Composition for preventing or treating asthma comprising resistin inhibitor as active ingredient

Abstract

The present invention relates to a composition for preventing or treating asthma, comprising a resistin inhibitor as an active ingredient. Obesity-associated asthma exhibits different patterns from general asthma as a result of structural changes in the lungs caused by fat deposition in the airways, systemic inflammatory responses, changes in sex-related hormonal mechanisms, etc. Accordingly, obesity-associated asthma has recently been newly defined as a phenotype on the basis of the onset of asthma or the presence or absence of sensitization to allergens. Therefore, there is a need for a therapeutic agent or treatment method specific to obesity-associated asthma as distinct from general asthma, but research thereon still remains insufficient. The resistin inhibitor provided in the present invention exhibits a remarkable therapeutic effect on asthma, especially asthma caused by obesity, and thus is expected to be actively used in the medical and health fields.

Description

A composition for the prevention or treatment of asthma comprising a resistin inhibitor as an active ingredient

[0001] The present invention relates to a composition for the prevention or treatment of asthma comprising a resistin inhibitor as an active ingredient.

[0002] Obesity is a disease with an increasing prevalence in Korea. According to the results of the Korea National Health and Nutrition Examination Survey, a body mass index (BMI) of 25 kg / m² 2Based on the above, the prevalence of obesity among adults in Korea showed a steady upward trend from 25.1% in 1998 to 38.4% in 2021. The prevalence of asthma is also increasing, similar to obesity. While asthma was generally known to occur mainly in the elderly population aged 60 to 70 and older, an analysis of data from approximately 92,000 people based on the Korea National Health and Nutrition Examination Survey from 2007 to 2018 revealed that the prevalence of asthma among those in their 20s increased significantly from about 0.7% in 2007 to about 5.1% in 2018. Asthma is a disease characterized by the recurrent and paroxysmal occurrence of symptoms such as coughing, wheezing, and shortness of breath due to bronchial constriction caused by a chronic allergic inflammatory response. Since excessive adipose tissue triggers the migration of mast cells through inflammation, and substances such as histamine and inflammatory cytokines secreted by mast cells significantly influence allergic diseases like asthma, a link between obesity and allergic diseases, particularly asthma, has long been proposed. Obesity-associated asthma exhibits characteristics different from general asthma due to structural changes in the lungs, systemic inflammatory responses, and alterations in sex-related hormonal mechanisms resulting from the deposition of fat in the airways. Consequently, obesity-associated asthma is recently being newly defined as a phenotype based on the onset of asthma or the presence of sensitization to allergens. Therefore, while there is a need for specific treatments or therapies for obesity-associated asthma to distinguish it from general asthma, research in this area remains insufficient.

[0003] Accordingly, the present invention has been devised to solve the above-mentioned problem and relates to a resistin inhibitor that exhibits a significant therapeutic effect on asthma, particularly asthma associated with obesity, and a pharmaceutical composition containing the same as an active ingredient.

[0004] One objective of the present invention is to provide a composition capable of preventing, improving, or treating asthma by including a resistin inhibitor as an active ingredient.

[0005] Another objective of the present invention is to provide a method for preventing, improving, or treating asthma using the above-described composition.

[0006] In a preferred embodiment of the present invention, the asthma may be asthma associated with obesity, but is not limited thereto.

[0007] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art from the description below.

[0008] Various embodiments described herein are described with reference to the drawings. In the following description, for a complete understanding of the invention, various specific details, such as specific forms, compositions, and processes, are described. However, specific embodiments may be practiced without one or more of these specific details, or in combination with other known methods and forms. In other examples, known processes and manufacturing techniques are not described as specific details so as not to unnecessarily obscure the invention. Reference throughout this specification to "one embodiment" or "an embodiment" means that the particular features, forms, compositions, or characteristics described in association with the embodiment are included in one or more embodiments of the invention. Accordingly, the context of "in one embodiment" or "an embodiment" expressed at various places throughout this specification does not necessarily represent the same embodiment of the invention. Additionally, particular features, forms, compositions, or characteristics may be combined in any suitable way in one or more embodiments.

[0009] Unless otherwise specifically defined in the specification, all scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains.

[0010] In the present invention, the term “resistin inhibitor” means a substance that inhibits the synthesis or activity of a resistin protein expressed by the RETN gene, or inhibits the expression of the RETN gene itself. Although not limited thereto, the inhibitor may specifically be a substance represented by the following chemical formula 1.

[0011] In the present invention, as a result of screening various candidate substances, a compound of the following chemical formula 1 was derived as a candidate substance for treating asthma.

[0012] [Chemical Formula 1]

[0013]

[0014] Hereinafter, the compound of the present invention, or the selected compound of the present invention, refers to the compound of Chemical Formula 1.

[0015] In one aspect of the present invention, the present invention provides a compound selected from the compound represented by Formula 1, its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates.

[0016] The above-mentioned pharmaceutically acceptable salt is a salt generally considered by those skilled in the art to be suitable for medical application (e.g., because such salt is not harmful to the subject to be treated with said salt), or a salt that causes acceptable side effects within each treatment. Generally, the above-mentioned pharmaceutically acceptable salt is a salt considered acceptable by regulatory authorities such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceuticals and Medical Devices Agency (PMDA) of the Japanese Ministry of Health, Labour and Welfare. However, in principle, the present invention also includes, for example, an intermediate in the preparation of a compound according to the present invention or a physiologically active derivative thereof, or a salt of a compound according to the present invention that is not pharmaceutically acceptable in itself as a pharmaceutically acceptable salt of the compound according to the present invention or as an intermediate in the preparation of a physiologically active derivative thereof. The above-mentioned salt includes water-insoluble salts, and in particular, includes water-soluble salts.

