Application of gaboxadol or pharmaceutically acceptable salt thereof in preparation of medicine for treating hepatic fibrosis diseases

Abstract

The invention discloses application of gaboxadol or a pharmaceutically acceptable salt thereof in preparation of a medicine for treating liver fibrosis diseases, and belongs to the technical field of biological medicines, and research shows that the compound can influence collagen fiber crosslinking through targeted inhibition of the function of prolyl-4-hydroxylase a1 (prolyl-4-hydroxylase alpha 1, P4ha1), so that the anti-fibrosis effect is achieved. The invention further discloses an application of the gaboxadol or the pharmaceutically acceptable salt thereof in preparation of the medicine for treating the liver fibrosis diseases, and the application of the gaboxadol or the pharmaceutically acceptable salt thereof in preparation of the medicine for treating the liver fibrosis diseases and the application of the gaboxadol or the pharmaceutically acceptable salt thereof in preparation of the medicine for treating the liver fibrosis diseases. In a carbon tetrachloride induced mouse hepatic fibrosis model, the content of hydroxyproline and collagen deposition in I-type collagen molecules of the liver can be remarkably reduced by injecting the gaboxadol hydrochloride into the intraperitoneal cavity, and the hardness of the liver is reduced. A surface plasma resonance experiment proves that the probe has specific binding capacity with P4ha1. Toxicity experiments show that the compound is good in safety under the effective dosage. Therefore, the invention provides a new drug candidate and a theoretical basis for the treatment of hepatic fibrosis.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, and in particular relates to the use of gabosadol or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of liver fibrosis. Background Technology

[0002] Abnormal synthesis and cross-linking of collagen molecules are core pathological features of fibrotic diseases (such as liver fibrosis). Collagen molecules are helical structures with extremely high tensile strength formed by three intertwined peptide chains with glycine-XY repeating sequences. The hydroxylation modification of proline residues at the "Y" site is crucial for the stability of the triple helix structure of collagen molecules and for the cross-linking to form functional collagen fibers.

[0003] Prolyl-4-hydroxylase alpha 1 (P4ha1) is a key collagen-modifying enzyme responsible for this process. It hydroxylates proline at the "Y" site of the glycine-XY repeat sequence in collagen to form 4-hydroxyproline, strengthening the cross-linking between collagen fibers and further increasing tissue stiffness, thus exacerbating the progression of liver fibrosis. Currently, there are no specific inhibitors targeting P4ha1, a limitation that restricts the advancement of related research and clinical translation. Against this backdrop, developing small-molecule drugs that target and inhibit P4ha1 function has significant clinical application value and is expected to become an effective strategy and focus for reversing liver fibrosis, while also providing some reference for the treatment of fibrosis in other organs.

[0004] Although several drugs with anti-liver fibrosis efficacy have entered clinical trials, most have toxic side effects and have failed to meet clinical trial endpoints. For example, potential anti-fibrosis candidates that once attracted significant industry attention, including Selonsertib, Simtuzumab, Emricasan, Elafibranor, Obeticholic Acid, Aldafermin, Seladelpar, EDP-305, and Centicriviroc, have all failed in clinical development for liver fibrosis caused by metabolic dysfunction-associated steatohepatitis (MASH) due to multiple reasons such as failure to meet efficacy endpoints, safety issues, or poor benefit-risk ratios. Resmetirom (trade name Rezdiffra), a selective thyroid hormone receptor-β (THR-β) agonist, was approved by the FDA on March 14, 2024, for the treatment of adult patients with non-cirrhotic MASH and intermediate-to-advanced liver fibrosis (F2-F3 stages). This is the world's first approved treatment for MASH. However, to date, no drugs have been marketed that directly target the core component of liver fibrosis: collagen fiber cross-linking. Therefore, developing new anti-liver fibrosis drugs based on "targeting and inhibiting P4ha1 function to affect collagen fiber cross-linking" has significant research and application value.

