Application of AC1903 in preparation of medicine for treating and preventing neutrophil asthma

Abstract

The invention belongs to the technical field of biological medicines, and discloses application of AC1903 in preparation of drugs for treating and preventing neutrophil asthma. The invention provides the application of the TRPC5 inhibitor (especially AC1903 or pharmaceutically acceptable salt thereof) in preparation of drugs for preventing and / or treating asthma (especially neutrophil asthma) for the first time. Experiments prove that by intraperitoneal injection of AC1903, the wheezing symptom of a TDI asthma mouse can be remarkably relieved, the airway hyperreactivity, the airway surrounding inflammation level, the total number of inflammatory cells in the airway and the neutrophil count of the TDI asthma mouse are relieved, and secretion of type-2 cytokines and type-17 cytokines of alveolar lavage fluid of the asthma mouse is inhibited. The traditional Chinese medicine composition has a good treatment effect on asthma and has no obvious toxic or side effect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to the use of AC1903 in the preparation of a drug for treating and preventing neutrophilic asthma. BACKGROUND

[0002] Asthma remains a pressing global health problem. The latest estimates show that about 400 million people worldwide are affected by asthma. Although glucocorticoids are the cornerstone of asthma treatment, 5% to 20% of patients have a poor response to high-dose glucocorticoid therapy and are diagnosed as having severe asthma. Severe asthma has a higher morbidity and mortality, and places a heavy economic burden on the global medical system. Occupational-related factors account for about 15% to 33% of new adult asthma cases, but the diagnosis of this disease is still often delayed, which leads to a gradual decline in lung function and a poorer prognosis. Toluene diisocyanate (TDI) is one of the main causes of occupational asthma, and it can induce mixed granulocyte inflammation, which is characterized by a predominance of neutrophils, with a low involvement of eosinophils. Notably, this inflammatory phenotype shows low sensitivity to systemic and inhaled glucocorticoids. Therefore, finding drugs for neutrophilic asthma is crucial for advancing the clinical management of severe asthma. AC1903 (N-(2-furanylmethyl)-1-(phenylmethyl)-1H-benzimidazol-2-amine) is a specific and selective inhibitor of TRPC5 (transient receptor potential canonical channel 5). The molecular formula of the compound is C 19 H 17 N3O, the molecular weight is 303.36, the CAS registration number is: 831234-13-0, and the chemical structure is . Previous literature reports that it can reduce glomerulonephritis in animal models. So far, there has been no report on the use of AC1903 in the treatment of neutrophilic asthma, and the known properties cannot infer the use of AC1903 in the treatment and prevention of neutrophilic asthma. SUMMARY

[0003] The first aspect of the present application aims to provide the use of a TRPC5 inhibitor in the preparation of a drug for preventing and / or treating asthma.

[0004] In order to achieve the above-mentioned purpose, the technical solution adopted by the present application is as follows: The first aspect of the present application provides the use of a TRPC5 inhibitor in the preparation of a drug for preventing and / or treating asthma.

[0005] In some embodiments of the present application, the asthma includes neutrophilic asthma airway inflammation induced by toluene diisocyanate.

[0006] In some embodiments of the present application, the drug achieves the purpose of treating asthma by inhibiting the secretion of inflammatory factors and / or reducing airway inflammatory cell infiltration, reducing airway epithelial shedding.

[0007] In some embodiments of the present application, the inflammatory factors include at least one of IL-4, IL-5, IL-13, and IL-6.

[0008] In some embodiments of the present application, the TRPC5 inhibitor includes AC1903 or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments of the present application, the pharmaceutically acceptable salt includes an organic acid salt or an inorganic acid salt.

[0010] In some embodiments of the present application, the organic acid salt includes an acetate salt, a maleate salt, a fumarate salt, a tartrate salt, a succinate salt, a lactate salt, a p-toluenesulfonate salt, a salicylate salt, or an oxalate salt.

[0011] In some embodiments of the present application, the inorganic acid salt includes a hydrochloride salt, a sulfate salt, a phosphate salt, a diphosphate salt, a hydrobromide salt, or a nitrate salt.

