Application of N-(4-methoxyphenyl)-4-(4-methoxyphenyl) benzenesulfonamide in preparation of drugs for treating allergic diseases

Abstract

The invention discloses an application of N-(4-methoxyphenyl)-4-(4-methoxyphenyl) benzenesulfonamide in preparation of drugs for treating allergic diseases, and belongs to the technical field of biological medicines. The invention discloses a new pharmaceutical application of N-(4-methoxyphenyl)-4-(4-methoxyphenyl) benzenesulfonamide for the first time, and the N-(4-methoxyphenyl)-4-(4-methoxyphenyl) benzenesulfonamide serving as an anti-allergic antagonist can effectively inhibit phospholipase C activity of stimulated cells and mediated calcium mobilization thereof in vitro. And the effective dose of the desloratadine, which is a positive drug, is lower in vivo to generate a comparable anti-allergic effect with the desloratadine. Meanwhile, in animal models of allergic rhinitis and atopic dermatitis, compared with a positive drug desloratadine, the compound can effectively inhibit the pathological progress of diseases at a lower dosage. Therefore, the compound has a definite effect of inhibiting in-vitro and in-vivo anaphylaxis, and can be effectively applied to the development of drugs for treating allergic diseases.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of N-(4-methoxyphenyl)-4-(4-methoxyphenyl)benzenesulfonamide in the preparation of drugs for treating allergic diseases. Background Technology

[0002] With changes in environmental and social factors, the global incidence of allergic diseases, such as allergic rhinitis and atopic dermatitis, continues to rise, becoming a significant public health challenge. Allergic diseases are a group of chronic illnesses caused by abnormal immune responses of the body's immune system to specific substances (allergens) in the external environment. Their core treatment follows three principles: avoiding allergen exposure, alleviating clinical symptoms, and modulating the immune response. Identifying and avoiding allergens through skin prick testing or serum-specific IgE testing is the cornerstone of effective prevention and control of allergic diseases. In terms of drug treatment, antihistamines (such as levocetirizine and desloratadine), corticosteroids (such as mometasone furoate and fluticasone), and leukotriene receptor antagonists (such as montelukast) constitute the current core therapies and are widely used for symptom control.

[0003] While existing antihistamines play a vital role in symptom control, they generally have limitations such as potential side effects and poor patient adherence. Regarding antihistamines, although third-generation antihistamines have largely overcome the central nervous system depressant defects of early drugs, they still carry the risk of cardiotoxicity, especially with overdose or concomitant use. Long-term, high-dose use of glucocorticoids can easily cause local adverse reactions (such as nasal dryness, bleeding, or Candida infection) and even lead to systemic risks, including growth inhibition and osteoporosis. Furthermore, due to factors such as genetic polymorphism and epigenetic regulation, drug efficacy exhibits significant individual differences, resulting in inconsistent clinical responses. Therefore, developing novel antagonists that combine high efficacy and safety to achieve more sustained and stable symptom control in patients with moderate to severe allergies is an important direction for the treatment of allergic diseases.

[0004] Benzylsulfonamides are an important class of drugs in the field of anti-allergy treatment. They exert their effects primarily through mechanisms such as blocking histamine H1 receptors and inhibiting the activation of inflammatory cells. Significant progress has been made in both clinical application and research and development. However, research on this class of drugs is still ongoing. In existing research on benzylsulfonamides for allergy treatment, there are currently no publicly reported studies on the structurally defined N-(4-methoxyphenyl)-4-(4-methoxyphenyl)benzenesulfonamide (referred to as compound Z27502564 in this article) in the treatment of allergic diseases. The potential application of this compound in the field of anti-allergy treatment remains to be explored. Summary of the Invention

[0005] The purpose of this invention is to provide, for the first time, the use of N-(4-methoxyphenyl)-4-(4-methoxyphenyl)benzenesulfonamide in the preparation of a medicament for treating allergic diseases.

[0006] To achieve the above objectives, the present invention employs the following technical solution: This invention discloses the use of N-(4-methoxyphenyl)-4-(4-methoxyphenyl)benzenesulfonamide (compound Z275025642) in the preparation of medicaments for the prevention and / or treatment of allergic diseases.

[0007] Preferably, the drug is a drug that inhibits histamine-mediated calcium mobilization.