[0005] Gaboxadol hydrochloride, chemical formula C6H9ClN2O2, is a potent... GABA receptor A (aminobutyric acid A type receptor) A receptor agonists and GABA-C receptor (GABA) C GABA receptor antagonists are often used as tool compounds in neuroscience research. A GABA receptors are widely distributed in the brain and are the main inhibitory receptors. Animal models have shown that their activation can inhibit neuronal firing, maintain the excitation-inhibition balance of neural networks, and play a role in regulating anxiety, sedation, memory, and motor control (rats, 5, 6, 15 mg / kg body weight). CThe receptor is mainly located in the retina, and its main function is to regulate visual signal processing (such as contrast and light adaptation), affecting visual perception. This receptor is expressed at extremely low levels in the central nervous system, and its sedative effect was not found in animal models of gamboxadol hydrochloride-induced hypnosis. Gabboxadol hydrochloride was previously developed by the US biopharmaceutical company Ovid Therapeutics as a Phase III clinical trial drug, aiming to improve sleep disorders associated with Angelman Syndrome, a rare neurodevelopmental disorder. However, it did not achieve the expected efficacy in the Phase III clinical trial and was not approved for the treatment of insomnia in humans. Therefore, research on gamboxadol hydrochloride is currently still in the laboratory stage and has not yet been approved as a clinical drug. Existing literature also does not report any findings regarding gamboxadol or its salts alleviating liver fibrosis. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention proposes the application of gabosadol or its pharmaceutically acceptable salts in the preparation of drugs for treating liver fibrosis. Furthermore, the degree of fibrosis is assessed using morphological indicators and physiological and biochemical parameters, thereby determining the role of gabosadol hydrochloride in the treatment of liver fibrosis and providing a theoretical basis for clinical trials.

[0007] To achieve the above objectives, the present invention provides the following technical solution: The use of gaposadol or its pharmaceutically acceptable salts in the preparation of medicaments for the treatment of liver fibrosis.

[0008] Beneficial effects: This invention reveals the clear mechanism of action of Gaboxadol or its pharmaceutically acceptable salt (gaboxadol hydrochloride) in treating liver fibrosis. Its core lies in targeting and inhibiting P4ha1 function, thereby affecting the key link of collagen fiber cross-linking, and is used to treat liver fibrosis.

[0009] Optionally, the chemically acceptable salt of the gapository is gapository hydrochloride, with the following structural formula: .

[0010] Optionally, the drug exerts its anti-fibrotic effect by targeting and inhibiting P4ha1 function to affect collagen fiber crosslinking.

[0011] Optionally, the route of administration of the drug may include intraperitoneal injection.

[0012] Furthermore, the dosage of the drug is 0.75-3 mg / kg body weight.

[0013] Furthermore, the dosage of the drug is 0.75 mg / kg body weight, 1.5 mg / kg body weight, or 3 mg / kg body weight.

[0014] Optionally, the drug may also include pharmaceutically acceptable excipients, carriers, and excipients.

[0015] Optionally, the dosage form of the drug includes injections, tablets, capsules, or sustained-release formulations.

[0016] Compared with the prior art, the present invention has the following advantages and technical effects: This invention discloses the effects of gaposadol hydrochloride (CAS Registry No. 85118-33-8) administered intraperitoneally for three consecutive weeks (0.75 mg / kg body weight, 1.5 mg / kg body weight, or 3 mg / kg body weight) on carbon tetrachloride (CCl4)-induced liver fibrosis in ICR mice. Experimental results show that intraperitoneal administration of this compound significantly improved the pathological state of CCl4-induced liver fibrosis, decreased the hydroxyproline content in type I collagen molecules, reduced intrahepatic collagen deposition, and decreased liver stiffness. Attached Figure Description

[0017] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1 Serological levels and liver tissue sections of mice after administration of different doses of gambogodiol hydrochloride are shown in Figure A. A shows the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in mice of each dose group. B shows liver tissue sections of mice of each dose group.

[0018] Figure 2 This study presents the results of hydroxyproline content per mole of type I collagen molecules in liver tissue after therapeutic administration of different doses of sorbitol hydrochloride in a CCl4-induced fibrosis mouse model.

[0019] Figure 3 The images show transmission electron microscopy (A) and statistical results of collagen fibrillary diameter after different doses of hydrochloride plus borsadol in a CCl4-induced fibrosis mouse model.

[0020] Figure 4 Images of liver tissue sections after different doses of therapeutic administration of hydrochloride and borsadol in a CCl4-induced fibrosis mouse model are shown. A represents a Sirius red staining image of the liver, and B shows the statistical results of the fibrotic area in the liver sections.

[0021] Figure 5 The results show the liver stiffness after different doses of therapeutic administration of boraxadione hydrochloride in a CCl4-induced fibrosis mouse model.