[0012] In some embodiments of the present application, the drug further includes a pharmaceutically acceptable excipient.

[0013] In some embodiments of the present application, the pharmaceutically acceptable excipient includes at least one of a filler, a disintegrant, a diluent, a lubricant, a binder, a humectant, a flavoring agent, a suspending agent, a solvent, a sustained-release agent, an emulsifying agent, an absorption enhancer, a surfactant, a preservative, a pigment, an essence, and a solvent.

[0014] In some embodiments of the present application, the filler is selected from starch, sucrose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, or glucose, etc.; the binder is selected from cellulose derivatives, alginates, starch, water, dextrin, gelatin, or polyvinylpyrrolidone, etc.; the disintegrant is selected from microcrystalline cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, or cross-linked sodium carboxymethyl cellulose; the lubricant is selected from stearic acid, polyethylene glycol, calcium carbonate, sodium bicarbonate, microfine silica, talc, or magnesium stearate; the suspending agent is selected from microfine silica, beeswax, cellulose, solid polyethylene glycol; the wetting agent is selected from glycerol, Tween-80, hydrogenated castor oil, or lecithin; the solvent is selected from ethanol, liquid polyethylene glycol, isopropyl alcohol, Tween-80, glycerol, propylene glycol, or vegetable oil, the vegetable oil is selected from soybean oil, castor oil, peanut oil, blended oil, etc.; the surfactant is selected from sodium dodecylbenzenesulfonate, stearic acid, polyoxyethylene-polyoxypropylene copolymer, fatty acid sorbitan, or polysorbate (Tween), etc.; the flavoring agent is selected from aspartame, sucralose, essence, stevioside, acesulfame potassium, citric acid, or saccharin sodium; the preservative is selected from at least one of methyl paraben or propyl paraben.

[0015] In some embodiments of the present application, the dosage form of the composition is a gastrointestinal administration dosage form or a non-gastrointestinal administration dosage form.

[0016] In some embodiments of the present application, the gastrointestinal administration dosage form includes at least one of a powder, a tablet, a granule, a capsule, a sustained-release agent, a solution, a dry suspension, an effervescent tablet, an emulsion, a suspension, a syrup, a drop, a chewable tablet.

[0017] In some embodiments of the present application, the non-gastrointestinal administration dosage form includes at least one of an injection administration dosage form, a respiratory administration dosage form, a skin administration dosage form, a mucous membrane administration dosage form, a cavity administration dosage form.

[0018] In some embodiments of the present application, the dosage form of the composition is an oral agent or an injection agent.

[0019] In some embodiments of the present application, the dosage form of the composition is any one of a powder, a granule, a tablet, a capsule, a gel, a suspension, a drop, a dripping pill, an injection, a suppository, an aerosol, an oral liquid, a paste, an emulsion, an irrigation agent.

[0020] In some embodiments of the present application, the effective dose of AC1903 or a pharmaceutically acceptable salt thereof in the drug is 15-60 mg / kg (of the subject); further 20-60 mg / kg (of the subject); still further 25-50 mg / kg (of the subject).

[0021] The beneficial effects of the present application are: The present application first proposes the use of TRPC5 inhibitors (especially AC1903 or a pharmaceutically acceptable salt thereof) in the preparation of a drug for preventing and / or treating asthma (especially neutrophilic asthma). Experiments have proved that by intraperitoneal injection of AC1903, the wheezing symptoms of TDI asthma mice can be significantly reduced, the airway hyperresponsiveness, airway peripheral inflammation level, total number of inflammatory cells in the airway, and neutrophil count of TDI asthma mice can be reduced, and the secretion of type 2 cytokines and type 17 cytokines in the bronchoalveolar lavage fluid of asthma mice can be inhibited. It is suggested that it has a good therapeutic effect on asthma and has no obvious toxic side effects.