[0008] Preferably, the drug is a drug that inhibits histamine-mediated PLC activity levels.

[0009] Preferably, the drug is a drug that can reduce the expression levels of inflammatory factors TNF-α, MCP-1, IL-8 and CXCL1.

[0010] Specifically, in vitro: Compound Z275025642 significantly reduced the levels of inflammatory factors TNF-α, MCP-1 and IL-8 in the supernatant of HUVEC cells.

[0011] Compound Z275025642 was able to prevent the gradual increase in the rate of decrease in transendothelial resistance (TEER) of HUVEC cells.

[0012] Compound Z275025642 can extend the cytoskeleton and promote the recovery of cell barrier function.

[0013] Specifically, within the body: Compound Z275025642 exhibits local anti-allergic effects (inhibiting swelling and exudation to varying degrees) and systemic anti-allergic effects (significantly inhibiting the levels of TNF-α, MCP-1, and CXCL1 in serum).

[0014] Preferably, the allergic disease is allergic rhinitis.

[0015] More preferably, the drug can reduce the inflammatory response and type 2 immune response in allergic rhinitis.

[0016] More preferably, the drug can restore the nasal functional barrier by reducing the proliferation of goblet cells in the nasal cavity.

[0017] Preferably, the allergic disease is allergic dermatitis.

[0018] More preferably, the drug can reduce the inflammatory response of allergic dermatitis.

[0019] More preferably, the drug can relieve symptoms of allergic dermatitis by inhibiting mast cell recruitment.

[0020] Compared with the prior art, the present invention has the following beneficial effects: This invention discloses for the first time a novel pharmaceutical use of N-(4-methoxyphenyl)-4-(4-methoxyphenyl)benzenesulfonamide (compound Z27502564). As an anti-allergic antagonist, it effectively inhibits phospholipase C activity and its mediated calcium mobilization in vitro, and produces an effective anti-allergic effect comparable to the positive control drug desloratadine at a lower dose in vivo. Furthermore, in animal models of allergic rhinitis and atopic dermatitis, this compound effectively inhibits the pathological progression of the disease at a lower dose. Therefore, this compound possesses a clear inhibitory effect on allergic reactions both in vitro and in vivo, and can be effectively applied to the development of drugs for allergic diseases. Attached Figure Description

[0021] Figure 1 Figure 1 shows the results of the targeting study of compound Z275025642. A represents the chemical structure of Z275025642. B shows the thermal stability of the complex after binding Z275025642 and H1R as determined by CETSA. C shows the quantitative analysis of H1R protein levels at different temperatures. D shows the enzymatic stability of the complex after binding Z275025642 and H1R as determined by DARTS. E shows the quantitative analysis of H1R protein levels under different enzymatic digestion conditions. F shows the molecular docking diagram of Z275025642 and H1R protein, with green representing H1R, purple representing Z275025642, and yellow dashed lines representing hydrogen bonding. G shows the 2D interaction diagram of Z275025642 and H1R protein. H shows the RMSD of the Z275025642-H1R complex during molecular dynamics simulation. I shows the RMSF of H1R protein during the binding of Z275025642 in molecular dynamics simulation. In the image, * p <0.05,** p <0.01.

[0022] Figure 2 This study investigated the in vitro pharmacodynamics of Z27502564; where A represents the IC50 value of Z275025642 inhibiting PLC activity in HUVEC cells after treatment with the concentration gradient. 50 The solution for the value; B is the change in fluorescence intensity of HUVEC cells after treatment with the concentration gradient Z275025642; C is the IC50 value of HUVEC cells inhibiting calcium mobilization after treatment with Z275025642. 50The values ​​are calculated as follows: DF represents the effect of Z275025642 on the levels of TNF-α (D), MCP-1 (E), and IL-8 (F) in the supernatant of HUVEC cells, respectively; G represents the change in transendothelial resistance (TEER) of HUVEC cells after treatment with Z275025642; H represents the effect of Z275025642 on the HUVEC cytoskeleton. In the figure, *** p <.0001.