[0017] In each case, a person skilled in the art can easily determine whether a specific compound according to the present invention or its physiologically functional derivative can form a salt, that is, whether the compound according to the present invention or its physiologically functional derivative has a charged group such as, for example, an amino group, a carboxylic acid group, etc.

[0018] Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, in particular pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmaceuticals, which are water-insoluble or particularly water-soluble acid addition salts. Depending on the substituents of the compounds of the present invention, salts with bases may also be suitable. Acid addition salts may be formed, for example, by mixing a solution of the compounds of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. Likewise, pharmaceutically acceptable base addition salts are alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); It may include salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium, and amine cations formed using counteranions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfons, and aryl sulfons).Exemplary examples of pharmaceutically acceptable salts include acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphosulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecyl sulfate, edetate, edicylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate. Hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, mandelate, methanesulfonate (mesylate), methyl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subverate, succinate, tannate, tartrate, tosylate, undecanoate, valerate, etc. are included but not limited thereto.

[0019] A salt that is not pharmaceutically acceptable and, for example, may be obtained as a process product during the manufacture of a compound according to the present invention on an industrial scale is also included in the present invention, and if desired, can be converted into a pharmaceutically acceptable salt by a method known to those skilled in the art.

[0020] Meanwhile, since the compounds according to the present invention may have asymmetric carbon centers, they may exist as R or S isomers or racemic compounds, and all of these optical isomers and mixtures may be included within the scope of the present invention.

[0021] In addition, the compounds of the present invention as well as their salts may contain varying amounts of solvent, for example, when separated into crystalline forms. Accordingly, solvates of the compounds of the present invention, particularly hydrates, as well as solvates of the salts of the compounds of the present invention, particularly hydrates, may be included within the scope of the present invention. More particularly, the present invention may include hydrates of compounds, salts, and / or physiologically functional derivatives according to the present invention, comprising one, two, or half molecules of water with respect to stoichiometry.

[0022] Hereinafter, the compound of the present invention refers to the compound described above.

[0023] In another aspect of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of asthma comprising a resistin protein or an inhibitor of the gene encoding it as an active ingredient. In this case, the resistin protein or the inhibitor of the gene encoding it may specifically be a compound selected from the compound represented by Formula 1, and its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates.

[0024] The above asthma may more preferably be obesity-associated asthma, in which obesity has influenced the onset or exacerbation of the asthma. Accordingly, in such cases, the pharmaceutical composition of the present invention is a pharmaceutical composition for the prevention or treatment of obesity-associated asthma comprising, as an active ingredient, a compound selected from the compound represented by Formula 1, and its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates, wherein "obesity-associated asthma" refers to a case where obesity was diagnosed in the same individual prior to the onset or exacerbation of the said asthma. In this case, the obesity is a condition in which there is an excess of adipose tissue in the body, and the body mass index (BMI: weight (kg) divided by the square of height (m)) is 25 or higher; or even if the BMI is less than 25, the body fat percentage is 25% or higher for men and 30% or higher for women. and cases in which dyslipidemia is diagnosed even if the body mass index is less than 25 and the body fat percentage is less than 25% for men and less than 30% for women;

[0025] The above pharmaceutical composition is intended for the purpose of preventing or treating asthma. The prevention or treatment described herein comprehensively includes activities that suppress the onset or exacerbation of asthma or improve symptoms of asthma associated with obesity.

[0026] In the present invention, the pharmaceutical composition may be characterized in that it is in the form of a capsule, tablet, granule, injection, ointment, powder, or beverage, and the pharmaceutical composition may be characterized in that it is intended for humans.

[0027] The pharmaceutical composition of the present invention is not limited to these, but may be formulated and used in the form of oral formulations such as powders, granules, capsules, tablets, and aqueous suspensions, as well as topical preparations, suppositories, and sterile injectable solutions, according to conventional methods. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. For oral administration, the pharmaceutically acceptable carrier may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, flavorings, etc. For injectable preparations, it may include buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc., in combination; and for topical administration, a base, excipients, lubricants, preservatives, etc. may be used. The formulations of the pharmaceutical composition of the present invention may be prepared in various ways by mixing with the pharmaceutically acceptable carriers described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injectables, it can be manufactured in the form of unit dosing ampoules or multiple dosing ampoules. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained-release formulation, etc.

[0028] Meanwhile, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil. Additionally, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc. may be additionally included.

[0029] Routes of administration of the pharmaceutical composition according to the present invention include, but are not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual, or rectal. Oral or parenteral administration is preferred. Parenteral administration includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intradural, intralesional, and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

[0030] The pharmaceutical composition of the present invention may vary depending on several factors including the activity of the specific compound used, age, body weight, general health, gender, diet, time of administration, route of administration, release rate, drug combination, and the severity of the specific disease to be prevented or treated, and the dosage of the pharmaceutical composition may be appropriately selected by a person skilled in the art, depending on the patient's condition, body weight, degree of disease, drug form, route of administration, and duration, and may be administered at a dose of 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg per day. Administration may be administered once a day or divided into several doses. The dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as a pill, coated tablet, capsule, liquid, gel, syrup, slurry, or suspension.

[0031] The pharmaceutical composition of the present invention may be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers.

[0032] The present invention also provides a method for the prevention, improvement, or treatment of asthma, comprising the step of administering to a subject requiring administration (e.g., a human) a pharmaceutically effective amount of a pharmaceutical composition comprising, as an active ingredient, a compound selected from the compound of the present invention, pharmaceutically acceptable salts, crystalline forms, cocrystalline forms, optical isomers, derivatives, hydrates, and solvates thereof. In this case, "administration" means providing a predetermined compound of the present invention to the subject by any appropriate method.

[0033] Specific details regarding the asthma disease, pharmaceutical composition, and route of administration in the above-mentioned method for the prevention, improvement, or treatment of asthma are omitted to avoid excessive complexity of the specification, as they overlap with those described in the above-mentioned “pharmaceutical composition comprising as an active ingredient a compound selected from the compounds of the present invention, pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates thereof.”

