Application of compound CLT-28643 in preparation of medicine for preventing and treating hepatic fibrosis

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of a compound CLT-28643 in preparation of a medicine for preventing and treating hepatic fibrosis. Specifically, research finds that the compound CLT-28643 can specifically inhibit an integrin alpha5beta1 signal channel, can inhibit bile duct reaction and improve liver functions in liver fibrosis, and can play an anti-fibrosis role by regulating cell aging, cilia regeneration and inflammation related signal channels; therefore, the compound has a prospect of being developed into a medicine for preventing and / or treating hepatic fibrosis. In a word, when the compound CLT-28643 is applied to treatment of hepatic fibrosis, the compound CLT-28643 has remarkable beneficial effects in multiple aspects, so that the compound CLT-28643 has a good practical application value.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to the application of compound CLT-28643 in the preparation of drugs for preventing and treating liver fibrosis. Background Art

[0002] Disclosing the information of this background art section is only intended to enhance the overall understanding of the present invention, and it is not necessarily regarded as an admission or an implication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Liver fibrosis is a chronic and progressive liver disease. Its essence is that the liver's repair response to various chronic injuries is excessive, resulting in excessive deposition of extracellular matrix, seriously affecting the normal function of the liver. If not effectively controlled, it can further develop into cirrhosis, liver failure, or even liver cancer, posing a major threat to human health. Currently, the incidence of liver fibrosis is on the rise globally, especially significant in the population of patients with chronic liver diseases. As a major country with liver diseases, the prevention and treatment situation of liver fibrosis in China is more severe. At the same time, in the research on diseases such as viral hepatitis (such as hepatitis B, hepatitis C), non-alcoholic fatty liver disease, and alcoholic liver disease, it is found that the continuous development of these diseases often leads to liver fibrosis, and there are also differences in the incidence of liver fibrosis caused by different etiologies. Currently, the existing clinical treatment methods for liver fibrosis mainly focus on delaying the progression of the disease, improving liver function, and preventing complications. In terms of drug treatment, anti-fibrotic drugs and drugs targeting the etiology are important components. Common anti-fibrotic drugs such as colchicine can inhibit the polymerization of tubulin in the process of collagen synthesis, interfering with the secretion and deposition of collagen; silymarin has antioxidant and anti-inflammatory effects, can protect liver cells, and to a certain extent alleviate the fibrosis process. Drugs targeting the etiology, such as the nucleoside (acid) analogues entecavir and tenofovir for the treatment of chronic hepatitis B, can indirectly delay the development of liver fibrosis by inhibiting virus replication and reducing liver inflammation; direct-acting antiviral drugs such as sofosbuvir / velpatasvir tablets for the treatment of hepatitis C can effectively clear the virus and reduce the risk of liver fibrosis. In addition, traditional Chinese medicine also plays an important role in the treatment of liver fibrosis. Through the mechanism of multi-component and multi-target action, it regulates the liver immune microenvironment, inhibits the activation of hepatic stellate cells, and promotes collagen degradation. For patients with end-stage cirrhosis, liver transplantation is an effective means to save lives, but there are problems such as shortage of donors, high surgical risks, and the need for long-term use of immunosuppressants after surgery. However, the existing treatment methods for liver fibrosis still face many difficulties and challenges. First, there is currently no drug that can completely reverse the formed liver fibrosis. Most drugs can only slow down the fibrosis process to a certain extent and are difficult to cure the disease fundamentally. Second, the problem of drug side effects cannot be ignored. Long-term use of colchicine may cause adverse reactions such as gastrointestinal discomfort and leukopenia; nucleoside (acid) analogs may cause problems such as drug resistance and renal function damage; and the use of immunosuppressants will increase the risk of infection in patients. Third, the causes of liver fibrosis are complex and diverse, including viral infections, alcohol intake, metabolic disorders, autoimmunity, etc. The pathological mechanisms of liver fibrosis caused by different causes are different, and the disease heterogeneity is significant, resulting in uneven treatment effects of the same drug in different patients, and the lack of accurate molecular typing and biomarkers to guide personalized treatment. Fourth, the treatment cycle of liver fibrosis is long and requires long-term medication. Whether it is anti-fibrotic drugs or drugs for treating the cause, it brings a heavy economic burden to patients and their families, and also causes great pressure on social medical resources. Summary of the Invention

[0004] In view of the deficiencies of the existing technology, the present invention provides the application of compound CLT-28643 in the preparation of drugs for preventing and treating liver fibrosis. Through research, the present invention finds that compound CLT-28643 can specifically inhibit the integrin α5β1 signaling pathway, inhibit ductular reaction and improve liver function in liver fibrosis, and play an anti-fibrotic role by regulating cell senescence, cilia regeneration and inflammation-related signaling pathways. Therefore, it has the prospect of being developed into a drug for preventing and / or treating liver fibrosis. The application of the present invention is disclosed for the first time and is different from the known drug use of compound CLT-28643.