[0022] The present application provides a new treatment idea for neutrophilic asthma, which is a clinically difficult disease type to treat, and is expected to improve the limitations of existing treatment methods, improve the quality of life of patients, and has important clinical value and social significance. BRIEF DESCRIPTION OF DRAWINGS

[0023] The present application will be further described below in combination with the drawings and examples, in which: Figure 1 AC1903 can significantly improve TDI-induced airway hyperresponsiveness and airway inflammation; wherein A is the HE staining of lung tissue sections of each group of mice, the original magnification under the microscope is 200x, and the scale is 100 μm; B is the HE staining of BALF smears of each group of mice, the original magnification under the microscope is 100x, and the scale is 200 μm; C-D are the HE staining of lung tissue sections of each group of mice, the airway peripheral inflammation (C) and the semi-quantitative score of perivascular inflammation (D), n = 5-8; E is a semi-quantitative analysis of the proportion of airway epithelial shedding of each group of mice, n = 5-8; F-H, the BALF inflammatory cells (F), neutrophils (G), and eosinophil counts (H) of each group of mice, n = 5-8; I is the total IgE level of each group of mice serum, n = 5-8; J is the airway resistance (lung resistance, R L ) indicates that the results are expressed as a percentage of the baseline value; n = 5. In the figure, .

[0024] Figure 2 AC1903 can inhibit TDI asthma Th2 / Th17 immune imbalance; wherein A is the Th2 cytokine (IL-4, IL-5, IL-13) level in the BALF of each group of mice; n = 5-8; B is the IL-6 level in the BALF of each group of mice; n = 5-8; C is the IL-1β, IL-18 level in the BALF of each group of mice; n = 5-8. In the figure, .

[0025] Figure 3AC1903 can inhibit airway mucus hypersecretion in TDI-induced asthmatic mice; wherein, A is glycogen staining of lung tissue sections of mice in each group, magnification under microscope is 200x and 1000x, and the scale is 100 μm and 20 μm, respectively; B is muc5ac immunohistochemical staining of lung tissue sections of mice in each group, magnification under microscope is 200x and 1000x, respectively, and the scale is 100 μm and 20 μm, respectively; C is semi-quantitative analysis of PAS staining; n = 5-8; D is semi-quantitative analysis of muc5ac positive area of airway epithelium of mice in each group; n = 5-8; E is mRNA level of mice in each group; n = 5-8; F is expression level of muc5ac in bronchoalveolar lavage fluid of mice in each group; n = 5-7. In the figure, muc5ac . .

[0026] Figure 4 Effect of AC1903 on airway inflammation in normal mice; wherein, A is HE staining of lung tissue sections of mice in each group, original magnification under microscope is 200x, and the scale is 100 μm; B is HE staining of BALF smears of mice in each group, original magnification under microscope is 400x, and the scale is 200 μm; C-F are BALF inflammatory cell count (C), neutrophil count (D), eosinophil count (E) and serum total IgE level (F) of mice in each group, n = 3-5. DETAILED DESCRIPTION

[0027] The concept and technical effects of the present application will be described below in combination with examples, so as to fully understand the purpose, features and effects of the present application. Obviously, the described examples are only a part of the examples of the present application, but not all the examples. Based on the examples of the present application, other examples obtained by those skilled in the art without creative labor are within the protection scope of the present application.

[0028] The specific conditions not mentioned in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments not mentioned by the manufacturer are all conventional products that can be obtained by market purchase.

[0029] The features and properties of the present application will be further described in combination with examples below.

[0030] Example 1 Evaluation of the role of AC1903 in the treatment and prevention of TDI-induced neutrophilic asthma airway inflammation Experimental materials 1. Experimental animals: 6-8 week old BALB / c mice (20-22 g) 2. Solution preparation Preparation of TDI (toluene diisocyanate) sensitizing solution and challenge solution: TDI sensitizing solution: 600 μL olive oil and 400 μL acetone were mixed in a 1.5 mL Ep tube, and 3 μL of pure TDI solution was added to prepare a TDI sensitizing solution with a concentration of 0.3%. The mixed solvent of olive oil and acetone with a volume ratio of 3:2 was used as a control.