[0022] Figure 6 To investigate the binding affinity of gabosadol hydrochloride to P4ha1 using surface plasmon resonance (SPR) technology. Detailed Implementation

[0023] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0024] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0025] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0026] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0027] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0028] This invention provides the use of gaboroxadol or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating liver fibrosis, wherein the pharmaceutically acceptable salt of gaboroxadol is gaboroxadol hydrochloride, the structural formula of which is shown in Formula 1: Formula 1 All raw materials used in this invention were purchased from the market.

[0029] The technical solution of the present invention will be further illustrated by the following embodiments.

[0030] The following detailed description illustrates the specific implementation method: This experiment was approved by the Ethics Committee of Capital Medical University. All experimental data are expressed as mean ± standard error. SPSS 25 statistical software was used to analyze the experimental results. Independent samples t-test was used for comparisons between two groups, and one-way ANOVA was used for comparisons among multiple groups. A p-value < 0.05 was considered statistically significant.

[0031] Example 1 Toxicity Test All animals used in the experiment were fed a normal diet and had free access to water and food. Five mice per cage were housed in an SPF-grade animal room at the Capital Medical University Experimental Animal Center, at (20±2)℃, with 12 hours of light and 12 hours of darkness. After a week of acclimatization, the mice were randomly divided into four groups and given four doses (0, 0.75 mg / kg body weight, 1.5 mg / kg body weight, and 3 mg / kg body weight) of gambogia hydrochloride. Mice in the 0-dose group received an equal volume of PBS solution. All mice were administered the medication intraperitoneally twice a week for three weeks. On day 21, the mice were sacrificed for tissue sampling. Prior to sacrifice, the mice were fasted for 6 hours but given regular water access.

[0032] ALT and AST levels in the serum of the mice were detected using an ALT and AST detection kit (Nanjing Jiancheng, Nanjing, China). Before use, solutions R1 and R2 from the kit were prepared at a ratio of 200 µL:50 µL and preheated at 37°C. 10 µL of the serum sample and a blank control (physiological saline) were placed in a 96-well microplate, and 250 µL of the R1 and R2 mixture was added. After mixing, the OD value was measured at 340 nm, and the OD values ​​and detection time points were recorded continuously over 6 minutes. Enzyme activity = (OD change per minute - Blank OD change) × 1746. Final results are expressed as mean ± standard error. The experiment was repeated three times.

[0033] Test results as follows Figure 1 As shown in Figure A, it can be seen that, compared with normal mice (0 dose group), administration of gambogia hydrochloride at doses of 0.75 mg / kg body weight, 1.5 mg / kg body weight, and 3 mg / kg body weight had no significant effect on serum ALT and AST levels, indicating that gambogia hydrochloride has no negative impact on liver function and has high biosafety.

[0034] Liver tissues from each group of mice were further collected for pathological sections, and liver damage was assessed using hematoxylin-eosin (H&E) staining. The H&E staining procedure is as follows: (1) Routine dewaxing of paraffin sections: xylene I for 10 minutes, xylene II for 10 minutes, 100% ethanol for 3-5 minutes, 100% ethanol for 3-5 minutes, 95% ethanol for 3-5 minutes, 90% ethanol for 3-5 minutes, 80% ethanol for 3-5 minutes, 70% ethanol for 3-5 minutes, 50% ethanol for 3-5 minutes, and distilled water for 2 minutes; (2) H&E staining: 1) Immerse the dewaxed sections in hematoxylin staining solution for 5 minutes; 2) Immerse the slices in 0.5% hydrochloric acid alcohol for 5 seconds for color separation; 3) After rinsing the slices in tap water for 15 minutes, soak them in distilled water for a short time; 4) Immerse the sections in eosin staining solution for 10 minutes; (3) Rinse with tap water; (4) Gradient alcohol dehydration: 50% ethanol for 3-5 minutes, 70% ethanol for 3-5 minutes, 80% ethanol for 3-5 minutes, 90% ethanol for 3-5 minutes, 95% ethanol for 3-5 minutes, 100% ethanol for 3-5 minutes, 100% ethanol for 3-5 minutes; (5) Immerse the slices in xylene I for 10 minutes, then in xylene II for 10 minutes; (6) Seal with neutral resin to avoid air bubbles.