[0005] Specifically, the present invention relates to the following technical solutions: In the first aspect of the present invention, there is provided the application of compound CLT-28643 and its derivatives in the preparation of drugs for preventing and / or treating liver fibrosis.

[0006] In the present invention, the prevention and / or treatment of liver fibrosis is specifically manifested as: (a) Inhibiting ductular reaction; (b) Improving liver function; (c) Inhibiting the expression of inflammation-related factors and inhibiting the inflammation of liver diseases; (d) Inhibiting the occurrence and development of liver fibrosis; (e) Inhibiting the formation of new blood vessels related to liver diseases.

[0007] According to the present invention, not only the application of compound CLT-28643 and its derivatives in the preparation of drugs for preventing and / or treating liver fibrosis is disclosed, but also it is disclosed that when administering a combination of compound CLT-28643 and its derivatives with at least one other pharmaceutically active ingredient, this effect can be enhanced. As an alternative or supplement to other pharmaceutically active ingredients, compound CLT-28643 and its derivatives can also be used in combination with other non-pharmaceutically active ingredients.

[0008] In view of this, in the second aspect of the present invention, there is provided a pharmaceutical composition for preventing and / or treating, said pharmaceutical composition being composed of compound CLT-28643 and its derivatives and at least one other pharmaceutically active ingredient and / or at least one other non-pharmaceutically active ingredient.

[0009] In the third aspect of the present invention, there is provided a method for preventing and / or treating liver fibrosis-related diseases, said method comprising: administering to a subject a therapeutically effective dose of compound CLT-28643 and its derivatives or the above-mentioned pharmaceutical composition.

[0010] In the present invention, the liver fibrosis-related diseases include but are not limited to hepatitis mediated by liver fibrosis, cirrhosis, liver failure, liver cancer, etc. No specific limitation is made here.

[0011] Beneficial technical effects of the above technical solutions: The above technical solution applies compound CLT-28643 to the treatment of liver fibrosis. The experimental results of the inhibitory effect on bile duct reaction show that compared with the mouse bile duct ligation (BDL) model group, the bile duct reaction in the CLT-28643 treatment group is significantly reduced, indicating that it can effectively inhibit the bile duct reaction; Mechanistically, it may be related to reducing the pathological changes associated with liver fibrosis. Specifically, a decrease in the degree of fibrosis can be observed through Sirius red and Masson staining.

[0012] In addition, in the mouse BDL model, serum liver function indexes (ALT, AST, ALP) and bilirubin metabolism indexes (TBIL, DBIL, TBA) are significantly down-regulated after CLT-28643 treatment, indicating that CLT can improve liver function abnormalities caused by acute cholestasis.

[0013] Through the study of key signaling pathways, it is shown that CLT-28643 treatment can down-regulate the expression of Integrin β1 gene, inhibit the inflammatory signaling pathway, and up-regulate the expression of cilia-related genes (such as Dnal1, Ift57), indicating that it can reduce liver fibrosis by inhibiting inflammatory factors and promoting cilia regeneration, and participate in the repair of the liver.

[0014] Compared with existing drugs, CLT-28643 has better safety. The side effects of existing drugs cannot be ignored. Long-term use of colchicine may cause adverse reactions such as gastrointestinal discomfort and leukopenia; nucleoside (nucleotide) analogs may cause problems such as drug resistance and renal function damage; and the use of immunosuppressants will increase the risk of infection in patients. The mechanism of action of CLT-28643 is relatively precise, specifically targeting the key targets of liver fibrosis and causing less interference to other normal physiological functions. This provides better safety guarantee for its long-term use in humans, is conducive to improving the treatment compliance of patients, and ensures the smooth implementation of the treatment plan.