[0031] TDI challenge solution: 12 mL of olive oil and 3 mL of acetone were added to a 15 mL centrifuge tube, and the tube was covered with a centrifuge tube cover and gently inverted to mix thoroughly. Before adding TDI, 450 μL of solvent was removed, and 450 μL of TDI was added to prepare a TDI challenge solution with a final concentration of 3%. The mixed solvent of olive oil and acetone with a volume ratio of 4:1 was used as a control.

[0032] 3. Intervention drug: AC1903 (content not less than 99%) was purchased from Selleck Company, and was first prepared into a storage solution with a concentration of 100 mg / mL using DMSO. Before use, the storage solution was diluted with PBS to a working solution with a concentration of 2.5 mg / mL (DMSO content was 2.5%), and was used for intervention at a concentration of 25 or 50 mg / kg per mouse.

[0033] Experimental method 1. Experimental grouping: All mice were randomly divided into 4 groups, namely: control group: 5-8, olive oil + acetone (3:2) sensitization and olive oil + acetone (4:1) challenge, no intervention group; TDI group: 5-8, TDI sensitization and challenge, intraperitoneal injection of 2.5% DMSO PBS group; TDI + AC1903 (25 mg / kg) group: 5-8, TDI sensitization and challenge, intraperitoneal injection of AC1903 (25 mg / kg) intervention group; TDI + AC1903 (50 mg / kg) group: 5-8, TDI sensitization and challenge, intraperitoneal injection of AC1903 (50 mg / kg) intervention group.

[0034] 2. Modeling and processing: According to the previous method, the TDI asthma mouse model was established (Chen S, Yao L, Huang P, He Q, Guan H, Luo Y, Zou Z, Wei S, Peng G, Yan J, Chen R, Zhang Q, Tao A. Blockade of the NLRP3 / Caspase-1 Axis Ameliorates Airway Neutrophilic Inflammation in a Toluene Diisocyanate-Induced Murine Asthma Model. Toxicol Sci. 2019; 170(2):462-475.): 0.3% TDI was used to contact the skin of the back of the mouse ears on days 1 and 8 for sensitization, and 3% TDI was inhaled by atomization for challenge on days 15, 18, and 21 (the control group used the corresponding challenge liquid). After each challenge, AC1903 (25 mg / kg, 50 mg / kg) was injected intraperitoneally, and the mice were euthanized on day 22. Lung tissue, bronchoalveolar lavage fluid (BALF), and other samples were collected. Bronchoalveolar lavage fluid smears and lung tissue sections were stained with HE to detect asthma bronchoalveolar lavage fluid inflammatory factors, airway peripheral inflammation levels, total number of inflammatory cells in the airway, and neutrophil count.

[0035] Bronchoalveolar lavage (BAL) and cell differential count, cell smear staining: (1) Bronchoalveolar lavage: After blood collection, the mouse was fixed on the operating table, and the tracheal anterior fascia and muscle were separated layer by layer with forceps to expose the trachea. A 22G indwelling needle was used for tracheal intubation, and a suture was used for fixation. A 1 mL syringe was used to draw 0.8 mL of normal saline (preheated to 37°C) and connect it to the indwelling needle. The lungs were lavaged slowly and evenly twice, and the lavage fluid was collected into a 1.5 mL Ep tube. The recovery rate was about 85%, and the procedure was repeated twice to collect 1.4 mL of lavage fluid. (2) Cell count: After mixing the bronchoalveolar lavage fluid, 10 μL of the lavage fluid was dropped onto a cell counting plate, and the total number of cells was counted under a microscope. (3) Cell smear: The remaining bronchoalveolar lavage fluid was placed in a centrifuge with the following parameters: room temperature, 1500 rpm, 10 min. The supernatant was stored in a -80°C freezer for later use. The bottom cells were resuspended with 50 μL of normal saline and evenly spread on a glass slide. After natural drying, they were fixed in 4% paraformaldehyde for 30 minutes. Then, hematoxylin-eosin staining was performed, and the cells were counted according to their morphology and staining (at least 200 cells per sample).