[0023] Figure 3 The results of in vivo local and systemic anti-allergic studies of Z275025642 are shown. A shows the effect of Z275025642 on histamine-induced Evans blue exudation in the mouse paws (left paw injected with histamine, right paw injected with saline). B shows H&E staining of mouse paw skin (scale bar: 50 μm). C shows the statistical analysis of the swelling rate of mouse paws after Z275025642 inhibited histamine stimulation. D shows the statistical analysis of the Evans blue exudation rate in mice after Z275025642 inhibited histamine stimulation. E shows the inhibitory effect of Z275025642 on histamine-induced hypothermia in mice. F and H show the effects of Z275025642 on serum TNF-α (F), MCP-1 (G), and CXCL1 (H) in mice, respectively. * In the figures... p <0.05, *** p <.0001.

[0024] Figure 4 This study evaluates the in vivo anti-allergic rhinitis effect of Z275025642. A shows the flowchart of establishing and intervening in an animal model of allergic rhinitis. B shows the mouse body weight during Z275025642 treatment. C shows the number of times mice scratched their noses within 5 minutes after OVA stimulation following Z275025642 treatment. D shows the number of times mice sneezed within 5 minutes after OVA stimulation following Z275025642 treatment. E shows the changes in spleen index in different groups of mice. F shows the statistical analysis of eosinophil count in mouse blood. G and J represent the inhibition of TNF-α (G), MCP-1 (H), IL-13 (I), and IL-4 (J) levels in mouse nasal lavage fluid by Z275025642, respectively. K shows the H&E staining image of Z275025642 inhibiting nasal mucosal thickening in mice. Image L shows PAS staining of Z275025642 inhibiting goblet cell proliferation in mice. * In the image... p <0.05,** p <0.01, *** p <.0001.

[0025] Figure 5This study evaluates the in vivo anti-allergic dermatitis effect of Z275025642. A shows the flowchart of establishing and intervening in an animal model of allergic dermatitis. B shows the mouse body weight records during Z275025642 treatment. C shows the number of times mice scratched their ears within 30 minutes after DNCB stimulation following Z275025642 treatment. D shows the ear thickness measurement of mice after Z275025642 treatment. E shows photographs of the ears of mice in different groups. F shows the ADI score of the mouse ears. G shows the changes in spleen index in different groups of mice. H and J represent the inhibition of TPS (H), TSLP (I), and TNF-α (J) levels in mouse serum by Z275025642, respectively. K shows the statistical analysis of the epidermal layer thickness of mouse ear skin. L shows H&E staining images of mouse ear skin. M shows the statistical analysis of the dermal layer thickness of mouse ear skin. N shows toluidine blue staining images of mouse ear skin. O shows the statistical analysis of mast cell recruitment in mouse ear tissue. In the figures, *** p <.0001. Detailed Implementation

[0026] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0027] It should be noted that the terms "first," "second," etc., in the specification, claims, and accompanying drawings of this invention are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that such data can be interchanged where appropriate so that the embodiments of the invention described herein can be implemented in orders other than those illustrated or described herein. Furthermore, the terms "comprising" and "having," and any variations thereof, are intended to cover a non-exclusive inclusion; for example, a process, method, system, product, or apparatus that comprises a series of steps or units is not necessarily limited to those steps or units explicitly listed, but may include other steps or units not explicitly listed or inherent to such processes, methods, products, or apparatus.

[0028] The present invention will now be described in further detail with reference to the accompanying drawings: The structural formula of Z275025642 described in this invention is as follows:

[0029] The core structure of this molecule is biphenyl-4-sulfonamide, with a methoxy group (-OCH3) attached to the 4' position of the biphenyl group; the nitrogen atom (-SO2NH-) of the sulfonamide is attached to a 4-methoxyphenyl group; the overall structure shows that the biphenyl group has a methoxy group at one end, and the nitrogen atom of the sulfonamide is attached to another methoxyphenyl group.

[0030] The chemical formula of this molecule is C 20 H 19 NO4S, CAS: 670271-50-8; named N-(4-methoxyphenyl)-4-(4-methoxyphenyl)benzenesulfonamide, the English equivalent is: N-(4-methoxyphenyl)-4-(4-methoxyphenyl)benzenesulfonamide.

[0031] The Z275025642 used in the following embodiments of the present invention is supplied by Life Chemicals Stock HTSLibrary, synthesized thereand purchased, Cat.# HY-L0087V, Lot# 851232, Size: 50 mg.

