Use of a compound for the manufacture of a medicament for the treatment of androgenetic alopecia

Abstract

The present application relates to the anti-falling agent, especially to a kind of compound in the preparation of treating androgen alopecia drug application.The present application based on the defects of existing drugs, provide a kind of small molecule compound I that can inhibit AR dimerization into nucleus, it does not affect the content of androgen and androgen receptor in vivo, can avoid the androgen level reduction caused by existing drugs such as non-steroidal antiandrogen on the market, sexual dysfunction, side effect is smaller, it is a kind of safe and effective, can promote androgen alopecia patient hair growth, alleviate androgen alopecia patient hair fine and soft hair follicle atrophy active substance.

Description

TECHNICAL FIELD

[0001] The present application relates to an anti-falling agent, in particular to the use of a compound in the preparation of a medicament for treating androgenic alopecia BACKGROUND

[0002] Nowadays, hair loss has become a common social problem. According to the data released by the National Health Commission, the number of people with hair loss in China reached 250 million in 2020, and one in every four men or one in every eight women is experiencing hair loss. What is more serious is that the hair loss symptoms are developing towards youth, and the proportion of hair loss among people under the age of 30 in China has reached nearly 50%, which is 20 years earlier than the previous generation. Although the hair loss does not affect the physical health, it causes anxiety and psychological burden to the patients, and therefore it is increasingly concerned.

[0003] Androgenic alopecia (AGA), also known as seborrheic alopecia, is the most common type of hair loss. Unlike other types of hair loss, androgenic alopecia is a polygenic recessive genetic disease with genetic predisposition, which cannot be cured by stopping external stimulation, stopping pulling and relieving stress, etc. It is characterized by progressive miniaturization of hair follicles, thinning of hair diameter, reduction of hair density, and usually accompanied by increased sebum secretion on the scalp. Both men and women can be affected. The main factors of androgenic alopecia are the increase of androgen receptor activity or the increase of 5α-reductase activity. In the scalp, free testosterone in the blood vessels near the hair follicle is transferred to the hair papilla cells by free diffusion, and is reduced to dihydrotestosterone with higher activity under the action of 5α-reductase, and promotes the dissociation of androgen receptor (AR) and heat shock protein. After the androgen-AR complex in the cytoplasm forms a dimer, it enters the nucleus, binds to the androgen receptor response element (ARE), and affects the expression of target genes, causing miniaturization of hair follicles and growth arrest of hair. It has been found that the DHT-AR complex inhibits the phosphorylation of GSK-3β, leading to the degradation of β-catenin and the inhibition of the downstream factor wnt10b of Wnt / β-catenin pathway, thereby weakening the growth regulation of hair follicle stem cells. In addition, androgens also affect the signal exchange between hair papilla cells and hair follicle stem cells through the regulation of SHH, TGF-β and other signal pathways, thereby affecting the hair growth cycle.

[0004] Currently, there are two FDA-approved drugs for treating androgenic alopecia: finasteride and minoxidil. Finasteride inhibits the conversion of testosterone to dihydrotestosterone, which has higher androgen receptor binding capacity and efficiency, so oral finasteride often causes problems such as decreased androgen levels, decreased reproductive ability, and sexual dysfunction. The above defects seriously affect the application of drugs for treating androgenic alopecia.

[0005] Therefore, it is a technical problem to be solved by those skilled in the art to find a drug that can treat androgenic alopecia without reducing androgen levels, reducing side effects such as decreased reproductive ability and sexual dysfunction. SUMMARY

[0006] OBJECTIVE

[0007] The present application provides a new use of a compound in the preparation of a drug for treating androgenic alopecia.

[0008] TECHNICAL SCHEME

[0009] In order to find a compound with androgen receptor dimerization activity, we first screened a batch of small molecule compounds capable of binding to androgen receptors by virtual screening, and further evaluated the therapeutic effect and mechanism of small molecule compounds on androgenic alopecia in vivo and in vitro.

[0010] The application of a compound in the preparation of a drug for treating androgenic alopecia is characterized in that the compound is any of the following:

[0011]

[0012] In the preparation of a drug for treating androgenic alopecia-related diseases, the drug is used as an active ingredient in the development of pharmaceutical preparations, including oral solid and liquid preparations, patches, ointments, cream preparations, gels, or sprays.

[0013] Further, the application provides a method for treating androgenic alopecia, comprising administering the compound to a subject in need thereof.