[0035] The results of pathological section observation of mice in each group are as follows: Figure 1 As shown in Figure B, the hepatocytes of mice in each group were regular in morphology, uniform in size, and neatly arranged. The hepatocyte nuclei were normal in morphology, with uniform chromatin distribution, no mitotic figures or abnormal nucleoli, and no obvious signs of inflammatory cell infiltration, fibrosis, or fibrosis. This indicates that administration of gaboxetine hydrochloride at doses of 0.75 mg / kg body weight, 1.5 mg / kg body weight, and 3 mg / kg body weight had no toxic side effects on the liver of normal organisms and demonstrated high safety.

[0036] Example 2: Determination of hydroxyproline content in type I collagen molecules All animals used in the experiment were fed a normal diet and had free access to water and food. Five mice per cage were housed in an SPF-grade animal room at the Experimental Animal Center of Capital Medical University at (20±2)℃, with 12 hours of light and 12 hours of darkness. After a week of acclimatization, the mice were randomly divided into two groups: CCl4 and CCl4 + borsadol hydrochloride. CCl4 was used to induce liver fibrosis in mice by intraperitoneal injection of CCl4 [CCl4 / olive oil = 1:9 (v / v)] at a dose of 1 mL / kg body weight, twice a week for four weeks. One week after CCl4 injection, the CCl4 + borsadol hydrochloride group received intraperitoneal injections of borsadol hydrochloride twice a week at doses of 0.75 mg / kg body weight, 1.5 mg / kg body weight, or 3 mg / kg body weight. On day 28 after intraperitoneal injection of CCl4, the mice were sacrificed for tissue collection. They were fasted for 6 hours before sacrifice but were given regular water.

[0037] The hydroxyproline content in type I collagen molecules in mouse liver tissue was detected using an ELISA kit (BioSwamp, Wuhan, China). This experiment consisted of two parts. The first part was a type I collagen immunoprecipitation assay. Dynabeads Protein G magnetic beads were suspended, and 10 µL was aspirated and washed twice with 1 mL PBS. After the last wash, the PBS was aspirated dry, and 100 µL PBS was added. Type I collagen antibody was added at a 1:50 ratio. The mixture was incubated at 4°C with gentle shaking for 2-4 hours, followed by three washes with 1 mL PBS, discarding the supernatant. Prepared liver tissue / cell protein samples were added, and the mixture was incubated overnight at 4°C with gentle shaking. The mixture was washed five times with 1 mL PBS, discarding the supernatant. Each wash was performed at 4°C with gentle shaking for 5 minutes. The mixture was then resuspended in 100 µL PBS, gently mixed, and boiled at 99°C for 5 minutes to release the antigen (type I collagen). The hydroxyproline content in type I collagen molecules was then detected according to the instructions, following these steps: Add 40 µL of sample to an ELISA plate and 10 µL of biotin-labeled anti-hydroxyproline antibody. Add enzyme: Add 50 µL of enzyme-labeled reagent to each well, except for blank wells. Seal the plate with sealing film and incubate at 37°C for 30 minutes. Remove the sealing film, discard the liquid, fill each well with washing buffer, let stand for 30 seconds, then discard. Repeat this process 5 times. Add 50 µL of chromogenic reagent A to each well, then add 50 µL of chromogenic reagent B, gently vortex to mix, and incubate at 37°C in the dark for 10 minutes. Add 50 µL of stop solution to each well to stop the reaction (the blue color turns yellow). Within 15 minutes, measure the absorbance (OD value) of each well sequentially at 450 nm wavelength, and calculate the hydroxyproline content in the sample based on the standard curve. The type I collagen content in an equal volume of liver tissue was detected using a type I collagen ELISA kit (CUSABIO, Wuhan, China), and the final results are presented as the hydroxyproline content per mole of type I collagen molecule.

[0038] The results are as follows Figure 2 As shown, compared with the CCl4 group mice, the content of hydroxyproline in type I collagen molecules in the liver of mice decreased after administration of the compound gaboxard hydrochloride, showing a dose-dependent effect, indicating that gaboxard hydrochloride has a significant therapeutic effect on liver fibrosis.