[0034] In the present invention, the "subject" requiring administration may include both mammals and non-mammalians. Here, examples of mammals may include, but are not limited to, humans, non-human primates such as chimpanzees, and other ape and monkey species; domesticated animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals such as rodents such as rats, mice, and guinea pigs. Additionally, examples of non-mammalians in the present invention may include, but are not limited to, birds and fish.

[0035] In the present invention, the “pharmaceuticalally effective amount” refers to a sufficient amount of agent to provide a desirable biological result. Such result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desirable change in the biological system. For example, the “effective amount” for therapeutic use is the amount of the compound disclosed in the present invention required to provide a clinically significant reduction in the disease. In any individual case, an appropriate “effective” amount may be determined by a person skilled in the art using routine experiments. Accordingly, the expression “effective amount” generally refers to an amount of the active substance that has a therapeutic effect.

[0036] In another aspect of the present invention, the present invention provides a food composition for the prevention or improvement of asthma comprising a resistin protein or an inhibitor of the gene encoding it as an active ingredient. In this case, the resistin protein or the inhibitor of the gene encoding it may specifically be a compound selected from the compound represented by Formula 1, and its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates.

[0037] The above asthma may more preferably be obesity-associated asthma, in which obesity has influenced the onset or exacerbation of the asthma. Accordingly, in such cases, the food composition of the present invention is a food composition for the prevention or improvement of obesity-associated asthma comprising, as an active ingredient, a compound selected from the compound represented by Formula 1, its pharmaceutically acceptable salt, crystalline form, co-crystal, optical isomer, derivative, hydrate, and solvate, wherein "obesity-associated asthma" refers to a case where obesity was diagnosed in the same individual prior to the onset or exacerbation of the said asthma. In this case, the obesity is a condition in which there is an excessive amount of adipose tissue in the body, and the body mass index (BMI: weight (kg) divided by the square of height (m)) is 25 or higher; or even if the BMI is less than 25, the body fat percentage is 25% or higher for men and 30% or higher for women. and cases in which dyslipidemia is diagnosed even if the body mass index is less than 25 and the body fat percentage is less than 25% for men and less than 30% for women;

[0038] The above food composition is intended for the purpose of preventing or improving asthma. Prevention or improvement as described herein comprehensively includes activities that suppress the onset or exacerbation of asthma or improve symptoms of asthma associated with obesity.

[0039] In the present invention, the food composition is used in various ways for the indications intended in the present invention, namely the prevention or improvement of asthma. The food composition containing the compound of the present invention may be manufactured in the form of various food products, such as beverages, chewing gum, tea, vitamin complexes, powders, granules, tablets, capsules, jellies, confectionery, rice cakes, bread, etc. When the composition of the present invention is included in the food composition, the amount may be added in a ratio of 0.1 to 100% of the total weight. Here, when the food composition is manufactured in the form of a beverage, there are no special limitations other than containing the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients, as in ordinary beverages. That is, as natural carbohydrates, it may include monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. Examples of the above-mentioned flavoring agents include natural flavoring agents (taumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.). In addition, the food composition of the present invention may contain various nutritional agents, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These ingredients may be used independently or in combination. The proportion of such additives is generally selected in the range of 0.1 to 100 parts by weight per 100 parts by weight of the composition of the present invention, but is not limited thereto.

[0040] In another aspect of the present invention, the present invention provides a cosmetic composition for the prevention or improvement of asthma comprising a resistin protein or an inhibitor of the gene encoding it as an active ingredient. In this case, the resistin protein or the inhibitor of the gene encoding it may specifically be a compound selected from the compound represented by Formula 1, and its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates.

[0041] The above asthma may more preferably be obesity-associated asthma, in which obesity has influenced the onset or exacerbation of the above asthma. Accordingly, in such cases, the cosmetic composition of the present invention is a cosmetic composition for the prevention or improvement of obesity-associated asthma comprising, as an active ingredient, a compound selected from the compound represented by Formula 1, and its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates; wherein "obesity-associated asthma" refers to a case where obesity was diagnosed in the same individual prior to the onset or exacerbation of the said asthma. In this case, the obesity is a condition in which there is an excessive amount of adipose tissue in the body, and the body mass index (BMI: weight (kg) divided by the square of height (m)) is 25 or higher; or even if the BMI is less than 25, the body fat percentage is 25% or higher for men and 30% or higher for women. and cases in which dyslipidemia is diagnosed even if the body mass index is less than 25 and the body fat percentage is less than 25% for men and less than 30% for women;

[0042] The above cosmetic composition is intended for the purpose of preventing or improving asthma. The prevention or improvement described herein comprehensively includes activities that suppress the onset or exacerbation of asthma or improve symptoms of asthma associated with obesity.

[0043] In the present invention, the cosmetic composition is used in various ways for the indication intended in the present invention, namely, the prevention or improvement of asthma, and the cosmetic composition containing the compound of the present invention may be manufactured in the form of a lotion, nourishing lotion, nourishing essence, massage cream, beauty bath additive, body lotion, body milk, bath oil, baby oil, baby powder, shower gel, shower cream, sunscreen lotion, sunscreen cream, tanning cream, skin lotion, skin cream, UV protection cosmetic, concealer, cleansing milk, anti-hair loss cosmetic, face and body lotion, face and body cream, skin whitening cream, hand lotion, hair lotion, cosmetic cream, jasmine oil, bath soap, liquid soap, beauty soap, shampoo, hand sanitizer (hand cleaner), medicinal soap (non-medical), cream soap, facial wash, body cleanser, scalp cleanser, hair rinse, cosmetic soap, teeth whitening gel, toothpaste, etc., and preferably It can be manufactured in the form of a cream. To this end, the composition of the present invention may further include a solvent or a suitable carrier, excipient, or diluent that is commonly used in the manufacture of cosmetic compositions.