[0032] Example 1: Targeting Study of Z27502564 1. Stability study of the complex of Z275025642 and H1R The study of Z275025642 (Cellular Thermal Shift Analysis) was conducted using the Cellular Thermal Shift Analysis (CETSA) method. Figure 1 Thermostability of the complex between Z275025642 and H1R. H1R-293T cells were seeded in 6-well plates and adhered overnight, then treated with Z275025642 (10 μmol / L, 37°C, 3 h). Cells were then digested and divided into 6 aliquots. Each aliquot was heated for 5 min at 6 temperature gradients from 37°C to 64°C, and then immediately cooled in an ice bath. Subsequently, the cells were subjected to three freeze-thaw cycles in liquid nitrogen, centrifuged at 12000 g for 10 min at 4°C, and the supernatant was collected. Protein concentration was determined using a BCA assay kit, and Western blot analysis was performed after adding loading buffer. The results showed that Z275025642 can target and bind to H1R, thus enhancing its thermostability. Figure 1 (Chinese BC).

[0033] The enzymatic stability of the Z275025642-H1R complex was investigated using the Drug Affinity Response Target Stability (DARTS) method. H1R-293T cell proteins were extracted using RIPA lysis buffer (containing 10% phosphatase and protease inhibitors). Protein concentrations were determined using a BCA kit and adjusted to 1–2 μg / μL. Z275025642 (10 μmol / L) was added to the experimental group, while DMSO was added to the control group. Incubation was performed at room temperature for 2 h. Subsequently, protease E was added at a 1:200 ratio and incubated at room temperature for 30 min. Loading buffer was added, and Western blot experiments were performed after heating at 95°C for 5 min. The results showed that Z275025642 targeting and binding to H1R resulted in better enzymatic stability (metabolic enzyme stability). See [see results for details]. Figure 1 Medium DE.

[0034] 2. Molecular dynamics simulation study of the interaction between Z275025642 and H1R Molecular docking was used in the Maestro software within the Schrödinger 2022-3 package to study the binding mode of Z275025642 to the protein. Z275025642 was plotted using Chem3D 20.0, and the crystal structure of the target protein H1R was downloaded from the PDB database (PDB ID: 3RZE). The results showed that the sulfonamide group on the Z275025642 compound forms hydrogen bonds with SER-111 and ASP-107 on the H1R protein. Figure 1 In addition, the compound also forms hydrophobic contacts with amino acids such as PHE-199, TRP-103, TRP-158, TRP-428, and ALA-195 on the protein, providing the molecule with strong van der Waals forces. Figure 1 (G).

[0035] All-atom molecular dynamics simulations were performed using the small molecule-protein complex obtained from docking as the initial structure, with the simulations conducted in AMBER 24 software. Prior to the simulations, the system underwent energy optimization, including a 2500-step steepest descent method and a 2500-step conjugate gradient method. After energy optimization, the system was slowly heated from 0 K to 298.15 K at a constant volume and heating rate of 200 ps. While maintaining the system at 298.15 K, a 500 ps NVT (isothermal-isovolume) ensemble simulation was performed to further homogenize the solvent molecules within the solvent box. Finally, an 500 ps equilibrium simulation was conducted under NPT (isothermal-isobaric) conditions. Finally, a 100 ns NPT ensemble simulation was performed on the complex system under periodic boundary conditions. The RMSD of the Z275025642-H1R complex increased rapidly in the initial stage and stabilized at around 25 ns, with overall fluctuations ranging from 0.29 to 0.35 nm, showing a good stabilization trend. This indicates that the overall structure of the complex completed adaptive adjustments in a short period of time and maintained a relatively stable conformation, suggesting that the simulation system was reasonably constructed and the protein-ligand binding was relatively stable. Figure 1 The H1R protein showed that most residues had an RMSF below 0.15 nm during simulation, indicating good overall rigidity, which is the basis for the stable binding of Z275025642. Figure 1 Middle I).

