Application of MAT2A inhibitor in preparation of medicine for treating psoriasis

Abstract

The invention relates to an application of a MAT2A inhibitor in preparation of a medicine for treating psoriasis. The invention provides an application of a novel MAT2A inhibitor (E)-5-2-chloro-6-fluorostyryl-N, N-dimethyl pyridine-2-amine, and an application of the MAT2A inhibitor in preparation of a medicine for treating psoriasis. Animal experiment results show that an external administration mode of the MAT2A inhibitor has a remarkable treatment effect on psoriasis mice, the influence on the body weight is small, and obvious toxic and side effects are not observed; the invention provides a new direction for treating psoriasis.

Description

Technical Field

[0001] The present invention relates to the use of a novel MAT2A inhibitor in the preparation of a drug for treating psoriasis, and belongs to the field of medicine. Background Art

[0002] Psoriasis is a chronic inflammatory disease. The skin lesions are mainly manifested as scaly erythematous plaques. It can occur all over the body, but is more common on the scalp and extensor sides of the limbs. The condition often worsens in winter. The typical manifestation of psoriasis is red papules or plaques on the skin, covered with multiple layers of silvery white scales, which can be distributed locally or widely on the body, such as the scalp, hands, feet, trunk and gluteal groove. Psoriasis can be divided into four types: common type, pustular type, arthrosis type and erythrodermic type, of which common type is the most common. The pathogenesis of psoriasis is very complex, and genetics, immunity and multiple environmental interactions may induce the occurrence of psoriasis. One of the pathophysiological characteristics of psoriasis is the abnormal proliferation and differentiation of keratinocytes (such as thickening of the epidermal spinous layer (acanthosis), nuclear retention in keratinocytes (parakeratosis), etc.).

[0003] 80% of patients with psoriasis vulgaris have mild symptoms, so local treatment is the preferred treatment for psoriasis vulgaris. Currently, commonly used topical drugs include glucocorticoid ointments (such as desonide cream, hydrocortisone butyrate cream), retinoic acid ointments (such as tazarotene gel), vitamin D3 derivatives (such as calcipotriol ointment), etc. These drugs can reduce inflammation, inhibit immune response and promote normalization of skin cells. Anthraquinone, tar preparations and glucocorticoids are limited in use due to their large side effects, and the therapeutic effects of retinoic acid, calcineurin inhibitors and vitamin D derivatives are not very ideal. The recently launched compound preparation of glucocorticoids and vitamin D derivatives, calcipotriol betamethasone ointment, is slightly better than calcipotriol, but its cost is high. The limited selection of topical drugs, the easy occurrence of tolerance and the safety of long-term medication have always been the bottleneck of local treatment of psoriasis, so the development of new drugs for the treatment of psoriasis is of great significance.

[0004] Methionine adenosyltransferase 2a (MAT2A) plays an important role in metabolism and epigenetics. The currently known functions and effects are:

[0005] 1. Participation in methionine metabolism: MAT2A is a member of the methionine adenosyltransferase family, which is mainly responsible for catalyzing the reaction of methionine with ATP to generate S-adenosylmethionine (SAM) and AMP. This reaction is the first step in methionine metabolism and is essential for maintaining normal methionine levels in the body.

[0006] 2. Influence on DNA methylation: SAM is an important methyl donor in the process of DNA methylation. Therefore, the activity of MAT2A directly affects the methylation state of DNA, which in turn may affect gene expression and regulation.

[0007] 3. Association with diseases: Studies have shown that abnormal expression or activity of MAT2A is associated with a variety of diseases, including tumors, cardiovascular diseases, and nervous system diseases. For example, in liver cancer, the expression level of MAT2A is often increased, which may be related to the proliferation and survival of tumor cells.