[0036] Lung histopathology examination: (1) Take and fix: After completing the alveolar lavage, the indwelling needle is inserted into the left main bronchus, and a syringe containing 0.3 mL of 4% paraformaldehyde solution is quickly connected, and the fixing solution is injected for internal fixation. Then the left lung is removed by clamping the left lung hilum with forceps and immersing it in 4% paraformaldehyde. (2) Dehydration: The lung tissue is fixed for at least 24 hours, then dehydrated by gradient alcohol (75% ethanol immersion for 20 minutes x 2 times, 85% ethanol immersion for 20 minutes x 2 times, 95% ethanol immersion for 20 minutes x 2 times, anhydrous ethanol immersion for 15 minutes x 2 times), xylene transparency (xylene immersion for 15 minutes x 2 times), and wax immersion (soft paraffin for 15 minutes x 2 times). The lung tissue is observed to be hard and not brittle, indicating that the dehydration effect is relatively ideal. (3) Embedding: The lung tissue is placed in melted hard paraffin, and the tissue block is completely immersed in paraffin for embedding. (4) Sectioning: The wax block is placed in a -20°C refrigerator for 2 hours to make it hard, which is beneficial for sectioning. Then the embedded wax block is fixed in the sample slot, and thin sections of 4 μm are cut. (5) Unfolding and fishing: The cut thin sections are unfolded in warm water at 42°C, then fished onto a glass slide, and naturally air-dried. (6) Baking and deparaffinization: The glass slide is placed in a 60°C constant temperature oven for 3 hours to completely dissolve the paraffin, then deparaffinized in the order of xylene immersion for 20 minutes x 2 times, anhydrous ethanol immersion for 5 minutes x 2 times, 95% ethanol immersion for 5 minutes x 2 times, 85% ethanol immersion for 5 minutes x 2 times, 75% ethanol immersion for 5 minutes x 2 times, and deionized water for 5 minutes. At this time, the lung tissue sample on the glass slide can be used for the next step of staining. (7) Hematoxylin-eosin (HE) staining: The glass slide is immersed in hematoxylin solution for 1 minute, then observed under a microscope after washing with running water for 1 minute. The cell nucleus is blue and the cell plasma is colorless, indicating good staining effect, which can be directly eosin-stained. If the cell plasma is obviously blue-stained, it needs to be differentiated with hydrochloric acid alcohol differentiation solution until the cell nucleus is blue and the cell plasma is colorless. If the cell nucleus is not colored enough, it needs to be immersed in hematoxylin staining solution again. The above steps are repeated until the cell nucleus is blue and the cell plasma is almost colorless. Then the glass slide is immersed in eosin staining solution for 30 seconds, washed with running water for 5 seconds, and observed under a microscope. The cell nucleus is stained blue and the cell plasma is stained red. The stained section is dehydrated with anhydrous ethanol and transparentized with xylene, then sealed with neutral balsam, and observed under a microscope.

[0037] The multiplex immunoassay (eBioscience) and ELISA method were used to detect the factors in BALF and lung tissue homogenate, including IL-4, IL-5, IL-13, IL-17A, IL-6, and IL-18. The principle of the experiment is as follows: the fluorescence-encoded microspheres are covalently cross-linked with monoclonal antibodies, and after binding with the target factors to be detected, the fluorescence-labeled detection antibodies are added, and then the single microspheres are identified by laser scanning fluorescence coding and the fluorescence intensity is measured to determine the concentration of the detected factors. Under the condition of using the same antibody pair, the measurement results of multiplex immunoassay can reach a similar level in accuracy, precision, and sensitivity as ELISA. The fluorescence-encoded microspheres applied have specific antibodies for different target factors, and different microspheres can be freely combined to a certain extent, so that multiple target molecules can be analyzed at the same time in one experiment. The specific detection steps are as follows: (1) After the standard sample is taken out, 50 μL of Universal Assay Buffer is added after centrifugation at 2000 g for 10 seconds; mix gently, mix all standard samples, add Universal Assay Buffer to 250 μL, and stand on ice; (2) Take out the PCR 8-tube, dilute the standard sample by 4-fold dilution method, and stand on ice; (3) vortex the microspheres for 30 seconds, and add 50 μL of the mixed microspheres to each well of the experimental titration plate; (4) wash the plate: place the magnetic plate washer on the plate for 2 minutes to let the microspheres settle; connect the Wash buffer to wash the microspheres, and set the parameters to 200 μL / well, wash 3 times; (5) add 25 μL of Universal Assay Buffer to each well, and then add 25 μL of standard sample or sample to the designated wells; seal the well plate, shake at 500 rpm at room temperature in the dark for 60-120 minutes; (6) wash the plate (same as (4)); then add 25 μL of detection antibody mixture; seal the well plate, shake at 500 rpm at room temperature in the dark for 30 minutes; (7) wash the plate (same as (4)); then add 50 μL of Streptavidin-Phycoerythrin; seal the well plate, shake at 500 rpm at room temperature in the dark for 30 minutes; (8) wash the plate (same as (4)); then add 120 μL of Reading Buffer; seal the well plate, shake at 500 rpm at room temperature in the dark for 5 minutes to make the microspheres suspended; (9) place the plate into Luminex 200™ to read the fluorescence value; (10) save and analyze the MFI results, calculate the concentration of each cytokine in the sample, and perform statistical analysis.

