Use of JWA gene activator for preventing or treating alopecia

Abstract

The present disclosure relates to the use of a JWA gene activator or a pharmaceutical composition thereof in the prevention or treatment of alopecia. The invention further relates to application of the JWA gene activator JAC4 or the pharmaceutical composition thereof in preventing or treating alopecia. The JWA gene activator provided by the invention can significantly promote hair regeneration and can effectively improve the hair regeneration effect.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims priority and benefits of the following Chinese patent application filed with the State Intellectual Property Office of China: Chinese Patent Application No. 202310924077.7 filed on July 26, 2023; the full text of the above patent application is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to the field of medical technology, and in particular, to the use of a JWA gene activator for preventing or treating hair loss. Background Art

[0004] As the pace of life continues to accelerate and the pressure of life continues to increase, the phenomenon of hair loss in the population is becoming increasingly prominent and is becoming younger. Hair loss can be divided into normal hair loss and pathological hair loss according to different causes. Normal hair loss refers to the loss of hair in the regression or resting phase. A normal person loses 70-100 hairs a day, which is caused by the metabolism of the hair follicle cells on the scalp and is part of the normal metabolism of the human body; while pathological hair loss refers to the loss of hair due to the degeneration of normal hair follicle cells or the entry into the resting phase, which causes insufficient nutrition of the hair. Pathological hair loss often leads to baldness, alopecia areata and other phenomena.

[0005] Androgenetic alopecia (AGA), also known as seborrheic alopecia, premature baldness, male pattern baldness, etc., is an androgen-dependent hereditary disease and the most common type of hair loss in clinical practice. It is characterized by a progressive decrease in hair density and is often related to genetic factors. It is characterized by progressive hair loss, with particularly strong pressure on the central scalp, which often begins in adolescence and seriously affects the patient's mental health.

[0006] The specific pathogenesis of AGA is still unclear, and it is the result of the combined action of multiple factors. Androgens play an important role in the onset of AGA. In individuals with genetic susceptibility, the disease will occur even if the androgen concentration in the blood is normal. Testosterone is metabolized to dihydrotestosterone under the action of 5-α reductase. This metabolite has a higher affinity with androgen receptors and is considered to be an important cause of androgen-mediated effects in the scalp of AGA patients. Under the action of androgens, hair follicle dermal papilla cells secrete a variety of cytokines, such as transforming growth factor-β (TGF-β), interleukin-1α (IL-1α) and tumor necrosis factor-α (TNF-α), which can induce the premature termination of the growth phase of hair follicles. In addition, genetic genes, prostaglandins, Wnt signaling pathways and iron reserves are all involved in the pathogenesis of AGA.

[0007] With the advancement of science and technology, there are more and more methods for treating AGA, mainly surgery, laser comb therapy, etc. However, due to cost-effectiveness reasons, drug therapy is still the most commonly used treatment for AGA. At present, the topical drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of AGA include minoxidil, and the oral drug is finasteride, but generally speaking, all these treatments have side effects. Finasteride can cause loss of libido and impotence in men, and its use in women is contraindicated. Minoxidil can cause blood precipitation reactions, angina pectoris, and unwanted hair growth. Therefore, there is still an unmet medical need for the treatment of androgenic alopecia.

[0008] JWA, also known as ARL6IP5 (GenBank AF070523, 1998), is a gene discovered and cloned from a retinoic acid-induced bronchial epithelial cell differentiation model. CN201610857409.4 discloses a compound JAC4 that can activate JWA expression, and its structural formula is shown below. Currently, there is no literature report on whether JWA gene activators can be used to treat androgenic alopecia.

[0009] Summary of the invention

[0010] The present disclosure relates to use of a JWA gene activator or a pharmaceutical composition thereof in preventing or treating hair loss.

[0011] In some embodiments, the hair loss is androgenetic alopecia.

[0012] In some embodiments, the JWA gene activator is selected from a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0013]

[0014] In some embodiments, the compound of formula (I) JWA gene activator is selected from

[0015] In some embodiments, the compound of formula (I) is selected from

[0016] In some embodiments, the pharmaceutical composition comprises the JWA gene activator and a pharmaceutically acceptable excipient.

[0017] In some embodiments, the pharmaceutical composition is administered orally or topically.