[0044] In the present invention, the type of solvent that may be further added to the cosmetic composition is not particularly limited, but, for example, water, saline solution, DMSO, or a combination thereof may be used. In addition, carriers, excipients, or diluents include, but are not limited to, purified water, oil, wax, fatty acid, fatty acid alcohol, fatty acid ester, surfactant, humectant, thickener, antioxidant, viscosity stabilizer, chelating agent, buffer, lower alcohol, etc. Additionally, whitening agents, moisturizers, vitamins, sunscreens, perfumes, dyes, antibiotics, antibacterial agents, and antifungal agents may be included as needed.

[0045] In the cosmetic composition of the present invention, hydrocarbon oil, silicone oil, hydrogenated vegetable oil, castor oil, cottonseed oil, olive oil, palm oil, jojoba oil, and avocado oil may be used as the oil, and beeswax, spermaceti, carnauba, candelilla, montan, ceresin, liquid paraffin, and lanolin may be additionally used as the wax.

[0046] In the cosmetic composition of the present invention, stearic acid, linoleic acid, and oleic acid may be used as the fatty acid, cetyl alcohol, octyl dodecanol, oleyl alcohol, panthenol, lanolin alcohol, stearyl alcohol, and hexadecanol may be used as the fatty acid alcohol, and isopropyl myristate, isopropyl palmitate, and butyl stearate may be used as the fatty acid ester. Cationic surfactants, anionic surfactants, and nonionic surfactants known in the art may be used as surfactants, and surfactants derived from natural products are preferred as much as possible.

[0047] In addition to the above, the cosmetic composition of the present invention may include hygroscopic agents, thickeners, antioxidants, etc., which are widely known in the field of cosmetics, and the types and amounts thereof are as known in the art.

[0048] In addition, the cosmetic composition of the present invention may include a color tone.

[0049] In addition, in the present invention, the cosmetic composition may be included in the powder in the form of an emulsion, and the powder may be a mixture of one or more selected from the group consisting of talc, kaolin, mica, sericite, silica, silica dimethyl silylate, nylon-12, methyl methacrylate crosspolymer, polymethyl methacrylate, boron nitride, alumina, titanium dioxide, zinc oxide, iron oxide, silica, pearl, organic dye, lake, and organic pigment, and is not limited thereto as long as it corresponds to powders commonly used in the art.

[0050] In another aspect of the present invention, the present invention provides an expression inhibitor of a resistin (RETN) protein or a RETN gene encoding the same, comprising a compound selected from the compound represented by Formula 1, its salt, crystalline form, co-crystal, optical isomer, derivative, hydrate, and solvate.

[0051] The above compound has the effect of inhibiting the expression of the resistin protein or the RETN gene encoding it. The resistin protein is a factor encoded by the RETN gene and is a cysteine-rich peptide hormone also known as adipose tissue-specific secretory factor (ADSF) or C / EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1).

[0052] It has been suggested that a compound represented by the above chemical formula 1 can be used as a treatment for Alzheimer's disease, muscular dystrophy, or diabetes because it has the function of increasing calcium absorption in the endoplasmic reticulum (ER); however, it has been identified for the first time in the present invention that it can be used as an expression inhibitor of the resistin protein or the gene encoding it. Therefore, the expression inhibitor of the present invention can be usefully utilized in the study of various diseases related to resistin.

[0053] In another aspect of the present invention, the present invention provides a method for preventing or treating asthma comprising the step of administering an effective amount of resistin protein or an inhibitor of the gene encoding it to an individual.

[0054] At this time, the inhibitor of the resistin protein or the gene encoding it may specifically be a compound selected from the compound represented by Chemical Formula 1, and its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates.

[0055] The above asthma may more preferably be obesity-associated asthma, in which obesity has influenced the onset or exacerbation of the asthma. Accordingly, in such cases, the preventive or therapeutic method of the present invention is a method of preventing or treating obesity-associated asthma by administering to an individual an effective amount of a compound represented by Formula 1, a compound selected from its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates, wherein "obesity-associated asthma" refers to a case where obesity was diagnosed in the same individual prior to the onset or exacerbation of the said asthma. In this case, the obesity is a condition in which there is an excess of adipose tissue in the body, and the body mass index (BMI: weight (kg) divided by the square of height (m)) is 25 or higher; or even if the BMI is less than 25, the body fat percentage is 25% or higher for men and 30% or higher for women. and cases in which dyslipidemia is diagnosed even if the body mass index is less than 25 and the body fat percentage is less than 25% for men and less than 30% for women;

[0056] Additionally, in the above-mentioned methods of prevention or treatment, “administration” may be administered via routes of the mouth, intravenous, intramuscular, arterial, bone marrow, dura mater, cardiac, transdermal, subcutaneous, intraperitoneal, nasal, intestinal, topical, sublingual, or rectal, though not limited thereto, and “pharmacologically effective amount” refers to a sufficient amount of agent to provide a desirable biological result. Such result may be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desirable change in the biological system. For example, “effective amount” for therapeutic use is the amount of the compound disclosed in the present invention required to provide a clinically significant reduction in the disease. In any individual case, an appropriate “effective” amount may be determined by a person skilled in the art using routine experiments. Accordingly, the expression “effective amount” generally refers to the amount of the active substance that has a therapeutic effect.

[0057] In another aspect of the present invention, the present invention provides a use of a resistin protein or an inhibitor of the gene encoding it for the prevention or treatment of asthma. In this case, the resistin protein or the inhibitor of the gene encoding it may specifically be a compound selected from the compound represented by Formula 1, and its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates.