[0038] The method used in this experiment is a typical double antibody sandwich enzyme-linked immunosorbent assay (ELISA). The brand is Biolegend (IL-1β); all need to be coated with antibodies. Preparation before detection: (1) Take out the ELISA kit (IL-1β) the day before the experiment, dilute the Capture antibody according to the corresponding kit instructions, add 100 μL per well to the 96-well microplate, label and seal the film, and incubate at 4°C overnight; (2) Take out the mouse BALF, lung homogenate or serum samples from the -80°C freezer, completely dissolve and place on ice for standby; Take out the ELISA kit from the 4°C refrigerator, and equilibrate at room temperature for 30 minutes; (3) Biotin-labeled antibody working solution (Detection Antibody): Dilute the antibody storage solution to 1x working solution with antibody diluent (4) Streptavidin-HRP working solution (Streptavidin-HRP): Dilute the Streptavidin-HRP storage solution to 1x working solution with diluent; (5) Wash solution TBS: Dilute 25x TBS with double distilled water to 1x TBS wash solution.

[0039] Detection process: (1) Take out the pre-coated plate, discard the liquid in the well, and wash the plate 2 times with an automatic plate washer (300 μL per well), add Blocking Buffer 250 μL, seal the film, and shake at room temperature for 2 hours; (2) Prepare the standard: Dissolve the recombinant mouse IL-1β standard according to the kit instructions; then dilute the standard in order of concentration gradient, and the last well in the same row only adds diluent as the zero well; (3) Add 100 μL of diluted standard or sample to be tested to each well, seal the plate, and shake at room temperature for 90 minutes; after the reaction, shake off the liquid in the enzyme-labeled plate, and wash the plate 3 times with a plate washer; (4) Add 100 μL of diluted Detection Antibody working solution to each well in turn, seal the plate, and shake at room temperature for 60 minutes; wash the plate 3 times with a plate washer, each time for about 1 minute; (5) Add 100 μL of Streptavidin-HRP working solution to each well in turn, seal the plate, and shake at room temperature for 60 minutes; (6) Wash the plate 3 times with a plate washer, each time for about 1 minute; add 100 μL of TMB color developing solution to each well, and react at room temperature for 25-30 minutes; (7) Add 100 μL of stop solution to each well, at which time the blue color immediately changes to yellow; (8) Measure the OD value at 450 nm with an enzyme-labeled instrument; set the TMB blank color developing well as the control. Subtract the absorbance value of this well from all absorbance values to obtain data that can be directly fitted to the standard curve; (9) Find the corresponding concentration on the coordinates according to the absorbance value of the sample.

[0040] Experimental results (1) Observation of clinical symptoms TDI group mice began to scratch symptoms after 2 sensitization, TDI challenge began to appear after the first wheezing, reduced activity, as the number of increased, wheezing symptoms gradually increased. And TDI + AC1903 (25 mg / kg) group and TDI + AC1903 (50 mg / kg) group of mice than TDI symptoms were significantly reduced, and there was no significant difference between the two groups.