[0039] Example 3: Determination of Collagen Fibrillar Diameter Liver tissue samples were fixed in 2.5% glutaraldehyde at 4°C for 2 hours, then washed three times with 0.1 mol / L phosphate buffer (PB solution) for 10 minutes each time. Afterward, they were fixed in 1% osmium tetroxide at 4°C for 2 hours, followed by three washes of 0.1 mol / L PB solution for 15 minutes each time. The samples were dehydrated in a gradient of 30% to 100% ethanol solutions (30%, 50%, 70%, 80%, and 90%, 10 minutes each; 100%, 10 minutes, three times), and then washed twice with propylene oxide for 10 minutes each time. The samples were gradually embedded in a mixture of SPON 812 and propylene oxide (1:1 and 3:1 ratios), followed by polymerization in pure SPON 812 at 37°C for 12 hours, 45°C for 12 hours, and 60°C for 48 hours. After double staining with uranium acetate and lead citrate, 70 nm ultrathin sections were observed using transmission electron microscopy, and the diameter of collagen fibrils was measured and quantified using ImageJ software.

[0040] The results are as follows Figure 3 As shown in the figure, compared with the CCl4 group mice, the diameter of collagen fibrils was significantly smaller after administration of the compound hydrochloride plus borsadol.

[0041] Example 4 Sirius Red Staining Liver tissues from each group of mice were collected for pathological sections, and the degree of liver fibrosis was assessed using Sirius red staining. The Sirius red staining procedure is as follows: (1) Routine dewaxing of paraffin sections: xylene I for 10 minutes, xylene II for 10 minutes, 100% ethanol for 3-5 minutes, 100% ethanol for 3-5 minutes, 95% ethanol for 3-5 minutes, 90% ethanol for 3-5 minutes, 80% ethanol for 3-5 minutes, 70% ethanol for 3-5 minutes, 50% ethanol for 3-5 minutes, and distilled water for 2 minutes; (2) Place the sections in 0.1% Sirius red staining solution and stain at 37°C for 30 minutes; (3) Rinse with tap water; (4) Gradient alcohol dehydration: 50% ethanol for 3-5 minutes, 70% ethanol for 3-5 minutes, 80% ethanol for 3-5 minutes, 90% ethanol for 3-5 minutes, 95% ethanol for 3-5 minutes, 100% ethanol for 3-5 minutes, 100% ethanol for 3-5 minutes; (5) Place the slices in xylene I for 10 minutes, then in xylene II for 10 minutes; (6) Seal with neutral resin to avoid air bubbles.

[0042] (7) Image analysis of liver tissue fibrosis: The liver tissue sections were observed and photographed under an optical microscope. Ten different fields of view were randomly selected from each liver tissue section, and the fibrotic areas were analyzed using ImageJ image analysis software. The specific operation was as follows: First, the total area S0 of each field of view was calculated. Next, the total fibrous area S1 of the field of view was circled (red blood vessels were not included in S1). Then, the blank area S2 of the field of view (mainly the blank area of ​​blood vessel sections) was circled. The quantitative value of fibrosis in the field of view was calculated according to the formula for fibrosis area. Finally, the average value of the fibrosis values ​​of all fields of view for each section was calculated as the quantitative value of each section. The formula for fibrosis area is as follows: ; The observation and statistical results of liver tissue sections of mice in each group are as follows: Figure 4 As shown in the figure, there is significant collagen fiber deposition in the liver of mice in the CCl4 group, while there is less collagen fiber deposition in mice in the CCl4 + borsadol hydrochloride group. This indicates that after administration of the compound borsadol hydrochloride, the collagen fiber deposition in mice is reduced accordingly, suggesting that borsadol hydrochloride has a significant therapeutic effect on liver fibrosis.

[0043] Example 5: Determination of Liver Tissue Stiffness The changes in stiffness in mouse liver tissue in Example 2 were detected using atomic force microscopy. The detection steps are as follows: Frozen liver sections (5 μm thick) from each group of mice were immersed in PBS solution containing protease inhibitors and placed on the stage of an atomic force microscope. An MLCT probe (6 levers, 0.01–0.5 N / m) was lowered onto the tissue sample. The probe tip of the cantilever was 50 × 50 μm. 2 Two-dimensional scanning was performed on the samples within the region. For each indentation, the indentation velocity was 20.3 μm / s, and the indentation depth was 50–80 nm. Three randomly selected regions were probed for each sample, and the hardness data were analyzed using NanoScope Analysis 1.9 software.