[0015] From the perspective of treatment precision, due to the heterogeneity of liver fibrosis diseases, the efficacy of existing drugs varies greatly among individuals. CLT-28643 targets the core pathogenic mechanism of liver fibrosis and theoretically may be effective for different subtypes of liver fibrosis. This provides a more extensive and effective treatment option for patients with different types of liver fibrosis, breaking the treatment dilemma caused by disease heterogeneity.

[0016] In addition, CLT-28643 has good economy. If CLT-28643 can effectively control the condition of liver fibrosis in the early stage, it can reduce the need for advanced complex treatment methods (such as liver transplantation) in the late stage and reduce the overall medical cost. On the other hand, with the development of technology, if large-scale production is achieved, its cost-benefit ratio may be better than that of existing expensive anti-fibrosis drugs, promising to reduce the long-term economic burden of patients, improve the accessibility of drugs, and benefit more patients.

[0017] In summary, CLT-28643 demonstrates multiple advantages in the treatment of liver fibrosis. Whether it is the treatment effect on the disease itself or in terms of safety, precision, and economic cost, it is of great significance and brings new hope to patients with liver fibrosis. The above technical solution opens up a new drug use for the compound CLT-28643, so it has good practical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The accompanying drawings forming a part of this invention are used to provide a further understanding of the invention. The schematic embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0019] Figure 1 For Example A of the present invention: Establishment of bile duct ligation model and treatment with CLT-28643 (CLT); B: Sirius red and Masson staining. Scale bar: 25 μm.

[0020] Figure 2 For Example of the present invention: Serum biochemical detection of liver function in mice in the bile duct ligation model and the effect of treatment with CLT-28643 (CLT).

[0021] Figure 3 Expression profile analysis of BDL and BDL+CLT in the embodiments of the present invention. A: PCA graph; B: Sample correlation coefficient graph; C: Expression of Integrin α5 and β1.

[0022] Figure 4 KEGG analysis in the embodiments of the present invention to compare the top 20 signaling pathways between BDL and normal control. The red arrow indicates inflammation-related.

[0023] Figure 5 KEGG analysis in the embodiments of the present invention of the effect of CLT on the signaling pathways of BDL.

[0024] Figure 6 GO analysis in the embodiments of the present invention of the effect of CLT on the ciliary pathway of the signaling pathways of BDL and BDL+CLT. Among them, A is the signaling pathway analysis of BDL and BDL+CLT; B is the expression result of cilia-related genes. Detailed implementation manners

[0025] It should be noted that the following detailed description is exemplary and is intended to provide further illustration of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which this application belongs.

[0026] It should be noted that the terms used herein are only for describing specific implementation manners and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0027] The present invention will be further described in conjunction with specific examples. The following examples are only for explaining the present invention and do not limit its content. If the specific experimental conditions are not indicated in the examples, they are usually in accordance with conventional conditions or the conditions recommended by the sales company; the materials, reagents, etc. used in the examples can be obtained through commercial channels without special instructions.

[0028] As introduced in the background art, in the prior art, there has been no report on the application of the compound CLT-28643 in the treatment of liver fibrosis so far.

[0029] In view of this, in a typical specific implementation manner of the present invention, there is provided the use of the compound CLT-28643 and its derivatives in the preparation of drugs for preventing and / or treating liver fibrosis. And thus, CLT-28643 is effective in preventing and / or treating diseases related to liver fibrosis.

[0030] The compound CLT-28643 of the present invention is an effective and specific α5β1-Integrin inhibitor (CAS No.: 1153631-91-4), and its structural formula is as follows: 。

[0031] According to the present invention, the concept of "prevention and / or treatment" means any measure applicable to the treatment of liver fibrosis-related diseases, or preventive treatment for such manifested diseases or symptoms, or avoidance of recurrence of such diseases, such as recurrence after the end of the treatment period or treatment of the symptoms of the already developed disease, or pre-interventional prevention or inhibition or reduction of the occurrence of such diseases or symptoms.

[0032] In another specific embodiment of the present invention, there is provided the use of CLT-28643 or a composition or preparation containing CLT-28643 in the preparation of a drug for preventing and / or treating liver fibrosis.

[0033] In the present invention, the prevention and / or treatment of liver fibrosis is specifically manifested as: a) inhibiting the ductular reaction; b) improving liver function; c) inhibiting the expression of inflammation-related factors and inhibiting the inflammation of liver diseases; d) inhibiting the occurrence and development of liver fibrosis; e) inhibiting the formation of new blood vessels related to liver diseases.