[0036] Example 2: In vitro pharmacodynamic study of Z27502564 1. Z275025642 inhibits histamine-induced PLC activity levels. Z275025642 was prepared into a 20 mmol / L stock solution using DMSO. The stock solution was diluted to different concentrations using empty culture medium and added to HUVEC cells for incubation for 2 h. Subsequently, histamine was added to stimulate the cells for 10–15 min. Total protein was extracted from the cells using lysis buffer, and the activity level of PLCs in the cells was measured using a PLC activity assay kit. The results showed that Z275025642 inhibited the PLC activity of HUVEC cells by an IC50 concentration of 20%. 50 The value was 0.05891 μmol / L ( Figure 2 (A)

[0037] 2. Z275025642 inhibits histamine-induced calcium mobilization. HUVEC cells were seeded in 96-well plates and incubated overnight at 37 °C with 5% CO2. Incubation solutions were prepared using a calcium ion fluorescent probe, and Z275025642 was diluted to a gradient concentration of 0.195–50 μmol / L using this solution. Cells were washed twice with calcium imaging buffer (CIB), and then incubated with the Z275025642-containing solution for 40 min. Cells were then washed twice with CIB, and under a fluorescence microscope, 30 μmol / L histamine was added as an agonist to stimulate the cells. Intracellular calcium levels were detected using imaging techniques. 2+ Fluorescence changes were analyzed to assess the effect of Z275025642 on calcium signaling. The results showed that it inhibited cellular calcium mobilization by an IC50 value. 50 The value was 0.4962 μmol / L ( Figure 2 (Chinese BC).

[0038] 3. Z275025642 inhibits the secretion of inflammatory cytokines by HUVEC cells. HUVEC cells were seeded in 96-well plates and incubated overnight at 37 °C with 5% CO2. Z275025642 and histamine were added to HUVEC cells simultaneously and incubated for 6–8 h. Cell supernatants were collected, and factor levels were measured using ELISA according to the manufacturer's instructions. The results showed that the addition of Z275025642 significantly reduced the levels of inflammatory factors TNF-α, MCP-1, and IL-8 in the HUVEC cell supernatant. Figure 2 (DF).

[0039] 4. Measurement of transendothelial resistance (TEER) in HUVEC cells HUVEC cells were seeded in the upper layer of the Transwell chamber of a 24-well plate, with culture medium added to the lower layer. After cell adhesion, the cells were treated with different concentrations of Z275025642 and incubated for 2 h. Before using a Millicell ERS-2 voltmeter-ohmmeter, the electrodes were wiped with 75% ethanol and equilibrated with 1×Hank's balanced salt solution for 30 min. After drying, measurements were taken. Initial resistance measurements were performed at 0 min, followed by histamine stimulation of the cells, and resistance values ​​were measured at different time points for each group.

[0040] The TEER reduction rate was calculated using equations (1) and (2). Over time, the TEER reduction rate gradually increased in the group that only added histamine, while the addition of Z275025642 prevented this process. Figure 2 (G).

[0041] TEER = (R) Treated - R Blank) ×Area(1) TEER reduction (%) = (TEER) t0 -TEER t1 ) / TEER t0 ×100%(2) Where: TEER - resistivity per unit area of ​​cell layer in each drug administration group (Ω·cm) 2 ); R Treated - The resistance value (Ω) measured in each drug administration group; R Blank - Resistance value measured by the empty membrane (Ω); Area: Effective membrane area of ​​the chamber bottom membrane (cm²) 2 The bottom area of ​​the chamber used in this experiment was 0.33 cm². 2 TEER t1 - The resistivity per unit area of ​​the cell layer (Ω·cm) after a certain time (t) of drug action. 2 ); TEER t0 - Cell layer resistivity per unit area (Ω·cm) before drug administration (0 min) 2 ).

[0042] 5. Effects of Z275025642 on the HUVEC cytoskeleton HUVEC cells were seeded in 96-well plates and incubated overnight at 37 °C and 5% CO2. Different concentrations of Z275025642 were added to HUVEC cells and incubated for 2 h, followed by histamine stimulation for 10-15 min. The supernatant was discarded, and the cells were washed twice with PBS and fixed with 4% paraformaldehyde for 15 min. F-actin in the cytoskeleton was stained by incubation with FITC-labeled phalloidin at room temperature in the dark for 90 min. The supernatant was discarded, and the cells were washed with PBS and then stained with DAPI at room temperature in the dark for 10 min. The results were recorded using a fluorescence microscope. The addition of histamine reduced the actin region, leading to cell shrinkage, while the cytoskeleton began to expand after treatment with Z275025642, indicating the restoration of cell barrier function. Figure 2 (H).