[0041] (2) Lung tissue HE staining and alveolar lavage fluid inflammatory cell count TDI exposure can lead to a large number of mice around the airway neutrophils, a small amount of eosinophilic infiltration, airway epithelial cell shedding. Intraperitoneal injection of AC1903 (25 mg / kg and 50 mg / k) can reduce TDI asthma mice airway hyperresponsiveness, airway inflammation levels, airway inflammation cell count, neutrophil count (P <0.05). Figure 1

[0042] Further detection of 25 mg / kg AC1903 on the influence of asthma alveolar lavage fluid inflammatory factors, the results show that 25 mg / kg of AC1903 can inhibit the secretion of asthma mice alveolar lavage fluid 2 type cytokines, 17 type cytokines (P <0.05). Figure 2 At the same time, AC1903 can inhibit airway mucus hypersecretion (P <0.05). Figure 3 In addition, in animal models, AC1903 can inhibit airway collagen deposition and eosinophilic inflammation (P <0.05). Figure 1 H), but because the TDI asthma model is mainly neutrophilic inflammation mixed granulocytic asthma animal model, so the inventors believe that it can effectively inhibit neutrophilic inflammation, to achieve the purpose of treating asthma.

[0043] Example 2 Evaluation of AC1903 in the treatment of asthma safety This example in the experimental process using 50 mg / kg AC1903 injection to ordinary 6-8 weeks BALB / c mice, as a parallel control experiment, to investigate the safety of AC1903 in the treatment of asthma, as follows: in the experimental 15, 18, 21 days intraperitoneal injection of AC1903 (50 mg / kg), the 22nd day euthanasia mice, collection of lung tissue, alveolar lavage fluid (BALF) and other samples, alveolar lavage fluid smear and lung tissue sections were stained with HE, detection of asthma alveolar lavage fluid airway inflammation cell count, neutrophil count. The experimental results are shown in Figure 4 , 50 mg / kg AC1903 on the airway inflammation, airway cells and other indicators of ordinary mice no effect, indicating that AC1903 has good safety.​

[0044] The embodiments of the present application are described in detail above with reference to the accompanying drawings, but the present application is not limited to the above-described embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present application. Furthermore, the embodiments of the present application and the features in the embodiments can be combined with each other without conflict.

Claims

1. Use of a TRPC5 inhibitor in the preparation of a medicament for preventing and / or treating asthma.

2. Use according to claim 1, characterized in that, The asthma includes neutral granulocyte asthma airway inflammation induced by toluene diisocyanate.

3. Use according to claim 1 or 2, characterized in that, The TRPC5 inhibitor includes AC1903 or a pharmaceutically acceptable salt thereof.

4. Use according to claim 3, characterized in that, The pharmaceutically acceptable salt includes an organic acid salt or an inorganic acid salt.

5. Use according to claim 4, characterized in that, The organic acid salt includes an acetate, a maleate, a fumarate, a tartrate, a succinate, a lactate, a p-toluenesulfonate, a salicylate or an oxalate; and the inorganic acid salt includes a hydrochloride, a sulfate, a phosphate, a diphosphate, a hydrobromide or a nitrate.

6. The use according to any one of claims 1 to 2, 4 to 5, characterized in that, The medicament achieves the purpose of treating asthma by inhibiting secretion of inflammatory factors and / or reducing inflammatory cell infiltration, reducing airway epithelial shedding.

7. Use according to claim 6, characterized in that, The inflammatory factors include at least one of IL-4, IL-5, IL-13 and IL-6.

8. Use according to claim 6, characterized in that, The medicament further includes a pharmaceutically acceptable excipient.

9. Use according to claim 8, characterized in that, The pharmaceutically acceptable excipient includes at least one of a filler, a disintegrant, a diluent, a lubricant, a binder, a humectant, a flavoring agent, a suspending agent, a solvent, a sustained-release agent, an emulsifying agent, an absorption enhancer, a surfactant, a preservative, a pigment, an essence and a solvent.

10. Use according to claim 3, characterized in that, The effective dose of AC1903 or the pharmaceutically acceptable salt thereof in the medicament is 15-60 mg / kg.

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