[0034] Among them, the improvement of liver function and the prevention of the progression and deterioration of liver diseases are specifically manifested as: reducing the expression of liver enzyme indexes and reducing the indexes of bilirubin and bile acid metabolism; Among them, the liver enzyme indexes include but are not limited to ALT, AST and ALP; the bilirubin, bile acid, liver protein, fat and sugar metabolism indexes include but are not limited to TBIL, DBIL, TBA, albumin, and plasma plasminogen, etc.

[0035] The inflammation-related factors include TNF-a and IL-17 and other inflammatory cell chemotactic factors and inflammatory cell activation factors, including but not limited to interleukins, chemokine CXC subfamily and CC subfamily. Through research, the present invention finds that the reduction of the inflammation level can not only relieve the progression of liver fibrosis and improve the quality of life of patients, but also reduce the continuous damage of inflammation to liver tissues and further prevent the deterioration of liver fibrosis.

[0036] According to the present invention, not only the use of the compound CLT-28643 in the preparation of a medicament for preventing and / or treating liver fibrosis is disclosed, but also it is disclosed that when the compound CLT-28643 is administered in combination with at least one other pharmaceutically active ingredient, this effect can be enhanced. As an alternative or supplement to other pharmaceutically active ingredients, the compound CLT-28643 can also be used in combination with other non-pharmaceutically active ingredients.

[0037] In another specific embodiment of the present invention, there is provided a single drug, pharmaceutical composition or combination for preventing and / or treating liver fibrosis, and the pharmaceutical composition or combination is composed of the compound CLT-28643 and at least one other pharmaceutically active ingredient and / or at least one other non-pharmaceutically active ingredient.

[0038] In the sense of the present invention, the pharmaceutical composition according to the present invention refers to a substance in which the compound CLT-28643 contained therein has the effects of inhibiting ductular reaction, improving immune response, improving liver function, inhibiting inflammatory reaction, inhibiting the occurrence and development of liver fibrosis and / or inhibiting the formation and development of new blood vessels.

[0039] In another specific embodiment of the present invention, the other pharmaceutically active ingredients include substances having the effects of inhibiting ductular reaction, improving immune response, improving liver function, inhibiting inflammatory reaction, inhibiting the occurrence and development of liver fibrosis and / or inhibiting the formation and development of new blood vessels, or assisting in inhibiting ductular reaction, improving immune response, improving liver function, inhibiting inflammatory reaction and / or inhibiting the occurrence and development of liver fibrosis and / or inhibiting the formation and development of new blood vessels.

[0040] In another specific embodiment of the present invention, the other non-pharmaceutically active ingredients include pharmaceutically acceptable excipients, carriers, diluents or excipients. The excipients and / or carriers can be targeting substances or bioactive substances.

[0041] Suitable excipients are known to those skilled in the art, and the present invention provides non-limiting examples of suitable excipients. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors known to those skilled in the art, including, but not limited to, the method of administration. For example, oral dosage forms such as tablets may contain excipients that are not suitable for parenteral dosage forms. The suitability of a particular excipient also depends on the specific active ingredient in the dosage form. For example, the decomposition of some active ingredients may be accelerated by certain excipients such as lactose or when in contact with water. Active ingredients containing primary and secondary amines are particularly sensitive to such accelerated decomposition. Accordingly, the pharmaceutical compositions or dosage forms provided by the present invention, if any, contain little lactose or other mono- or di-saccharides. As used in the present invention, the term "lactose-free" means that, if any, the amount of lactose present is substantially insufficient to increase the degradation rate of the active ingredient. In one embodiment, the lactose-free composition comprises the active ingredient provided by the present invention, a binder / filler, and a lubricant. In another embodiment, the lactose-free dosage form comprises the active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0042] The pharmaceutical composition containing the above CLT-28643 in the present invention can be administered in unit dosage form. The dosage form can be a liquid dosage form or a solid dosage form. The liquid dosage form can be a true solution type, a colloid type, a particulate dosage form, an emulsion dosage form, or a suspension dosage form. Other dosage forms such as tablets, capsules, dripping pills, aerosols, pills, powders, solutions, emulsions, granules, suppositories, lyophilized powder injections, inclusion compounds, landfill agents, patches, liniments, large volume infusions, small volume infusions, etc.

[0043] The compounds provided by the present invention can be administered alone or in combination with one or more other compounds provided by the present invention. The combination methods include, but are not limited to, simultaneous co-administration and sequential administration.