[0014] The present application first constructs an AR binding site screening based on the AR protein structure in the PDB database and the Chemdiv and Zinc databases, uses Autodock vina software and MOE software to perform preliminary docking and re-verification of the compound and AR protein, respectively, to obtain 24 compounds with potential binding activity and purchase them from Chemdiv.

[0015] Virtual docking results show that drug No. 5 can bind to the binding pocket of the LBD domain of the androgen receptor, and no pharmacological activity of this compound has been published.

[0016] Cell experiments show that drugs Nos. 1, 2, 5, 6, 11 and 14 can effectively inhibit the proliferation of human prostate cancer cell line (LNCaP), and drugs Nos. 5 and 14 can significantly inhibit the expression of mRNA level and protein level of androgen receptor downstream genes, which indicates that the compound can effectively inhibit the effect of androgen receptor into the nucleus and combine with androgen response element to start the expression of downstream genes, and this conclusion is verified by immunofluorescence experiment of AR and cell nucleus co-localization.

[0017] Animal efficacy experiments show that drug No. 5 can inhibit hair loss caused by the rise of androgen level. After the AGA model is caused by depilation and subcutaneous injection of androgen for 21 days, the mice are continuously administered with drug No. 5 for 28 days. On the 0th, 7th, 14th and 28th days of administration, hair growth scoring is performed, and compared with the model group, the hair coverage area and growth condition score of the mice in the administration group are significantly improved, and the hair growth state is not inferior to that of the positive drug finasteride.

[0018] After the 28th day of administration, the skin of the back of the mice is taken for histological section, and the following conclusions can be drawn: compared with the model group, the number of hair follicles per unit area of the mice in the administration group is significantly increased, the size of the hair follicles is restored to the level of the control group, the thickness of the true epidermis layer of the skin is significantly increased, and the average growth of the hair follicle diameter is 52%. The concentration of the compound used in the experiment is consistent with that of the positive drug control group, finasteride, and the effect is equivalent to that of finasteride, but it avoids directly lowering the androgen level in the body, and has fewer side effects and adverse reactions, and is safer.

[0019] In addition, TUNEL staining of longitudinal section of hair follicle shows that the compound can effectively reduce the apoptosis of hair papilla cells caused by androgen, and the scratch experiment shows that the compound can promote the migration of hair follicle stem cells, that is, it can promote the growth of hair follicles, reduce the release of apoptosis signals by hair papilla cells, and optimize the growth cycle of hair follicles.

[0020] Beneficial effects

[0021] 1. The present application provides a new use of a compound in the preparation of a drug for treating androgenic alopecia, the compound being any one of drugs 1, 2, 5, 6, 11 and 14, the drug efficacy of the above-mentioned compound has not been reported in the literature and is first discovered. The present application is based on the defects of existing drugs, and the mechanism of action is completely different from that of the prior art such as finasteride, that is, it does not inhibit 5α-reductase, but inhibits AR dimerization into the nucleus, so it does not affect the content of androgen and androgen receptor in the body, and can avoid the decrease of androgen level, sexual dysfunction and other problems caused by existing drugs such as finasteride on the market, and has smaller side effects. It is a safe and effective active substance that can promote hair growth in patients with androgenic alopecia and relieve hair thinning and softening and hair follicle atrophy in patients with androgenic alopecia.

[0022] Specifically:

[0023] Finasteride actually acts on androgen itself, that is, it prevents the conversion of active forms of androgen by competitively inhibiting 5α-reductase, thereby reducing the binding to androgen receptor and entering the nucleus to prevent hair loss. However, oral finasteride often causes problems such as decreased androgen levels, decreased reproductive ability, and sexual dysfunction. The present application has a different mechanism of action than finasteride. The present application does not act on androgen itself, but by inhibiting androgen receptor dimerization, reducing androgen receptor entry into the nucleus, promoting hair follicle cell growth, and promoting the application of hair follicle stem cell migration, thereby promoting hair growth. Therefore, the compound does not produce side effects such as decreased androgen levels, decreased reproductive ability, and sexual dysfunction as with finasteride. At the same time, the drug can inhibit the apoptosis of hair follicle stem cells, hair papilla cells and other hair follicle cells, and improve the signal-mediated environment in the hair follicle.