[0018] In another aspect, the present disclosure provides a method for preventing or treating hair loss, comprising administering a therapeutically effective amount of a JWA gene activator or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0019] In another aspect, the present disclosure provides use of a JWA gene activator or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating hair loss.

[0020] In another aspect, the present disclosure provides a JWA gene activator for preventing or treating hair loss or a pharmaceutical composition thereof.

[0021] The JWA gene activator provided by the present disclosure can significantly promote hair regeneration and can effectively increase the hair regeneration effect.

[0022] Definitions and explanations of terms

[0023] Unless otherwise defined herein, scientific and technical terms related to the present disclosure shall have the meanings understood by those of ordinary skill in the art.

[0024] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition or disorder, or (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0025] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0026] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or an organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0027] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0028] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0029] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be construed as having an open and non-exclusive meaning, ie, "including but not limited to".

[0030] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0031] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0032] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.

[0033] In some embodiments, the pharmaceutical composition may also be suitable for topical administration, such as applying to an affected area.

[0034] In all the methods of administration of the compounds of formula (I) described herein, the daily dosage may be from 0.01 mg / kg to 1000 mg / kg body weight, in the form of single or divided doses.

[0035] Abbreviations:

[0036] JAC4: The structural formula is It is a racemate.

[0037] R-JAC4: The structural formula is It is the R configuration of JAC4.

[0038] S-JAC4: The structural formula is It is the S configuration of JAC4. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is a standard chart for scoring mouse skin color changes.

[0040] Figure 2 This is a graph showing the treatment days versus skin color scores in Example 1.

[0041] Figure 3 This is a photograph of hair growth on the back of mice on the 17th day in Example 1.

[0042] Figure 4 This is a graph showing the treatment days versus skin color scores in Example 2.

[0043] Figure 5 These are photos of hair growth on the back of mice on days 1, 10, 18, and 26 in Example 2.

[0044] Figure 6 is the HE staining picture of the mouse skin tissue in each group in Example 2, wherein Figure 6 -A is a longitudinal section, Figure 6 -B is a cross-section diagram. DETAILED DESCRIPTION

[0045] The present disclosure is further described below in conjunction with specific examples, and the advantages and features of the present disclosure will become clearer as the description proceeds. Where specific conditions are not specified in the examples, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0046] The embodiments of the present disclosure are merely exemplary and do not constitute any limitation on the scope of the present disclosure. It should be understood by those skilled in the art that the details and forms of the technical solutions of the present disclosure may be modified or replaced without departing from the spirit and scope of the present disclosure, but these modifications and replacements all fall within the scope of protection of the present disclosure.

[0047] Example 1: Therapeutic effect of topical administration of R-JAC4 on androgen-induced alopecia mouse model

[0048] 6-8 week old C57BL / 6J male mice (weight 21-23g) were divided into three groups, 12 in each group. After the mice were adaptively raised, the mice in the model control group and the experimental group were subcutaneously injected with testosterone propionate (5mg / kg.d) once a day during the whole experimental period. After 14 days of testosterone propionate injection, the mice were anesthetized with isoflurane gas and then depilated on the back. First, a 2cm×3cm area was shaved with a shaver, and then Veet depilatory cream was evenly applied on the mouse skin surface. After standing for 30 seconds, the hair was gently shaved against the hair direction with a depilatory razor, and finally washed with clean water. Wipe off any residual depilatory cream on the skin surface to avoid burning the mouse skin, and confirm that the mouse hair is in the resting phase (the skin is pink) and the skin is not damaged. The day of hair removal is counted as day 0, and group medication begins on the first day after hair removal. After hair removal, dihydrotestosterone is continuously injected until the end of the experiment. Observe the condition of the mice and whether the skin is wrinkled or damaged, weigh them on days 0, 7, 10, 14, 17, and 21, take photos of the mouse hair growth and perform hair growth scoring until the end of the experiment, and record the time when the mouse skin begins to darken and the time when it begins to grow. See the scoring criteria for skin color changes for details. Figure 1 .