[0044] In yet another specific embodiment of the present invention, a method for preventing and / or treating liver fibrosis-related diseases is provided, the method comprising: administering to a subject a therapeutically effective dose of the compound CLT-28643 and its derivatives or the above-mentioned single drug, pharmaceutical composition, or combination.

[0045] The liver fibrosis-related diseases include, but are not limited to, hepatitis mediated by liver fibrosis, cirrhosis, liver failure, drug-induced liver diseases, trauma-induced liver diseases, liver diseases caused by other diseases, and liver cancer, etc.

[0046] The liver fibrosis-related diseases include, but are not limited to, infectious liver and non-infectious liver diseases; the liver diseases include, but are not limited to, acute and chronic liver diseases.

[0047] The subject refers to an animal that has been the object of treatment, observation or experiment, preferably a mammal, and most preferably a human. The "therapeutically effective amount" refers to the amount of an active compound or agent, including the compounds of the present invention, that can cause a tissue system, biological or medical response in an animal that is sought by a researcher, veterinarian, doctor or other medical personnel, which includes alleviating or partially alleviating the symptoms of a disease, syndrome, disorder or condition being treated. It must be recognized that the optimal dosage and interval of administration of the active ingredient described in the present invention are determined by its nature and external conditions such as the form, route and site of administration and the particular mammal being treated, and this optimal dosage can be determined by conventional techniques. It must also be recognized that the optimal course of treatment, i.e., the daily dosage of the compound over a specified period of time, can be determined by methods well known in the art.

[0048] The technical solution of the present invention will be further described below in conjunction with specific embodiments.

[0049] Example 1) Effect of CLT-28643 on bile duct response To detect the effect of CLT-28643 (CLT) on liver fibrosis, CLT was intraperitoneally injected every other day starting from 2 days after surgery for a total of 10 days, and then the liver was removed for section staining, and EpCAM+ cells were isolated for organoid culture ( Figure 1 A). Sections of mouse liver tissue were stained with Sirius red and Masson to show the degree of fibrosis ( Figure 1 B). The results showed that compared with the BDL group, the bile duct response in the CLT treatment group was greatly reduced, suggesting an inhibitory effect on bile duct response.

[0050] 2) Response of liver function to CLT-28643 (CLT) treatment in a liver fibrosis model Serum from the BDL and control groups was collected after the experiment was completed and analyzed for changes in liver function. The results showed that liver enzymes including ALT, AST and ALP were upregulated in BDL and downregulated after administration of CLT. Similarly, bilirubin and bile acid metabolism indicators TBIL, DBIL and TBA all showed the same trend. However, the changes in ALB and γ-GT were not significant ( Figure 2 ). The results suggest that CLT-28643 treatment improves liver function in acute cholestasis, but further experiments at different time points are needed to determine its role throughout the acute cholestasis process.

[0051] 3) Effect of CLT-28643 (CLT) treatment on key signaling pathways in a liver fibrosis model To understand the effect of CLT-28643 (CLT) treatment on regeneration in acute hepatic cholestasis, we isolated EpCAM+ cells from the livers of the above different groups and cultured them into cholangiolar organoids. After 2 weeks of in vitro culture, expression profiling (RNA-seq) was performed for analysis. The PCA plot showed certain differences in the expression profiles of BDL and BDL+CLT ( Figure 3 A), but the correlation analysis showed that the differences among the groups were not particularly obvious, suggesting that this acute model only partially changed the liver expression profile ( Figure 3 B). Meanwhile, both Integrinα5 and β1 genes were expressed, and CLT downregulated the expression of β1 ( Figure 3 C).

[0052] 3.1) Effect of BDL on biliary inflammation Compared with the normal control group, KEGG analysis showed that inflammatory signaling pathways still accounted for the main factors in BDL, such as bacterial infection, viral infection, TNF-a, and IL-17 pathways (indicated by red arrows) ( Figure 4 ).

[0053] 3.2) Changes in the BDL signaling pathway by CLT-28643 (CLT) treatment in the liver fibrosis model - Cellular senescence Comparing BDL+CTL with the control group BDL+PBS, the results of KEGG analysis found that CTL might reduce fibrosis by inhibiting the cellular senescence pathway (red arrow). Cellular senescence, as an important cellular response in biliary epithelial cell inflammation fibrosis, especially leading to ductular reaction (DR), inhibiting its activity is of great significance for reducing inflammatory response and alleviating fibrosis. One of the methods to reduce cellular senescence is to inhibit the cell cycle (Cell cycle), which is also reflected in Figure 5 (green arrow), and the in-depth mechanism exploration is underway.