[0024] 2. The compound described in the present application can be used as an active ingredient and applied in the field of anti-androgenic alopecia or hair growth-promoting drugs, thereby widening the application of the compound and providing a new choice for drugs for inhibiting androgenic alopecia. Specifically, the compound has the effect of promoting hair growth, including accelerating the natural growth rate of hair, increasing the coverage area of hair, increasing the ratio of recovered dermal epidermal layer thickness, increasing the number of hair follicles per unit area and the diameter of hair follicles, increasing hair length and weight, increasing the proportion of hair follicles in the growth phase, and counteracting other alopecia-related symptoms caused by androgens. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 : Molecular docking diagram of the compound and androgen receptor, A is the high-level structure of the protein; B is the protein surface simulation;

[0026] Figure 2 : Cell viability of 24 kinds of compounds stimulating dihydrotestosterone modeling human prostate cancer Lncap cells;

[0027] Figure 3: RT-qPCR results of two compounds with inhibitory activity on Lncap cell transcription level;

[0028] Figure 4 : WB results of two compounds with inhibitory activity on AR downstream key protein PSA expression;

[0029] Figure 5 : Compound hair restoration gross observation chart of androgen alopecia model mice;

[0030] Figure 6 : Compound hair restoration scoring linear statistical chart of androgen alopecia model mice;

[0031] Figure 7 : Compound treatment of androgen alopecia model mice after mouse hair follicle diameter schematic (A) and statistical chart (B);

[0032] Figure 8 : Compound treatment of androgen alopecia model mice after mouse skin cross-section, longitudinal section HE staining chart;

[0033] Figure 9 : Compound treatment of androgen alopecia model mice after mouse skin cross-section, longitudinal section HE staining chart;

[0034] Figure 10 : Compound treatment of androgen alopecia model mice after mouse skin cross-section, longitudinal section HE staining chart;

[0035] Figure 11 : Compound treatment of androgen alopecia model mice after mouse skin cross-section, longitudinal section HE staining chart;

[0036] Figure 12 : Compound treatment of androgen alopecia model mice after mouse skin cross-section, longitudinal section HE staining chart; DETAILED DESCRIPTION

[0037] The compounds used for verification in the examples are purchased from chemdiv company.

[0038] Example 1 Virtual docking

[0039] According to the AR structure formula and the dimerization formation process, 1.6 million entity compounds from the chemdiv library are screened for AR drugs. The 1.6 million compound base is large and has high diversity. The strength of the binding free energy of the compound and the AR-LBD target can be used as one of the screening criteria. Compounds with binding free energy lower than -10.5 kcal / mol can be used as candidate compounds for further screening.

[0040] We screened 24 compounds according to the structure of androgen receptor and the basic information of LBD domain, and obtained the screening 24 compounds by MOE molecular docking calculation. The 24 candidate compounds were purchased from chemdiv company for cell level drug primary screening (see example 2), and finally determined that the No. 5 drug was the most effective compound for animal level drug efficacy exploration.

[0041] Further, the AR molecule docking was simulated by MOE software, Figure 1 It can be seen that the compounds with the same mother nucleus have the possibility of binding to androgen receptor.

[0042] Table 1 Structure of 24 small molecule compounds with potential AR binding obtained by high-throughput molecular docking

[0043]

[0044]

[0045] Example 2 In vitro drug efficacy screening experiment

[0046] In order to obtain the most effective compound for subsequent animal in vivo drug efficacy exploration, we first screened 24 compounds in vitro.

[0047] 1. Cell proliferation inhibition level primary screening

[0048] The cells were selected as LNCaP human prostate cancer cells, which had high androgen receptor expression content and fast cell growth, and had advantages in cell level large-scale screening.

[0049] LNCaP cells were cultured in 96-well plates at a density of 1×10 5 Cells / well, using RPMI-1640 medium containing 10% FBS for culture, and the cells were adhered after overnight plating culture. 10 -6 μM of DHT was given for modeling treatment, and each compound was added in concentration gradient of 0.1, 10, 25, 50 and 100 μM, and a solvent control group was set. After 24 and 48 hours of drug treatment, the LNCaP cell activity was determined by CCK-8 method. The absorbance was read at 450 nm, and the concentration-cell activity curve was calculated according to the following formula.

[0050] Cell activity = (test sample A-blank group A) / (solvent group A-blank group A)

[0051] As Figure 2As shown, 6 compounds among the 24 compounds can effectively inhibit the proliferation of LNCaP cells, namely: drug No. 1, drug No. 2, drug No. 5, drug No. 6, drug No. 11, and drug No. 14. The inhibition rate on LNCaP proliferation is concentration-dependent, and the inhibition effect is better with time, showing pharmacodynamic activity at the cellular level, while other compounds show poor effect or no effect.

