and functional status of the liver of mice. Figure 1 The results show that after STC gavage treatment, the liver weight ratio of mice decreased significantly.

[0046] Example 3 Oil red O staining, HE staining and sirius red staining pathological imaging analysis

[0047] Oil red O fat staining method is a classical and authoritative method for staining fat in tissues in daily pathological diagnosis and scientific research, which can specifically color neutral fat such as triglyceride in tissues as red. HE staining is one of the most basic and widely used technical methods in histology and pathology teaching and scientific research. Hematoxylin dye is alkaline, which can dye the alkali-philic structure of the tissue (such as ribosome, nucleus and ribonucleic acid in cytoplasm, etc.) into blue-violet; eosin is an acidic dye, which can dye the acid-philic structure of the tissue (such as intracellular and intercellular proteins, including Lewy body, alcohol body and most of the cytoplasm) into pink, so that the morphology of the whole cell tissue is clear and visible. It can show the structure of the tissue and inflammatory cell infiltration. Sirius red is a very strong acid dye, which can react with collagen fibers to produce obvious birefringence phenomenon. Sirius red staining collagen fibers appear red, nuclei appear green, and the rest appear yellow.

[0048] Take the largest leaf liver tissue of the animal, fix it with 4% paraformaldehyde and then paraffin-embed. Slice the largest cross-section of the wax block embedding the liver tissue, and observe the histopathological condition by HE staining. Obtain high-definition HE-stained pathological pictures (10 times) by using high-definition monochrome pathological image and text analysis system SlideViewer, and the results are shown in Figure 2 The results show that the liver tissue of the model group mice presents obvious fat accumulation, ballooning, lobular inflammation and increased fibrosis, while the fat accumulation, ballooning, lobular inflammation and fibrosis in the liver tissue of the mice are significantly reduced after treatment with formula 1.

[0049] Example 4 Triglyceride content determination of MASH mice

[0050] Triglyceride is a kind of lipid in human body, which is composed of three fatty acids and glycerol, and is an important energy source for human body. However, when the content of triglyceride is too high, it will cause harm to the human body, causing the occurrence of metabolic diseases such as arteriosclerosis and fatty liver. The content of the liver tissue of the animal is detected to evaluate the condition of fatty liver. The specific method is as follows: take half of the largest leaf liver tissue of the model animal prepared in Example 1, record the wet weight, and follow the operation of Nanjing Jiancheng Biological Engineering Technology Co., Ltd. kit instructions to determine the content of triglyceride. The results are shown in Table 2 and Figure 3 From Table 2, it can be seen that compared with the model group, the content of triglyceride in the liver tissue of MASH mice can be significantly reduced after treatment with formula 1.

[0051] Table 2 Triglyceride content of MASH mice reduced by formula 1

[0052]

[0053]

[0054] In the experiment, it was found by pathological examination, pathological imaging and other means that Formula 1 can significantly inhibit the metabolic dysfunction-related fatty liver caused by high-fat high-cholesterol diet; significantly reduce the content of triglyceride in the liver tissue of MASH mice. The above experimental results prove that Formula 1 has excellent therapeutic prospects in metabolic dysfunction-related fatty liver.

[0055] Example 5 Determination of the content of AST and ALT in the serum of MASH mice

[0056] AST and ALT are the most widely used biochemical indicators in clinical application to reflect liver cell damage. The content of AST and ALT in the serum of MASH mice model will increase significantly. The specific detection method is as follows: the serum of the model animals prepared in Example 1 is taken, and the content of AST and ALT is measured by Bioseal Pathology Company. The results are shown in Table 3 and Table 4. Figure 4 From Table 3, it can be seen that compared with the model group, the content of AST and ALT in the serum of MASH mice can be significantly reduced after treatment with Formula 1.

[0057] Table 3 Formula 1 reduces the content of AST and ALT in the serum of MASH mice

[0058] Group Model group Treatment group P value AST(U / L) 466.94±65.36 371.26±48.21 0.009 ALT(U / L) 429.74±63.50 329.51±69.63 0.014

[0059] The above experimental results show that Formula 1 of the present application has a significant anti-fatty liver effect and can be used as an active ingredient for preparing a drug for metabolic dysfunction-related fatty liver.

[0060] The above-described examples only describe the preferred modes of the present application and do not limit the scope of the present application. Without departing from the design spirit of the present application, various modifications and improvements to the technical solutions of the present application made by those skilled in the art shall fall within the protection scope determined by the claims of the present application.

Claims

1. Use of a MASH therapeutically active ingredient for the preparation of a medicament for the prevention and / or treatment of metabolic dysfunction-associated steatohepatitis, characterized in that, The MASH therapeutic active ingredient is used as a pharmacologically active ingredient for preparing a medicine for preventing and / or treating metabolic dysfunction-related fatty hepatitis; The MASH therapeutic active ingredient is a compound having the structure of Formula 1.

2. Use of the MASH therapeutically active principle according to claim 1 for the preparation of a medicament for the prevention and / or treatment of metabolic dysfunction-associated steatohepatitis, characterized in that, The MASH therapeutic active ingredient is combined with a pharmaceutically acceptable excipient to prepare the medicine for preventing and / or treating metabolic dysfunction-related fatty hepatitis.

3. Use of the MASH therapeutically active principle according to claim 1 for the preparation of a medicament for the prevention and / or treatment of metabolic dysfunction-associated steatohepatitis, characterized in that, The MASH therapeutic active ingredient is combined with a pharmaceutically acceptable excipient to prepare a preparation of the medicine for preventing and / or treating metabolic dysfunction-related fatty hepatitis.

4. Use of the MASH therapeutically active principle according to claim 3 for the preparation of a medicament for the prevention and / or treatment of metabolic dysfunction-associated steatohepatitis, characterized in that, The preparation is an oral or injection preparation.

5. A medicine for preventing and / or treating metabolic dysfunction-associated fatty liver hepatitis, characterized by, The preparation contains a pharmaceutically effective amount of the active ingredient of Formula 1 used in any one of claims 1 to 4.

6. The preventive and / or therapeutic drug for metabolic dysfunction-associated fatty hepatitis according to Claim 5, wherein The preparation further contains a pharmaceutically acceptable excipient.

7. The preventive and / or therapeutic drug for metabolic dysfunction-associated fatty hepatitis according to claim 6, wherein The preparation has a pharmaceutically acceptable administration form.

8. The preventive and / or therapeutic drug for metabolic dysfunction-associated fatty hepatitis according to claim 7, wherein The administration form includes an oral or injection form.

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