[0008] Since MAT2A is closely related to the occurrence and development of many diseases, it is expected to become a new diagnostic marker or therapeutic target for these diseases. For example, by detecting the expression level of MAT2A in blood or tissue, it can assist in the diagnosis of diseases such as liver cancer. At the same time, inhibitors or agonists targeting MAT2A may also provide new ideas and methods for the treatment of these diseases. Understanding the function and mechanism of action of MAT2A will help develop drugs or treatments targeting it. For example, reducing the amount of SAM produced by inhibiting the activity of MAT2A may help inhibit the proliferation and survival of tumor cells. In addition, drugs or compounds that can enhance the activity of MAT2A can also be studied to promote the proliferation and repair of normal cells.

[0009] In summary, methionine adenosyltransferase 2a (MAT2A) is an enzyme that plays a key role in methionine metabolism, and its abnormal expression or activity is closely related to the occurrence and development of a variety of diseases. Therefore, in-depth research on the function and mechanism of action of MAT2A is of great significance for the diagnosis and treatment of diseases, and can also find new solutions for the treatment of psoriasis. Summary of the invention

[0010] In view of the problems existing in the prior art, one of the objects of the present invention is to provide a use of a MAT2A inhibitor, specifically the use of (E)-5-2-chloro-6-fluorophenylvinyl-N,N-dimethylpyridin-2-amine in the preparation of a drug for treating psoriasis; the structural formula of the MAT2A inhibitor is shown in Formula I:

[0011]

[0012] Accordingly, the compound of formula I has the chemical formula C 15 H 14 ClFN2, chemical name is (E)-5-2-chloro-6-fluorostyryl-N,N-dimethylpyridin-2-amine, (E)-5-(2-chloro-6-fluorostyryl)-N,N-dimethylpyridin-2-amine. Preferably, the above-mentioned psoriasis is psoriasis vulgaris.

[0013] Preferably, the above-mentioned drug is a drug that alleviates and improves psoriasis by inhibiting the activity of methionine adenosyltransferase 2a.

[0014] A second object of the present invention is to provide a pharmaceutical composition, wherein the above-mentioned MAT2A inhibitor is an active ingredient of the pharmaceutical composition.

[0015] Preferably, the above-mentioned medicine is an external medicine; in a preferred embodiment, it is an external medicine in the form of a cream.

[0016] Preferably, the external medicine further comprises an external matrix, and the external medicine is prepared by mixing the above-mentioned MAT2A inhibitor with the matrix.

[0017] More preferably, the matrix is ​​selected from white vaseline, stearyl alcohol, glyceryl monostearate, p-hydroxybenzoic acid, glycerin, sodium lauryl sulfate and water; wherein white vaseline, stearyl alcohol, glyceryl monostearate and p-hydroxybenzoic acid are the oil phase, and glycerin, sodium lauryl sulfate and water are the aqueous phase.

[0018] The mass percentage of the active ingredient in the external medicine is 0.5% to 3%, and the optimal mass percentage is 2%.

[0019] Compared with the prior art, MAT2A inhibitor is a new target. From the results of animal experiments, it can be seen that the topical administration of (E)-5-2-chloro-6-fluorophenylvinyl-N,N-dimethylpyridin-2-amine has a significant therapeutic effect on psoriasis mice, with little effect on body weight, and no obvious toxic side effects are observed; the present invention provides a new direction for the treatment of psoriasis. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is a photo of the back of mice in the animal experiment of the external preparation obtained in Example 1;

[0021] Figure 2 This is the HE staining result of the animal experiment of the external preparation obtained in Example 1;

[0022] Figure 3 This is a statistical result diagram of the animal spleen weight experiment of the external preparation obtained in Example 1;

[0023] Figure 4 This is a statistical graph of the PASI test results of the external preparation obtained in Example 1;

[0024] Figure 5 This is a statistical graph of the animal body weight experiment results of the external preparation obtained in Example 1; DETAILED DESCRIPTION

[0025] The present invention is further described in detail and completely below in conjunction with the embodiments. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0026] The experimental methods in the following examples, unless otherwise specified, are generally carried out under conventional conditions such as those described in the Pharmacology Experimental Manual, 3rd edition, Science Press, 2002, wherein the methods for modeling imiquimod (IMQ) and the efficacy of psoriasis are based on published literature ("Lysophosphatidylcholine facilitates the pathogenesis of psoriasis through activating keratinocytes and T cells differentiation via glycolysis" in Journal of the European Academy of Dermatology and Venereology), or according to the conditions recommended by the manufacturer. Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products and can be purchased through commercial channels.