[0058] The above asthma may more preferably be obesity-associated asthma in which obesity has influenced the onset or exacerbation of the above asthma. Accordingly, in such cases, the present invention is for the prevention or treatment of asthma using a compound selected from the compound represented by Formula 1, its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates, wherein obesity-associated asthma refers to a case where obesity was diagnosed in the same individual prior to the onset or exacerbation of the said asthma. At this time, the obesity is a condition in which there is an excess of adipose tissue in the body and includes cases where the body mass index (Body mass index: value obtained by dividing weight (kg) by the square of height (m)) is 25 or higher; cases where the body fat percentage is 25% or higher for men and 30% or higher for women even if the body mass index is less than 25; and cases where dyslipidemia is diagnosed even if the body mass index is less than 25 and the body fat percentage is less than 25% for men and less than 30% for women.

[0059] The resistin inhibitor provided in the present invention exhibits a significant therapeutic effect on asthma, particularly asthma associated with obesity, and is therefore expected to be actively utilized in the medical and healthcare fields.

[0060] Figure 1 shows the results of confirming the association between resistin and inflammation in a bronchial epithelial cell line according to one embodiment of the present invention.

[0061] FIG. 2 is a schematic diagram of a drug administration substance and schedule for preparing an asthma or obesity-associated asthma mouse model according to one embodiment of the present invention and for overexpressing or inhibiting resistin in the model.

[0062] Figure 3 shows the change in body weight of an HFD mouse in a test using an anti-resistin antibody according to one embodiment of the present invention.

[0063] Figure 4 shows the results of measuring airway hypersensitivity (AHR) in a test using an anti-resistin antibody according to one embodiment of the present invention.

[0064] FIG. 5 shows the results of staining mouse lung tissue with H&E, PAS, or MT in a test using an anti-resistin antibody according to one embodiment of the present invention.

[0065] FIG. 6 shows the results of counting inflammation-related cells by staining bronchoalveolar lavage fluid (BALF) obtained from mouse lung tissue in a test using an anti-resistin antibody according to one embodiment of the present invention.

[0066] FIGS. 7 and 8 show the results of confirming inflammation-related cytokine expression in mouse lung homogenates with ELISA in a test using an anti-resistin antibody according to one embodiment of the present invention.

[0067] Figure 9 shows the results of confirming whether the resistin gene was properly suppressed or overexpressed by qPCR after extracting RNA from the lung tissue of a mouse in a test using an anti-resistin antibody according to one embodiment of the present invention.

[0068] FIG. 10 is a schematic diagram of a drug administration substance and schedule for preparing an asthma or obesity-associated asthma mouse model according to one embodiment of the present invention and confirming the effect of the resistin inhibitor CDN1163 in the model.

[0069] Figure 11 shows the change in body weight of an HFD mouse in a test using CDN1163 according to one embodiment of the present invention.

[0070] FIG. 12 shows the results of measuring air resistance in a test using CDN1163 according to one embodiment of the present invention.

[0071] FIG. 13 shows the results of counting inflammation-related cells by staining bronchoalveolar lavage fluid (BALF) obtained from mouse lung tissue in a test using CDN1163 according to one embodiment of the present invention.

[0072] Figure 14 shows the results of confirming changes in GTT and ITT caused by resistin inhibition in a test using CDN1163 according to one embodiment of the present invention.

[0073] FIG. 15 shows the staining results using an anti-resistin antibody in a test using CDN1163 according to one embodiment of the present invention.

[0074] FIG. 16 shows the results of staining mouse lung tissue with H&E, PAS, or MT in a test using CDN1163 according to one embodiment of the present invention.

[0075] FIG. 17 shows the results of confirming the change in fibrosis area due to resistin inhibition in a test using CDN1163 according to one embodiment of the present invention.

[0076] FIG. 18 shows the results of confirming inflammation-related cytokine expression in mouse lung homogenates with ELISA in a test using CDN1163 according to one embodiment of the present invention.

[0077] FIG. 19 is a schematic diagram of a drug administration substance and schedule for overexpressing resistin or inhibiting NF-κB in an asthma or obesity-associated asthma mouse model prepared to verify the hypothesis that resistin alleviates inflammation by regulating NF-κB according to one embodiment of the present invention.

[0078] FIG. 20 shows the change in body weight of an HFD mouse in a correlation test between resistin and NF-κB according to one embodiment of the present invention.

[0079] FIG. 21 shows the results of measuring airway resistance in a correlation test between resistin and NF-κB according to one embodiment of the present invention.

[0080] FIG. 22 shows the results of counting inflammation-related cells by staining bronchoalveolar lavage fluid (BALF) obtained from mouse lung tissue in a correlation test between resistin and NF-κB according to one embodiment of the present invention.

[0081] FIG. 23 shows the results of confirming inflammation-related cytokine expression in mouse lung homogenates with ELISA in a correlation test between resistin and NF-κB according to one embodiment of the present invention.

[0082] FIG. 24 shows the results of confirming changes in the expression levels of NF-kB and resistin following resistin overexpression or treatment with an NF-kB inhibitor in a correlation test between resistin and NF-κB according to one embodiment of the present invention.

[0083] FIG. 25 shows the results of confirming the expression of resistin as IF in a correlation test between resistin and NF-κB according to one embodiment of the present invention.

[0084] FIG. 26 shows the results of confirming the expression of resistin under various conditions in a cell test for confirming the correlation between resistin and NF-κB according to one embodiment of the present invention.

[0085] An asthma mouse model was prepared using ovalbumin (OVA), and obesity was induced using a high-fat diet (HFD). The substances administered and the administration schedule for preparing the mouse model are schematically illustrated in Figure 10, and the compound [CDN1163] of [Formula 1] was used as the resistin inhibitor. Mice fed the HFD diet showed approximately a twofold increase in body weight compared to those fed a normal diet at week 13. When airway resistance was measured, it was observed that airway resistance was significantly lower in the HFD / OVA / CDN1163 treatment group compared to the HFD / OVA (obese asthma) group. This indicates that asthma was alleviated due to the inhibition of resistin by CDN1163.