[0052] 2. Screening of mRNA inhibition levels

[0053] LNCaP cells were cultured in 6-well plates. -6 μMDHT model was treated with six compounds at a concentration of 10 μM. RNA was extracted 48 hours later and reverse transcribed into cDNA. RT-qPCR technology was used to determine the relative expression of classical genes downstream of the androgen receptor in prostate cancer cells, including prostate cancer-specific antigen (KLK3 / PSA), transmembrane serine protease 2 (TMPRSS2), and kallikrein-related peptidase (KLK2), using Graphpad prism software.

[0054] Depend on Figure 3 It can be seen that two of the six compounds (drugs 5 and 14) significantly downregulated AR downstream genes in LNCaP cells. This indicates that the drug downregulated the binding of the androgen receptor to the androgen response element in the cell nucleus and reduced the expression of androgen receptor downstream genes.

[0055] 3. Protein inhibition level screening

[0056] Drugs 5 and 14 were treated with the aforementioned cell model and administered as described above, and compared to the positive drug finasteride. Drugs 5 and 14 were stimulated at a concentration of 10 μM, while finasteride was stimulated at concentrations of 10 and 15 μM. After protein extraction, Western Blot analysis was performed to investigate whether these two compounds could downregulate the expression of PSA, a key protein downstream of the androgen receptor, and to compare their effects with the positive drug finasteride.

[0057] Depend on Figure 4 It can be seen that compared with the DHT cell model group, both drugs No. 5 and No. 14 downregulated the PSA antigen, but compared with the positive drug finasteride, only drug No. 5 showed better downregulation of PSA. After comprehensive consideration, drug No. 5 was selected as the final candidate drug for efficacy research in animals.

[0058] Example 3 Animal in vivo efficacy experiment

[0059] 1. Experimental Animals

[0060] The experimental animals are male C57BL / 6J, 5-6 weeks old, weighing 18-20 g, purchased from the Comparative Medicine Center of Yangzhou University. C57BL / 6J mice are fed under normal conditions, temperature 25±2℃, humidity 50%-70%, light and dark alternately for 12h, free to eat and drink, the sawdust bedding is changed every two days, and the mice are adapted to the feeding environment for 7 days before the experiment.

[0061] 2. Drug preparation

[0062] 1) Intragastric administration of drug solution: 5# drug purchased from chemdiv company, 5mg of compound was weighed, 1078.6μL of DMSO was added, and it was filtered with a 0.22um filter membrane in a clean bench, which was 10 4 mol / L compound stock solution. Take 420μL stock solution, add 20mL normal saline, 80mg sodium carboxymethyl cellulose, and place overnight to constant volume to 28mL, and store at 4 degrees after dispensing.

[0063] 2) Testosterone propionate solution: 80mg of testosterone propionate was dissolved in 40mL of soybean oil to prepare a suspension of 2mg / mL. The suspension effect was ensured by vortex before use.

[0064] 3) 4% chloral hydrate solution: 2g of chloral hydrate powder was dissolved in 50mL of normal saline, filtered with a 0.22μm microporous filter to remove bacteria, and stored at 4℃ in the dark for standby.

[0065] 4) Finasteride solution: 3mg of finasteride powder was dissolved in 0.5mL of DMSO, added with normal saline to constant volume to 20mL, the concentration was 0.15mg / mL, and stored at 4℃ in the dark.

[0066] 5) Control group normal saline solution: 420μL of DMSO was added to 28mL of normal saline as a control.

[0067] 3. Establishment of hormone alopecia model

[0068] Randomly selected 6-week-old C57BL / 6 mice were randomly divided into 4 groups: control group (Control), androgen alopecia group (AGA) and 5# drug group (compound I), positive drug finasteride group (Finasterid), 5 mice in each group. Each mouse was injected intraperitoneally with 0.1-0.15ml of 4% chloral hydrate anesthesia, the back skin with an area of 4cm×3cm was pushed off using a hair pusher, and the mouse was depilated on the back with depilatory cream. Except for the control group, the other three groups were injected subcutaneously with 0.1mL of testosterone propionate every day for 21 days, and the control group was injected subcutaneously with 0.1mL of soybean oil as a control. The number of hair follicles and the reduction of hair follicle diameter in the back skin tissue sections showed that the model was successful.