[0043] Example 3: In vivo anti-allergic reaction study of Z275025642 1. In vivo local anti-allergic activity analysis of Z275025642 Six- to eight-week-old male C57 / BL6 mice were randomly divided into a control group and a treatment group. The control group was administered saline by gavage, while the treatment groups were administered desloratadine or different concentrations of Z275025642. Thirty minutes later, the mice were anesthetized by intraperitoneal injection of sodium pentobarbital. The thickness of the left and right hind paws was then measured, and Evans blue solution was injected via the tail vein to ensure uniform distribution in the bloodstream. Next, histamine (an agonist) and saline were injected subcutaneously into the left and right hind paws, respectively. Fifteen minutes later, the mice were sacrificed, and the thickness of the left and right hind paws was measured again. The degree of paw swelling was observed, and the permeability of the Evans blue solution was measured. The results showed that Z275025642 could inhibit the exudation of Evans blue on the mouse paws after histamine stimulation. Figure 3 (A). Further hematoxylin-eosin (H&E) staining revealed that different concentrations of Z275025642 significantly inhibited the capillary dilation effect of histamine-stimulated mouse paw skin. Figure 3 (B). Meanwhile, statistical analysis of the paw swelling rate and Evans blue exudation rate in mice injected with histamine and saline showed that Z275025642 could inhibit paw swelling and exudation in mice to varying degrees. Figure 3 Medium CD).

[0044] 2. In vivo and systemic anti-allergic analysis of Z275025642 Six- to eight-week-old male C57 / BL6 mice were randomly divided into a blank control group, a positive control group, and an administration group. The blank control group received no treatment, the positive control group was administered physiological saline by gavage, and the administration groups were administered desloratadine or different concentrations of Z275025642. Thirty minutes later, histamine solution was injected into each group via the tail vein. Subsequently, the body temperature of each mouse was measured at 3-minute intervals over 30 minutes. The results showed that Z275025642 could inhibit the decrease in body temperature in mice after histamine stimulation. Figure 3 E). 6-8 h later, blood was collected through the orbital cavity and the mice were euthanized. The collected blood was centrifuged at 2000×g for 20 min at 4°C, and serum was separated. ELISA analysis showed that Z275025642 significantly inhibited the levels of TNF-α, MCP-1, and CXCL1 in mouse serum. Figure 3 (FH).

[0045] Example 4: Evaluation of the in vivo anti-allergic rhinitis effect of Z275025642 1. Establishment and intervention of an animal model of allergic rhinitis Female C57 / BL6 mice aged 6-8 weeks were intraperitoneally injected with OVA (ovalbumin) aluminum hydroxide solution on days 1, 7, and 14 to induce sensitization. Subsequently, OVA was administered intranasally from days 21 to 30 to induce a sustained sensitization response. From days 23 to 30, the treatment group mice were administered Z275025642 or the positive control drug desloratadine daily by gavage. Figure 4 (A). During the treatment period, daily monitoring of mouse body weight showed no significant change, indicating that the treatment drug had no significant toxicity. Figure 4 (B)

[0046] 2. Z275025642 inhibits the inflammatory response of allergic rhinitis. On day 31, 30 minutes after the last intranasal OVA stimulation of mice, the number of scratching and sneezing behaviors within 5 minutes was recorded in a blinded manner. After treatment with Z275025642, the number of scratching and sneezing behaviors in mice stimulated by OVA was significantly reduced. Figure 4 (CD). Measurement of spleen weight in mice revealed a decrease in spleen index after Z275025642 treatment, indicating inhibition of immune cell activation and proliferation. Figure 4 E), the decrease in eosinophils in the blood further reflects the reduction in the inflammatory response (E), Figure 4 (F). Nasal lavage fluid was collected after mouse euthanasia. ELISA was used to detect a decrease in the levels of TNF-α, MCP-1, IL-4, and IL-13 in the nasal lavage fluid after treatment with Z275025642. Figure 4 The presence of GJ in the middle of the spectrum indicates a decrease in inflammatory response and type 2 immune response.

[0047] 3. Z275025642 restores the nasal functional barrier in allergic rhinitis. After sectioning and processing, mouse nasal tissue was stained with H&E. The results showed that Z275025642 significantly inhibited nasal mucosal thickening induced by OVA stimulation, and its effect was consistent with that of desloratadine. Figure 4 (K); Periodic acid-Schiff (PAS) staining revealed reduced proliferation of nasal goblet cells in mice treated with Z275025642. Figure 4 The presence of L indicates that the nasal functional barrier has returned to normal.