[0049] Animals were divided into normal control group, model control group and experimental group. The experimental group was administered with 1% R-JAC4 through skin application, while the model control group was applied with solvent (40% Transcutol P, 30% anhydrous ethanol, 25% glycerol, 5% Span 20) once a day for 20 days, and both were applied to the hair removal area. Figure 2 As shown: After administration of compound R-JAC4, the hair growth of mice was significantly accelerated and the skin color score was significantly higher than that of mice in the model control group. Figure 3 This is a photo of mouse hair growth on day 17. Figure 3 It can be seen that after administration of compound R-JAC4, the hair density of mice on the 17th day was significantly higher than that of mice in the model control group.

[0050] Example 2: Therapeutic effect of oral administration of JAC4 on androgen-induced alopecia mouse model

[0051] 6-8 week old C57BL / 6J male mice (weight 21-23g) were selected and divided into five groups, 5 mice in each group. After the mice were adaptively raised, the mice in the model control group and the experimental group were subcutaneously injected with testosterone propionate (5mg / kg.d) once a day throughout the experimental period. After 14 days of testosterone propionate injection, the mice were anesthetized with isoflurane gas and then depilated on the back. First, a 2cm×3cm area was shaved with a shaver, and then Veet depilatory cream was evenly applied to the surface of the mouse skin. After standing for 30 seconds, the hair was gently shaved against the direction of the hair with a depilatory razor. Finally, the residual depilatory cream on the skin surface was fully wiped with clean water to avoid burning the mouse skin. It was confirmed that the mouse hair was in the resting phase (the skin was pink) and the skin was not damaged. The day of depilation was counted as day 0, and the group administration began on the first day after depilation. After depilation, dihydrotestosterone was continuously injected until the end of the experiment. Observe the condition of the mice and whether their skin is wrinkled or damaged. Weigh them on the 1st, 10th, 18th, and 26th days, take photos of the mice's hair growth, and score their hair growth until the end of the experiment. Record the time when the mice's skin starts to darken and when it starts to grow. See the scoring criteria for skin color changes for details. Figure 1 .

[0052] Animal groups: G1 normal control group, G2 model control group, G3 JAC4 50mg / kg group, G4 JAC4 150mg / kg group, G5 5% minoxidil group. G2 model control group was intragastrically administered with drug solvent (47.5% polyethylene glycol + 2.5% anhydrous ethanol + 50% saline), G3 JAC4 50mg / kg group and G4 JAC4 150mg / kg group were intragastrically administered with corresponding doses of JAC4, and G5 5% minoxidil group was smeared on the skin (applied to the depilated area). G2-G5 were administered once a day for 35 days. At the end of the experiment, the skin of the treated area of ​​the mice was fixed with formalin for subsequent pathological preparation and evaluation of hair follicle growth in skin tissue.

[0053] The experimental results are as follows Figure 4-6 As shown. Figure 4 As shown: After administration of compound JAC4, the hair growth of mice was significantly accelerated and the skin color score was significantly higher than that of mice in the model control group. Figure 5 These are photos of mouse hair growth on days 1, 10, 18, and 26. It can be seen from the pictures that after administration of compound JAC4, the hair density of mice on days 10 and 18 was significantly higher than that of mice in the model control group. Figure 6 -A is the HE staining (longitudinal section) of the skin tissue of mice in each group. The pathological staining results show that JAC4 can inhibit the miniaturization of hair follicles and increase the thickness of the dermis in mice with androgenic alopecia model; Figure 6 -B is the HE staining (cross-section) of the skin tissue of each group of mice. The pathological HE staining results show that JAC4 can promote the increase of hair follicles in androgenic alopecia model mice.

Claims

1. Use of a JWA gene activator or a pharmaceutical composition thereof in the preparation of a drug for preventing or treating hair loss.

2. The use according to claim 1, wherein The hair loss is selected from androgenetic alopecia.

3. The use according to claim 1 or 2, wherein The JWA gene activator is selected from the compound of formula (I) or a pharmaceutically acceptable salt thereof, 4. The use according to claim 3, wherein The compound of formula (I) is selected from 5. The use according to claim 4, wherein The compound of formula (I) is selected from 6. The use according to any one of claims 1 to 5, wherein The pharmaceutical composition comprises the JWA gene activator and pharmaceutically acceptable excipients.

7. The use according to claim 6, wherein The pharmaceutical composition is administered orally or topically.

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