[0069] Evaluation of the therapeutic effect of drug 4.5 on androgenic alopecia model mice

[0070] After successful model establishment, animals in each group were anesthetized with 4% chloral hydrate and then depilated. The compound and finasteride groups were treated by oral gavage at a dose of 0.75 mg / kg / day for finasteride and 0.75 mg / kg / day for the compound group. The control group and the androgenic alopecia group received daily oral gavage with normal saline to eliminate solvent interference. After 28 consecutive days of treatment, the mice were sacrificed by cervical dislocation, and dorsal skin tissue was fixed in 4% paraformaldehyde for subsequent HE staining and immunohistochemistry.

[0071] 5. Experimental Results

[0072] The gross observation results of mice were as follows Figure 5 The results showed that compared with the model group, the hair coverage area of ​​the mice in the drug group was significantly increased, and the hair growth status was better than that of the positive drug finasteride. Figure 6 As shown; Figure 7 As shown in Figure 2, the hair follicle diameter of the model group mice was reduced to 48% of that of the control group, while the hair follicle diameter of the compound treatment group mice recovered to the same level as that of the control group; the HE staining results of the transverse and longitudinal sections are shown in Figure 2. Figure 8 As shown in the results, the hair of the mice in the compound treatment group recovered faster, the hair follicles in the compound treatment group grew deeper than those in the model group, and the thickness ratio of the dermis to the epidermis was higher. Figure 9 As shown, compared with the model group, the number of hair follicles per unit area increased by 37%, which is equivalent to the recovery effect of positive drugs.

[0073] Example 4 TUNEL staining experiments on pathological sections demonstrated that the compound inhibited apoptosis of hair follicle cells

[0074] 1. Reagents used: Beyotime One-Step TUNEL Cell Apoptosis Detection Kit (Green Fluorescence), Product No. C1086

[0075] 2. Operation steps:

[0076] (1) Cut the hair follicles into paraffin sections and dewax them in xylene for 5-10 minutes. Replace with fresh xylene and dewax for another 5-10 minutes. Dewax the sections in anhydrous ethanol for 5 minutes, 90% ethanol for 5 minutes, 80% ethanol for 2 minutes, 70% ethanol for 5 minutes, and distilled water for 2 minutes. Add 20 μg / ml DNase-free proteinase K dropwise and incubate at 37°C for 15-30 minutes. Wash with PBS three times for 3 minutes each time.

[0077] (2) Prepare TUNEL assay solution. For each sample, add 5 μl of TdT enzyme to 45 μl of fluorescent labeling solution to make 50 μl of TUNEL assay solution. Circle the tissue section with a histochemical pen, add a drop of TUNEL assay solution to the section, and incubate in a humidified chamber at 37°C in the dark for 60 minutes.

[0078] (3) Rinse with PBS three times, add DAPI staining solution, cover the slide with a coverslip, store in the dark, and photograph under a laser confocal microscope.

[0079] 3. Experimental results:

[0080] like Figure 10 As shown, tunel staining of longitudinal sections of hair follicles showed that apoptosis occurred in the dermal papilla cells and the inner and outer root sheaths of the hair follicles of the model group mice, but there was almost no apoptosis in the dermal papilla of the compound-treated group, and only a small amount of apoptosis occurred in the bulge at the upper end of the hair follicle, indicating that the compound alleviated the apoptosis of dermal papilla cells of the hair follicles caused by androgenic alopecia, thereby reducing the release of apoptosis signals from dermal papilla cells to hair follicle stem cells, prolonging the hair follicle growth cycle, and thus alleviating the decrease in the number of hair follicles.

[0081] In summary, drug No. 5 has the effect of significantly reducing hair apoptosis and increasing the number of hair follicles during the hair growth process in mice, and its efficacy is comparable to that of the positive drug finasteride.

[0082] Example 5 Apoptosis of primary hair follicle cells Flow cytometry proves that drug No. 5 inhibits apoptosis of hair follicle cells

[0083] 1. Reagents used: Annexin V-APC / PI Apoptosis Kit, BD FACS Celesta flow cytometer

[0084] 2. Operation steps:

[0085] (1) Before the experiment, hair follicles were extracted by mechanical separation of the vibrissae pads of newborn mice, and primary hair follicle cells were cultured in L-DMEM complete medium containing 10% FBS. After three generations of culture, flow cytometry identification results showed that they were positive for CD133, CD140a, and CD44, and negative for CD45, CD31\CD49-F, which met the standards for dermal papilla cell surface markers. The first five generations of primary cells were suitable for experiments.