[0086] The present invention will be described in more detail below through examples. These examples are intended solely to explain the present invention more specifically, and it will be obvious to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the invention.

[0087] [Experimental Method]

[0088] 1. Screening of compounds for treating asthma

[0089] The inventors of the present invention screened various candidate substances to discover a therapeutic substance effective for asthma, specifically asthma associated with obesity, and derived a compound of the following chemical formula 1 as a useful candidate substance.

[0090] [Chemical Formula 1]

[0091]

[0092] The compound represented by the above chemical formula 1 was identified as 4-(1-methyl ethoxy)-N-(2-methyl-8-quinolinyl)-benzamide.

[0093] 2. Animal Model Design

[0094] Male C57BL / 6 mice under 5 weeks of age were housed in a pathogen-free animal facility, with 5 mice assigned to each group. Mice in the obesity model group were fed a high-fat diet (HFD, D12492; Research Diets, Inc., New Brunswick, NJ; fat accounted for 60% of calories) for 13 weeks, while control mice were fed a standard diet (D12450B; Research Diets, Inc.; fat accounted for 10%). To establish traditional asthma and obesity-related asthma models, C57BL / 6 mice were assigned to an ovalbumin (OVA) group and an obesity model group. In the OVA model, a mixture of OVA (20 mg per mouse, Sigma-Aldrich, St. Louis, MO, USA) and Inject Alum (100 µl per mouse, Thermo Scientific, Rockford, IL, USA) was injected intraperitoneally twice at 2-week intervals, and OVA (20 mg per mouse) was injected intranasally for 3 consecutive days one week after the second injection. Resistin antibodies, Retnl α antibodies, and / or Retnl β antibodies were injected intravenously three times a day for 5 days, and dexamethasone (Sigma, St. Louis, MO, USA) and recombinant resistin protein were injected intraperitoneally three times a day for 5 days.

[0095] 3. Measurement of Airway Hyperresponsiveness

[0096] Airway hyperresponsiveness (AHR) to inhaled aerosol methacholine (MCh; Sigma-Aldrich) was measured on the day of mouse sacrifice using a forced oscillatory technique (FlexiVent; SCIREQ, Montreal, QC, Canada). Briefly, aerosol phosphate-buffered saline or MCh at various concentrations (0 mg / mL, 6.25 mg / mL, 12.5 mg / mL, 25.0 mg / mL, 50.0 mg / mL, and / or 100 mg / mL) was administered to mice for 10 seconds via a nebulizer connected to a ventilator, and AHR was evaluated by measuring airway resistance.

[0097] 4. Counting of inflammatory cells in bronchoalveolar lavage fluid

[0098] To collect bronchoalveolar lavage fluid (BALF), lung lavage was performed using 1 mL of Hank's balanced salt solution (HBSS) through a tracheal tube. The recovered BALF was centrifuged and suspended in 300 µL of HBSS, and the total cell count was determined using a hemocytometer and trypan blue staining. BALF cells were centrifuged using a cell centrifuge and pelleted onto cell spin slides; the slides were stained with hematoxylin and eosin (H&E Hemacolor; Merck, Darmstadt, Germany), and 200 inflammatory cells were differentially counted per slide.

[0099] 5. Preparation of waste homogenates

[0100] After collecting BALF, the remaining lung tissue was resected and treated with lysis buffer and protease inhibitor solution (Sigma-Aldrich), then homogenized using a tissue homogenizer (Biospec Products, Bartlesville, OK, USA). The tissue was cultured and centrifuged to obtain the supernatant, and the final product was stored at -80°C for cytokine analysis.

[0101] 6. Histological analysis

[0102] Lung tissue not used for BALF collection was fixed in 4% formalin and embedded in paraffin, and lung sections were sectioned to a thickness of 3-4 μm and stained with H&E, periodic acid-Schiff, or Masson trichrome (M&T) for histological analysis. Stained slides were observed under an optical microscope (×200 magnification). Fibrotic areas were measured using the MetaMorph program (Molecular Devices, Sunnyvale, CA, USA) by estimating the number of color pixels for preset threshold colors on M&T-stained slides at ×200 magnification.

[0103] 7. Cell Culture and Processing

[0104] Beas 2b cell line (CRL-3588), epithelial cells isolated from normal human bronchial epithelium, were cultured in DMEM / F12 medium containing 10% fetal bovine serum (FBS, Gibco; Thermo Fisher Scientific) and 1% penicillin / streptomycin at 37°C under 5% CO2 conditions. Subsequently, to establish an in vitro model, resistin (Santa Cruz, sc-39722) siRNA, Retnl α (Santa Cruz, sc-39724) siRNA, and / or Retnl β (Santa Cruz, sc-39725) siRNA were transfected using Lipofectamine 2000 (Thermo, MA, USA). Afterwards, cells were treated for 48 hours using lipopolysaccharide (LPS, 10 µg / ml, Sigma-Aldrich, St. Louis, MO, USA) and / or insulin (10 µg / ml).

[0105] 8. Real-time q-quantitative PCR

[0106] RNA was extracted from tissues using TRIzol reagent (soombio, Seoul, Ko) according to the manufacturer's instructions. cDNA synthesis was performed using cDNA synthesis mix (Gendepot, TX, USA). Real-time PCR analysis (ThermoFisher Scientific) was used to detect the expression of resistin, Retnl α, Retnl β, and / or NF-κb genes. The primer sequences for the amplification of each gene are shown in Table 1 below.