[0027] The main materials involved in the embodiments of the present invention are as follows:

[0028] 1. Experimental Animals

[0029] Specific pathogen-free (SPF) BAL B / C male mice, 6-8 weeks old, weighing 20-25 g, were purchased from Hunan Slake Jingda Laboratory Animal Co., Ltd. and raised in the Experimental Animal Center of Central South University. This study has passed the ethical review of experimental animal welfare of Central South University. The "3R" principle was strictly followed during the experiment to minimize the pain and discomfort of the animals.

[0030] 2. Experimental Reagents

[0031]

[0032] Example 1

[0033] 1. Preparation of topical cream preparations

[0034] Weigh (E)-5-2-chloro-6-fluorophenylvinyl-N,N-dimethylpyridin-2-amine (hereinafter referred to as CX-8a) with weighing paper, 100 mg is dissolved in 250 μL of DMSO to prepare a solution for use. Add 0.4 g of octadecanol, 0.6 g of white vaseline, 0.01 g of p-hydroxybenzoic acid and 0.1 g of glyceryl monostearate to a beaker according to the indicated proportion, and then put it into a constant temperature heating magnetic stirrer preheated to 70°C, and heat it in a 70°C water bath to dissolve, and obtain the oil phase of the cream; at the same time, add 0.05 g of sodium dodecyl sulfate, 0.35 g of glycerol and 3.5 g of water to another beaker in proportion and heat it to dissolve, and obtain the water phase of the cream. Then slowly add the water phase to the oil phase and stir for 10 minutes, and finally slowly add the CX-8a solution and continue stirring for 10 minutes to obtain the above-mentioned external ointment for treating psoriasis, place it at room temperature and stir it quickly with a glass rod to a semi-solid state at room temperature, and bottle it for use.

[0035] Comparative Example 1

[0036] The difference between this comparative example and Example 1 is that CX-8a is not added as an active ingredient, and the amount of cream excipients is the same as that of Example 1. White vaseline, octadecyl alcohol, glyceryl monostearate and p-hydroxybenzoic acid are added to a beaker in proportion, placed in a DF-101S heat-collecting constant temperature heating magnetic stirrer, heated in a 70°C water bath to dissolve, and stirred for 10 minutes to obtain the oil phase of the cream; at the same time, glycerol, sodium lauryl sulfate and water are added to another beaker in proportion and heated to dissolve, stirred for 5 minutes to obtain the water phase of the cream. Then slowly add the water phase to the oil phase and stir for 10 minutes, place at room temperature and stir quickly with a glass rod to a semi-solid state at room temperature to obtain a control cream preparation without CX-8a.

[0037] Experimental study on the treatment of Imiquimod (IMQ)-induced psoriasis in mice

[0038] 1. Imiquimod (IMQ) modeling

[0039] The imiquimod-induced mouse model can well simulate psoriasis symptoms similar to those of humans in terms of skin thickening, abnormal keratinocyte-related proteins, inflammatory cell infiltration and related inflammatory cytokines. This model has become one of the most widely studied and applied psoriasis models due to its simplicity, ease of operation and stability.