[0054] 3.3) Changes in the BDL signaling pathway by CLT-28643 (CLT) treatment in the liver fibrosis model - Cilium changes DBL caused ciliary damage. For example, in the genes downregulated by BDL, the Ciliary Plasma pathway changed ( Figure 6 Left panel of A, yellow arrow); however, after administration of CLT, many cilia-related genes were upregulated ( Figure 6 Right panel of A, blue-black arrow), and in molecular function (MF), many cilia-related signaling pathways were also upregulated. For the expression of some genes in the pathway, such as Dnal1 and Ift57, it could be seen that they were downregulated in the BDL group but upregulated after CLT treatment ( Figure 6 B). The results showed that CLT upregulated cilia genes and functions, which had an improvement effect on cilia regeneration.

[0055] The above analysis of preliminary results shows the reparative effects of CLT-28643 on the cholangiolar response to acute cholestasis caused by DBL and the damaged cilia. Analyses at the protein level and ultrastructural analyses are in progress. Completion of these experiments will facilitate the progress of the project.

[0056] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Use of compound CLT-28643 and its derivatives in the preparation of a medicament for preventing and / or treating liver fibrosis.

2. The application according to claim 1, characterized in that The prevention and / or treatment of liver fibrosis is specifically manifested as: (a) Inhibiting ductular reaction; (b) Improving liver function; (c) Inhibiting the expression of inflammation-related factors and suppressing the inflammation of liver diseases; (d) Inhibiting the occurrence and development of liver fibrosis; (e) Inhibiting the formation of new blood vessels related to liver diseases.

3. The application according to claim 2, characterized in that, The improvement of liver function, prevention of the progression and deterioration of liver diseases is specifically manifested as: reducing the expression of liver enzyme indexes, as well as reducing bilirubin and bile acid metabolism indexes; further, the liver enzyme indexes include but are not limited to ALT, AST and ALP; the bilirubin, bile acid, liver protein, fat, and sugar metabolism indexes include but are not limited to TBIL, DBIL, TBA, albumin and plasma plasminogen.

4. The application according to claim 2, wherein The inflammation-related factors include TNF-a, IL-17 and other inflammatory cell chemotactic factors, inflammatory cell activation factors, including but not limited to interleukins, chemokine CXC subfamily and CC subfamily.

5. A single drug, pharmaceutical composition or combination for preventing and / or treating liver fibrosis, characterized in that, The pharmaceutical composition is composed of compound CLT-28643 and its derivatives and at least one other pharmaceutically active ingredient and / or at least one other non-pharmaceutically active ingredient.

6. The pharmaceutical composition according to claim 5, characterized in that, The administration methods of CLT-28643 and other pharmaceutically active ingredients include but are not limited to co-administration and sequential administration.

7. The pharmaceutical composition according to claim 5, characterized in that, The other pharmaceutically active ingredients include substances having the effects of inhibiting ductular reaction, improving immune response, improving liver function, inhibiting inflammatory response, inhibiting the occurrence and development of liver fibrosis and / or inhibiting the formation and development of new blood vessels, or assisting in inhibiting ductular reaction, improving immune response, improving liver function, inhibiting inflammatory response and / or inhibiting the occurrence and development of liver fibrosis and / or inhibiting the formation and development of new blood vessels.

8. The pharmaceutical composition according to claim 5, wherein The other non-pharmaceutically active ingredients include pharmaceutically acceptable excipients and / or carriers; further, the excipients and / or carriers are targeting substances or bioactive substances.

9. A method for preventing and / or treating liver fibrosis-related diseases, characterized in that, The method includes: administering a therapeutically effective dose of compound CLT-28643 and its derivatives or the single drug, pharmaceutical composition or combination according to any one of claims 5-8 to a subject.

10. The method according to claim 9, wherein The liver fibrosis-related diseases include but are not limited to hepatitis mediated by liver fibrosis, cirrhosis, liver failure, drug-induced liver diseases, trauma-induced liver diseases, liver diseases caused by other diseases and liver cancer; Further, the liver fibrosis-related diseases include but are not limited to infectious liver and non-infectious liver diseases; Further, the liver diseases include but are not limited to acute and chronic liver diseases; The subject refers to an animal that has already been the object of treatment, observation or experiment, preferably a mammal, and most preferably a human.

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