[0107] ResistinF (Sequence No. 1)TGGCTACAGGAGATTTGACACCR (Sequence No. 2)GGAATGTTTGATTCTAAATGTGGGTRetnl αF (Sequence No. 3)CCCTCCACTGTAACGAAGACTR (Sequence No. 4)AGGAATATACTCACCAGCAGGGRetnl βF (Sequence No. 5)AGCACCTTCTCTTGACAGAGCR (Sequence No. 6)GTTACTCACCAGCAGGACNF-κbF (Sequence No. 7)TCAGGAAGAGGTTTGGATGCR (Sequence No. 8)AGCCCCTAATACACGCCTC

[0108] 9. Cytokine Analysis

[0109] The expression concentrations of IL-1β (R&D, DY401-05), TNF-α (R&D, D410), IL-13 (R&D, DY413-05), IL-6 (R&D, DY406-05), IL-5 (R&D, DY405-05), resistin (R&D, DY1069), and / or TGF-β (R&D, DY1679-05) in lung homogenates were evaluated by enzyme-linked immunosorbent assay (R&D Systems, San Diego, CA, USA). All samples were evaluated twice, and the average value was calculated.

[0110] 10. Analysis of the Effects of Resistin Inhibitors

[0111] The compound of [Formula 1] (CND1163) was administered by intraperitoneal injection at a concentration of 50 mg / kg three times a week for a total of 12 times over 4 weeks to mice in the ovalbumin (OVA) group and mice in the obesity model group.

[0112] 11. Statistical Analysis

[0113] All experimental results of the present invention are expressed as mean ± standard error. AHR data were analyzed using ANOVA, followed by a Turkey test. One-way ANOVA was performed to evaluate the significance of differences in BALF cell count, cytokine levels, and / or quantitative fibrosis between groups, and all statistical analyses were performed using PASW statistics 18 (SPSS Inc., Chicago, IL, USA). p-values ​​<0.05 were considered statistically significant.

[0114] [Experimental Results]

[0115] 1. Confirmation of the association between resistin and inflammation in vitro

[0116] Inflammation was induced in Beas 2b (bronchial epithelial cells) using LPS to create an asthma-like environment, or insulin was administered to create an obesity-like environment, and resistin-related family RNAs (Retnl α and Retnl β) were inhibited using siRNA. Additionally, resistin overexpression was induced by administering recombinant resistin protein. Dexamethasone was administered as a control. Subsequently, changes in the expression levels of inflammation-related proteins were measured using ELISA. The results showed that inflammation-related proteins increased significantly in the group with induced resistin overexpression compared to the groups treated with LPS or insulin. Conversely, in the group where resistin-related family RNAs were inhibited with siRNA, the expression of inflammation-related proteins decreased (Fig. 1). These results suggest that resistin is associated with the increase or decrease of inflammation.

[0117] 2. Confirmation of the association between obesity and asthma using anti-resistin antibodies in vivo

[0118] An asthma mouse model was prepared using ovalbumin (OVA), and obesity was induced with a high-fat diet (HFD) (Fig. 2). An antibody was used as the resistin inhibitor, and a recombinant protein was used for resistin overexpression.

[0119] Mice fed the HFD diet showed approximately a twofold increase in body weight compared to those on a normal diet at week 13 (Fig. 3). Measurement of airway resistance revealed that the group with resistin inhibited by an anti-resistin antibody showed significantly lower airway resistance compared to the HFD / OVA (obesity-type asthma) and HFD / OVA / resistin recombinant (obesity-type asthma-resistin overexpression) groups (Fig. 4). This implies that asthma is alleviated when resistin is inhibited. PAS staining of mouse lung tissue confirmed that goblet cells, which were increased in the HFD / OVA group, were significantly reduced in the resistin inhibition group. Similarly, MT staining confirmed that fibrosis, which was increased in the HFD / OVA group, was significantly reduced in the resistin inhibition group (Fig. 5). Additionally, inflammation-related cells were counted by staining bronchoalveolar lavage fluid (BALF) obtained from mouse lung tissue. As a result of verification, it was confirmed that eosinophils, which increase in asthmatic conditions, significantly increased in the HFD / OVA group and the HFD / OVA / resistin recombination group, and significantly decreased in the resistin inhibition group (Fig. 6). When inflammation-related proteins in mouse lung homogenates were identified using ELISA, most inflammation-related proteins were found to increase in the HFD / OVA and HFD / OVA / resistin recombination groups and decrease in the resistin inhibition group (Figs. 7 and 8). Furthermore, RNA was extracted from mouse lung tissue and qPCR was performed to determine whether the resistin gene was properly inhibited or overexpressed by checking the expression levels of resistin, Retnl α, or Retnl β; the results indicated that the corresponding resistin inhibition or overexpression was successfully manipulated in the mouse groups of the present invention (Fig. 9).

[0120] 3. Confirmation of the association between obesity and asthma using resistin-inhibiting small molecule compounds in vivo

[0121] An asthma mouse model was prepared using ovalbumin (OVA), and obesity was induced using a high-fat diet (HFD). The substances administered and the administration schedule for preparing the mouse model are schematically illustrated in Fig. 10, and the compound of [Formula 1] (CDN1163) was used as the resistin inhibitor.

[0122] Mice fed the HFD diet showed approximately a twofold increase in body weight compared to those on a normal diet at week 13 (Fig. 11). When airway resistance was measured, it was observed that the HFD / OVA / CDN1163 treatment group had significantly lower airway resistance compared to the HFD / OVA (obesity-type asthma) group (Fig. 12). This implies that asthma was alleviated as resistin was inhibited by CDN1163. When inflammation-related cells were counted by staining bronchoalveolar lavage fluid (BALF) obtained from mouse lung tissue, a significant decrease was observed in the group administered CDN1163 compared to HFD and OVA / HFD (Fig. 13). Furthermore, faster recovery was observed in the Glucose Tolerance Test (GTT) and Insulin Tolerance Test (ITT) when CDN1163 was administered (Fig. 14). This indicates that CDN1163 has a positive effect on metabolic regulation. IF results, obtained by staining mouse lung tissue with anti-resistin antibodies, clearly showed that resistin was inhibited by CDN1163 (Fig. 15). Additionally, PAS staining results confirmed that goblet cells, which were increased in the HFD / OVA group, were significantly reduced in the CDN1163 administration group (Fig. 16). Similarly, MT staining confirmed that fibrosis, which was increased in the HFD / OVA group, was significantly reduced in the CDN1163 administration group (Fig. 17). Furthermore, ELISA analysis of inflammation-related proteins in mouse lung homogenates revealed that most inflammation-related proteins were increased in the HFD / OVA group but decreased in the CDN1163 administration (resistin inhibition) group (Fig. 18).