[0044] The results of stiffness detection in the liver tissue of mice in each group are as follows: Figure 5 As shown in the figure, compared with the CCl4 group mice, the CCl4 + hydrochloric acid plus borsadol group mice had significantly reduced liver stiffness.

[0045] Example 6 Surface Plasmon Resonance (SPR) Experiment SPR experiments were performed using a Biacore T200 instrument (GE Healthcare, Uppsala, Sweden). All SPR-based materials were purchased from Cytiva (Uppsala, Sweden). Purified P4ha1 protein was immobilized on a CM5 chip (Cytiva, BR100530) using an amine conjugation kit. Interaction analysis was performed using run buffer [PBS (pH 7.4) containing 0.05% Tween-20]. Small molecule drugs (hydrochloride plus borsadol) were prepared serially at two-fold dilutions using run buffer as the solvent. A reference flow cell without immobilized P4ha1 served as a non-specific binding control. The equilibrium constant (KD) was calculated using the "affinity" model in Biacore T200 evaluation software version 2.0.

[0046] Test results as follows Figure 6 As shown, it can be seen that gabosadol hydrochloride has a good binding ability with the target protein P4ha1.

[0047] The above experiments demonstrate that, through SPR technology (Example 6), this invention directly confirms that gabardine hydrochloride can specifically bind to P4ha1, exhibiting good affinity. This molecular interaction is the starting point for its pharmacological action. Based on this, in vivo experiments further validated the biological effects of this action: Inhibition of collagen deposition: In a mouse model of CCl4-induced liver fibrosis, administration of gabosadol hydrochloride significantly reduced the hydroxyproline content in type I collagen molecules in liver tissue (Example 2), indicating inhibition of P4ha1 activity; transmission electron microscopy revealed a decrease in the diameter of collagen fibrils (Example 3), proving that collagen fiber cross-linking was affected; Sirius red staining showed a significant reduction in the area of ​​fibrotic regions (Example 4), directly reflecting the reduction in collagen deposition.

[0048] Reducing liver tissue stiffness: Atomic force microscopy showed a significant decrease in liver tissue stiffness (Example 5).

[0049] Good safety profile: Within the effective dose range (0.75-3 mg / kg), it has no adverse effects on liver function and tissue structure in normal mice (Example 1), indicating that it has a wide therapeutic window.

[0050] In summary, the mechanism of action of this invention can be summarized as follows: Gabosadol specifically binds to and inhibits P4ha1 enzyme activity → blocks the 4-hydroxylation modification of collagen molecules → affects collagen fiber cross-linking and deposition → reduces liver tissue stiffness → thereby improving liver fibrosis. That is, this invention intervenes at a key upstream node in the formation of fibrosis, exhibiting higher specificity and potential efficacy, providing a novel molecular target and drug candidate for the treatment of liver fibrosis.

[0051] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. Use of a gabosadol or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of liver fibrosis.

2. The use of gapository or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating liver fibrosis, characterized in that, The pharmaceutically acceptable salt of gaboxado is gaboxado hydrochloride, with the following structural formula: 。 3. The use of gapository or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating liver fibrosis, characterized in that, The drug exerts its anti-fibrotic effect by targeting and inhibiting the function of prolyl-4-hydroxylase a1 to affect collagen fiber cross-linking.

4. The use of gapository or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating liver fibrosis, characterized in that, The drug can be administered via intraperitoneal injection.

5. The use of gapository or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating liver fibrosis, characterized in that, The dosage of the drug is 0.75-3 mg / kg body weight.

6. The use of gapository or a pharmaceutically acceptable salt thereof according to claim 5 in the preparation of a medicament for treating liver fibrosis, characterized in that, The dosage of the drug is 0.75 mg / kg, 1.5 mg / kg or 3 mg / kg body weight.

7. The use of gapository or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating liver fibrosis, characterized in that, In addition to the active ingredient, the drug also contains pharmaceutically acceptable excipients, carriers, or excipients.

8. The use of gapository or a pharmaceutically acceptable salt thereof according to claim 7 in the preparation of a medicament for treating liver fibrosis, characterized in that, The dosage forms of the drug include injections, tablets, capsules, or sustained-release formulations.

9. The use of gapository or a pharmaceutically acceptable salt thereof according to claim 8 in the preparation of a medicament for treating liver fibrosis, characterized in that, The drug is in the form of an injection.

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