[0086] (2) The cells were divided into three groups when plating. The NC group was not treated, and the DHT group and the drug-treated group were treated with 10 -6 mol / L DHT treatment, the drug group was treated with 7μM compound (I) at the same time. After 48 hours of culture, the cells were treated with 0.25% EDTA-free

[0087] Trypsinize the primary hair follicle cells, wash them with pre-cooled PBS, and collect 1-5×10 6 cells (including cells in the culture supernatant).

[0088] (3) Dilute 5x Binding Buffer with DEPC to lx working solution, take 500 μl lx Binding Buffer to resuspend cells. Add 5 μl Annexin V-APC and 10 μl PI to each tube. After vortexing gently, incubate at room temperature for 5 minutes in the dark.

[0089]

[0090] (4) Perform flow analysis on the machine, select APC and PI channels, and use flowjo software to analyze flow data.

[0091] 3. Experimental results:

[0092] As shown in the table, the apoptosis rate of hair follicle primary cells after DHT stimulation increased to 35%, while the apoptosis rate of cells after compound treatment decreased by more than 20%, indicating that the compound inhibited the apoptosis of hair follicle primary cells, which is consistent with the results of animal experiments that the drug can reduce the apoptosis of hair papilla cells. Figure 11 As shown above, drug No. 5 can effectively reverse the apoptosis of hair follicle primary cells caused by androgens, and prevent the transformation of hair follicle cells into the resting phase.

[0093] Example 6: Androgen receptor immunofluorescence experiment shows that drug No. 5 can prevent AR from entering the nucleus

[0094] 1. Experimental instrument: laser confocal microscope (Olympus FV3000)

[0095] 2. Operation steps

[0096] (1) First, culture the hair follicle cells in a laser light focusing culture dish for 24 h, and divide the cells into three groups: blank control group (NC), androgen stimulation group (DHT) and drug administration group. Pay attention to the number of cells when plating to prevent cell stacking growth from affecting staining and observation.

[0097] (2) After complete adhesion, stimulate the DHT group and the drug administration group with 10 -6 mol / L DHT, and stimulate the drug administration group with 8 μM drug No. 5 at the same time. Take out the culture dish after 48 hours.

[0098] (3) Remove the cell culture medium, slowly add PBS buffer along the wall for two times, discard the PBS, and add 500 μL

[0099] 4% paraformaldehyde solution into the dish for room temperature fixation for 15 min.

[0100]

[0101]

[0102] ​​​(4) After removing the fixative, add 1 ml of PBS buffer and rinse. Repeat 3 times for 3 minutes each time.

[0103] (5) Add 100 μL of PBS containing 0.5% Triton X-100 and permeabilize for 15 min at room temperature;

[0104] (6) Rinse twice with PBS buffer, add androgen receptor antibody (1:250 primary antibody dilution), and incubate overnight at 4°C in the dark;

[0105] (7) Rinse twice with PBS buffer, add green fluorescent secondary antibody (A549) (1:400 PBS dilution), and incubate at room temperature for 2 hours; (8) Rinse twice with PBS buffer, add DAPI working solution, and incubate at room temperature in the dark for 5 minutes; After rinsing twice with PBS, use the

[0106] Confocal microscopy was used for image acquisition.

[0107] 3. Experimental Results

[0108] like Figure 12 As shown, DHT significantly promotes AR nuclear translocation, while in the compound-stimulated group, AR is dispersed in the cytoplasm, meaning that expression is more evenly distributed in the cytoplasm and nucleus, resulting in a significant inhibition of AR nuclear translocation. These results indicate that Drug 5 can effectively prevent androgens from entering the nucleus and exerting their effects, thereby reducing the binding of androgen receptors to androgen response elements, thereby inhibiting the transcription and translation of androgen receptor downstream genes and regulating the dermal papilla cell cycle.

Claims

1. Use of a compound for the manufacture of a medicament for the treatment of androgenetic alopecia, characterized in that, The structure of the compound is shown below:

2. Use according to claim 1, characterized in that, The compound as an active ingredient forms a preparation including oral solid liquid preparation, patch, ointment, cream preparation, gel or spray.

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