[0040] 2. Therapeutic experiments

[0041] 1) Dosage regimen

[0042] Eighteen SPF 6-8 week old BALB / C mice were randomly divided into three groups, each with six mice, and the back hair was shaved in an area of ​​2 cm × 2 cm. The treatment of each group was as follows:

[0043] Experimental Group Dosage Blank control group (Control) Do nothing IMQ control group (topical administration) Apply the cream preparation obtained in Comparative Example 1 on the back 3 hours after applying imiquimod External medication group Apply the cream preparation obtained in Example 1 on the back 3 hours after applying imiquimod

[0044] After 5 consecutive days of application of the drug in each group, in order to evaluate the severity of skin inflammation in mice, the Psoriasis Lesion Area and Severity Index (PASI) was used to score the back lesions of mice in each group to examine the psoriasis-like symptoms of mice. The severity of erythema and scales was 0, none; 1, mild; 2, moderate; 3, obvious; 4, severe. The daily food intake, body weight and PASI score were recorded. Then the mice were weighed and photographed and killed, and the back lesions were taken for HE staining to examine the thickness of the epidermis, that is, the proliferation of keratinocytes.

[0045] 2) Experimental results

[0046] Figures 1 to 5 The following are the comparison charts of the experimental results of the blank control group, IMQ control group and external medication group; Figure 1 is the treatment effect phenotype diagram of the topical medication group, such as Figure 1 As shown in the figure, the back skin lesions of the positive control group showed obvious erythema, thickening and scaling compared with the blank control group, proving that the psoriasis model was successfully induced after applying imiquimod. Compared with the IMQ control group, the erythema, infiltration and thickening of the topical medication group were significantly reduced, indicating that the topical medication group can effectively treat psoriasis. Figure 2 As shown in the figure, HE staining also showed obvious pathophysiological changes in the skin lesions of the IMQ control group: hyperkeratosis with incomplete keratinization, thickening of the stratum corneum, epidermal hyperplasia, inflammatory cell infiltration, and visible Munro microabscesses. The skin lesions of the topical medication group were significantly improved. Figure 3 As shown in the figure, compared with the blank control group, the spleen weight of mice in the IMQ control group and the topical administration group A increased significantly, indicating that IMQ application caused a significant inflammatory response. Figure 4 As shown in the figure, compared with the IMQ control group, statistical analysis also found that the PASI score of mice in the topical administration group A was significantly improved, indicating that CX-8a can effectively treat psoriasis (*P<0.05, **P<0.01, ***P<0.001). Figure 5 As shown, taking the blank control group as a benchmark, the weight loss of mice in the topical administration group A was significantly alleviated compared with the IMQ control group, indicating that CX-8a played a certain protective role.

[0047] Finally, it is necessary to explain here that the above embodiments are only used to further illustrate the technical solution of the present invention in detail and cannot be understood as limiting the scope of protection of the present invention. Any technician familiar with this profession, without departing from the scope of the technical solution of this application, using the above-disclosed technical content to make slight changes, modifications, substitutions, combinations, and simplifications should all be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A use of a MAT2A inhibitor, characterized in that: Application of (E)-5-2-chloro-6-fluorophenylvinyl-N,N-dimethylpyridin-2-amine in the preparation of drugs for treating psoriasis.

2. The use according to claim 1, characterized in that The psoriasis is psoriasis vulgaris.

3. A pharmaceutical composition, characterized in that The active ingredient of the pharmaceutical composition is the MAT2A inhibitor (E)-5-2-chloro-6-fluorophenylvinyl-N,N-dimethylpyridin-2-amine.

4. The pharmaceutical composition according to claim 3, characterized in that The pharmaceutical composition is an external medicine.

5. The pharmaceutical composition according to claim 3, characterized in that The pharmaceutical composition is a cream for external use.

6. The pharmaceutical composition according to claim 4, characterized in that The external medicine also includes an external matrix, and the external medicine is prepared by mixing (E)-5-2-chloro-6-fluorophenylvinyl-N,N-dimethylpyridin-2-amine with the matrix.

7. The pharmaceutical composition according to claim 4, characterized in that The mass percentage of the active ingredient in the external medicine is 0.5% to 3%.

8. The pharmaceutical composition according to claim 4, characterized in that The mass percentage of the active ingredient in the external medicine is 2%.

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