[0048] Example 5: Evaluation of the in vivo anti-allergic dermatitis effect of Z275025642 1. Establishment and intervention of an animal model of allergic dermatitis Contact hypersensitivity (CHS) was induced using the contact sensitizer 1-chloro-2,4-dinitrobenzene (DNCB). C57 / BL6 mice were sensitized by topical application of 2% DNCB (50 μL acetone) to the abdominal skin once daily for 3 consecutive days. After a 4-day interval, on day 8, control mice were only stimulated by topical application of 1% DNCB (25 μL) to both ears once daily for 3 consecutive days. Treatment mice, in addition to stimulation, received either ear application of the positive control drug dexamethasone acetate ointment (DEX) or oral administration of Z275025642 (0.86 mg / kg) for 6 consecutive days. Figure 5 (A). During the treatment period, daily monitoring of mouse body weight showed no significant change, indicating that the treatment drug had no significant toxicity. Figure 5 (B)

[0049] 2. Z275025642 inhibits the inflammatory response of allergic dermatitis. On day 14, the mice's ears were stimulated for the last time, and the number of spontaneous scratches was recorded within 30 minutes. The results showed that after treatment with DEX and Z275025642, the number of times the mice scratched their ears was significantly reduced, and Z275025642 was more effective than the positive control drug DEX. Figure 5 (C). Using vernier calipers to measure mouse ear thickness, it was found that treatment with Z275025642 could alleviate ear thickening caused by allergies. Figure 5 (D), and the ADI score was used to assess the severity of the ear condition in mice. The results showed that after treatment, the degree of erythema, edema, and lichenification in the ears of mice was reduced. Figure 5 (EF). Further measurement of spleen weight in mice revealed a decrease in spleen index after treatment with Z275025642, indicating that the activation and proliferation of immune cells were inhibited. Figure 5 (G). Serum was collected after mice were sacrificed, and ELISA was used to detect a decrease in the levels of TPS, TSLP, and TNF-α in the serum after treatment with Z275025642. Figure 5 The presence of HJ in the middle of the spectrum indicates that the inflammatory response is under control.

[0050] 3. Z275025642 restores the skin barrier in allergic dermatitis Further H&E staining analysis of mouse ear skin tissue showed that treatment with Z275025642 reduced the thickness of the epidermis and dermis, with an effect equivalent to the positive control drug DEX. Figure 5 (M). Simultaneously, toluidine blue staining of mouse ear skin to label mast cells revealed that Z275025642 treatment reduced mast cell infiltration in the ear, demonstrating superior efficacy compared to the positive control drug DEX (…). Figure 5The presence of NO indicates that Z275025642 can alleviate allergic dermatitis symptoms by inhibiting mast cell recruitment.

[0051] The above content is only for illustrating the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. Any modifications made to the technical solution based on the technical concept proposed in this invention shall fall within the scope of protection of the claims of this invention.

Claims

1. Use of N-(4-methoxyphenyl)-4-(4-methoxyphenyl)benzenesulfonamide in the preparation of medicaments for the prevention and / or treatment of allergic diseases.

2. The application according to claim 1, characterized in that, The drug described is one that inhibits histamine-mediated calcium mobilization.

3. The application according to claim 1, characterized in that, The drug described is a drug that inhibits histamine-mediated PLC activity levels.

4. The application according to claim 1, characterized in that, The drug mentioned is capable of reducing the expression levels of inflammatory factors TNF-α, MCP-1, IL-8, and CXCL1.

5. The application according to any one of claims 1-4, characterized in that, The allergic disease mentioned is allergic rhinitis.

6. The application according to claim 5, characterized in that, The medication described can reduce the inflammatory response of allergic rhinitis.

7. The application according to claim 5, characterized in that, The drug described can reduce the type 2 immune response in allergic rhinitis.

8. The application according to claim 5, characterized in that, The drug can restore the nasal functional barrier by reducing the proliferation of goblet cells in the nasal cavity.

9. The application according to any one of claims 1-4, characterized in that, The allergic disease mentioned is allergic dermatitis.

10. The application according to claim 9, characterized in that, The medication described can reduce the inflammatory response of allergic dermatitis.

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