[0123] The above results suggest that the compound of [Chemical Formula 1] (CDN1163) could be a promising treatment for obesity-induced asthma as a resistin signaling inhibitor.

[0124] 4. Confirmation of the correlation between resistin and NF-κB

[0125] To test the hypothesis that resistin alleviates inflammation by regulating NF-κB, an asthma mouse model was prepared using ovalbumin (OVA) and obesity was induced with a high-fat diet (HFD) (Fig. 19). Recombinant protein was used for resistin overexpression, and MG132 was used for NF-κB inhibition.

[0126] Mice fed the HFD diet showed approximately a twofold increase in body weight compared to the normal diet at week 13 (Fig. 20). When airway resistance was measured, airway resistance was significantly reduced in both the group treated with the NF-kB inhibitor alone and the group treated with the NF-kB inhibitor and recombinant resistin protein compared to the HFD and HFD / OVA groups (Fig. 21). Additionally, when inflammation-related cells were counted by staining bronchoalveolar lavage fluid (BALF) obtained from mouse lung tissue, total cells, macrophages, and eosinophils were significantly reduced in both the group treated with the NF-kB inhibitor alone and the group treated with the NF-kB inhibitor and recombinant resistin protein (Fig. 22), and inflammation-related cytokine levels were also significantly reduced compared to the HFD and HFD / OVA groups (Fig. 23). In other words, the fact that NF-kB levels increased in the resistin overexpression group but decreased in the group treated with an NF-kB inhibitor suggests that resistin is an upstream regulator of NF-kB (Fig. 24). The results of confirming resistin expression in mouse lung tissue and adipose tissue using IF also showed the same meaning as above (Fig. 25), and the same results regarding the association between resistin and NF-kB were demonstrated at the cellular level (Fig. 26).

[0127] Foregoing, specific parts of the present invention have been described in detail. It is evident to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the actual scope of the invention is defined by the appended claims and their equivalents.

[0128] The resistin inhibitor provided in the present invention exhibits a significant therapeutic effect on asthma, particularly asthma associated with obesity, and is therefore expected to be actively utilized in the medical and healthcare fields.

Claims

1. A pharmaceutical composition for the prevention or treatment of asthma, comprising as an active ingredient a resistin protein or an inhibitor of the gene encoding it.

2. In Paragraph 1, A pharmaceutical composition wherein the inhibitor is a compound selected from a compound represented by the following chemical formula 1, its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates: [Chemical Formula 1] .

3. In Paragraph 1, A pharmaceutical composition in which the above asthma is asthma associated with obesity.

4. In Paragraph 1, The above pharmaceutical composition is prepared in the form of an oral formulation of a powder, granule, capsule, tablet, powder, or aqueous suspension; an external preparation; a suppository; or a sterile injectable solution.

5. A food composition for the prevention or improvement of asthma comprising a resistin protein or an inhibitor of the gene encoding it.

6. In Paragraph 5, A food composition wherein the inhibitor is a compound selected from a compound represented by the following chemical formula 1, its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates: [Chemical Formula 1] .

7. In Paragraph 5, A food composition in which the above asthma is an asthma associated with obesity.

8. In Paragraph 5, The above food composition is a food composition manufactured in the form of a beverage, gum, tea, vitamin complex, powder, granule, tablet, capsule, jelly, confectionery, rice cake, or bread.

9. A cosmetic composition for the prevention or improvement of asthma, comprising a resistin protein or an inhibitor of the gene encoding it.

10. In Paragraph 9, A cosmetic composition wherein the inhibitor is a compound selected from a compound represented by the following chemical formula 1, pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates thereof: [Chemical Formula 1] .

11. In Paragraph 9, A cosmetic composition in which the above asthma is an asthma associated with obesity.

12. In Paragraph 9, The above cosmetic composition is manufactured in the form of a toner, nourishing lotion, nourishing essence, massage cream, beauty bath additive, body lotion, body milk, bath oil, baby oil, baby powder, shower gel, shower cream, sunscreen lotion, sunscreen cream, tanning cream, skin lotion, skin cream, UV protection cosmetic, concealer, cleansing milk, hair loss treatment cosmetic, face and body lotion, face and body cream, skin whitening cream, hand lotion, hair lotion, cosmetic cream, jasmine oil, bath soap, liquid soap, beauty soap, shampoo, hand sanitizer (hand cleaner), medicinal soap (non-medical), cream soap, facial wash, body cleanser, scalp cleanser, hair rinse, cosmetic soap, teeth whitening gel, or toothpaste.

13. An expression inhibitor of a resistin protein or a gene encoding the same, comprising a compound represented by the following chemical formula 1, a compound selected from the pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates thereof: [Chemical Formula 1] .

14. A method for the prevention or treatment of asthma, comprising the step of administering to an individual a pharmaceutically effective amount of resistin protein or an inhibitor of the gene encoding it.

15. In Paragraph 14, Method in which the inhibitor is a compound selected from the compound represented by the following chemical formula 1, its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates: [Chemical Formula 1] .

16. In Paragraph 14, The above asthma is an asthma associated with obesity.

17. Use of inhibitors of the resistin protein or the gene encoding it for the prevention or treatment of asthma.

18. In Paragraph 17, The above inhibitor is a compound selected from the compound represented by the following chemical formula 1, its pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates, for use: [Chemical Formula 1] .

19. In Paragraph 17, The above asthma is an asthma associated with obesity.

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