NOVEL ADIPONECTIN-DERIVED PEPTIDE DERIVATIVE AND ITS USE

Abstract

The present invention relates to a novel peptoid derivative, which is a partially modified adiponectin receptor peptide and has higher stability and superior p-AMPK activity than existing adiponectin receptor peptides, and has the advantage of being advantageous for drug formulation due to improved physical properties and activity. Therefore, the peptoid derivative of the present invention can be used for preventing or treating skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, or cancer, and for preventing or improving aging, sensitive skin, wrinkles, or moisture.

Description

[Technical field]

[0001] The present invention relates to a novel adiponectin-derived peptoid derivative and uses thereof. [Background technology]

[0002] Skin aging is generally a result of both external and internal processes, with the increase in wrinkling and sagging of the skin. External aging is mainly caused by repeated exposure to ultraviolet rays (UV), and is therefore commonly referred to as "photoaging." Naturally aged skin is smooth, pale and has fine lines, but photoaged skin develops thick wrinkles, hyperpigmentation and telangiectasia.

[0003] Subcutaneous fat plays an important role in maintaining energy homeostasis by secreting hormones and adipokines that regulate the metabolism of other tissues.Recently, it has been reported that ultraviolet light, an environmental factor that induces various diseases such as photoaging, inflammation, immunosuppression, and cancer, reduces the fat content of human subcutaneous adipose tissue, and adiponectin, a product derived from fat, is reduced in aged skin, inducing an increase in MMP-1 and a decrease in collagen.

[0004]

[0005] The human body has more than 1.3 million hairs, and the head has 100,000 to 150,000 hairs. Each hair grows, maintains, and falls out through three different cycles: anagen (the active growth phase), catagen (the apoptotic regression phase), and telogen (the resting phase). This cycle repeats for 3 to 6 years, resulting in an average of 50 to 100 hairs falling out normally each day. In general, "hair loss" refers to a condition in which there is less hair or no hair due to some cause.

[0006] At present, the causes of hair loss include internal factors such as the action of male hormones, and external factors such as mental stress in daily life and accumulation of lipid peroxides on the scalp, and it is known that hair loss symptoms occur due to the complex involvement of such factors. Recently, the number of women suffering from hair loss has been increasing due to not only male pattern hair loss but also changes in dietary habits and increased stress due to social environments, and the number of people suffering from abnormal symptoms of the scalp and hair as described above is gradually increasing, and the age of such people is also decreasing.

[0007] Currently available hair growth agents have problems such as a lack of clear effects, side effects, need to be taken continuously, and cause side effects such as decreased sexual function, allergies, and depression.

[0008]

[0009] Metabolic disease refers to a syndrome in which risk factors such as obesity, diabetes, high blood pressure, arteriosclerosis, and nonalcoholic fatty liver disease (NAFLD) occur together due to excess nutrient accumulation in the body and lack of exercise. Recently, it was officially named metabolic syndrome or insulin resistance syndrome through the Adult Treatment Program III established by the World Health Organization and the Heart, Lung, and Blood Institute of the National Institutes of Health in the United States. According to the ATP published by the US National Cholesterol Education Program (NCEP) in 2001, if a patient has three or more of the following five risk factors, they are diagnosed as having a metabolic disease: abdominal obesity with a waist circumference of 40 inches (102 cm) or more for men and 35 inches (88 cm) or more for women, triglycerides of 150 mg / dL or more, HDL cholesterol of 40 mg / dL or less for men and 50 mg / dL or less for women, blood pressure of 130 / 85 mmHg or more, and fasting blood glucose of 110 mg / dL or more. For Asians, the waist circumference of 90 cm or more for men and 80 cm or more for women is slightly adjusted to be considered abdominal obesity, and recent research has shown that when these regulations are applied, about 25% of the Korean population shows symptoms of metabolic syndrome.

[0010]

[0011] Meanwhile, adiponectin is a type of adipokine, a protein hormone secreted specifically by fat cells, and is known to play an important role in regulating cardiovascular diseases such as hyperglycemia, hyperinsulinism, obesity, and arteriosclerosis by promoting insulin function and suppressing insulin resistance, blocking inflammation and preventing fat accumulation in blood vessels. Adiponectin also has the function of suppressing the metastasis and inflammatory response of cancer cells, and promotes not only the proliferation of keratinocytes but also the expression of filaggrin, hyaluronic acid, and extracellular matrix in the skin, thereby performing functions such as wound healing, fibrosis inhibition, improvement of skin wrinkles, and moisturizing.

[0012] Adiponectin is composed of 244 amino acids and consists of a signal sequence, a collagen-like domain located at the N-terminus, and a C1q-like globular domain located at the C-terminus. The major oligomers are hexamers and 400 kDa high molecular weight complexes (HMW complexes), which are known to be more active than low molecular weight complexes (LMW complexes).

[0013] The development of peptides modified from adiponectin, which is known to have various physiological activities, has been a target for many researchers and pharmaceutical companies both in Japan and abroad, but the chances of ultimate success have been relatively low due to the difficulty of polymer formation in the body.

[0014] Recently, research has been conducted on peptoids, which are peptides that have been modified to increase their resistance to protein degradation. These peptoids have been reported to have better pharmacokinetic properties than existing peptides, but some have been reported to be cytotoxic.

[0015]

[0016] Under these circumstances, the present inventor developed a short peptoid derived from adiponectin that has high physiological activity without cytotoxicity, and confirmed its effects of increasing adiponectin expression, promoting hair growth, and suppressing neutral fats, thereby completing the present invention. Summary of the Invention [Problem to be solved by the invention]

[0017] An object of the present invention is to provide novel peptoid derivatives.

[0018] Another object of the present invention is to provide a composition for increasing adiponectin expression, which contains the peptoid derivative as an active ingredient.

[0019] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory skin diseases, wounds, hair loss, fibrosis, metabolic diseases, or cancer, which contains the peptoid derivative as an active ingredient.

[0020] Another object of the present invention is to provide a cosmetic composition for preventing or ameliorating inflammatory skin diseases, wounds, hair loss, fibrosis, metabolic diseases, or cancer, which contains the peptoid derivative as an active ingredient.

[0021] Another object of the present invention is to provide a pharmaceutical composition for preventing or improving aging, sensitive skin, wrinkles, or moisturization, which contains the peptoid derivative as an active ingredient.

[0022] Another object of the present invention is to provide a cosmetic composition for preventing or improving aging, sensitive skin, wrinkles, or moisturization, which contains the peptoid derivative as an active ingredient.

[0023] However, the technical problem that the present invention aims to achieve is not limited to the problems mentioned above, and further problems not mentioned will be clearly understood by those skilled in the art from the following description. [Means for solving the problem]

[0024] In order to achieve the above object, the present invention provides a peptoid derivative represented by the following formula 1. [Chemical formula 1]

[0025] [ka]

[0026] In the above [Chemical Formula 1],

[0027] R 1 is an amino group (NH 2 ), acetylamino group (Ac-NH), NH 2 -(CH 2 CH 2 O)m -CH 2 CONH,C. 15 -C 20 and combinations thereof, wherein m may be an integer of 1 to 5, and preferably 3; and the amide group is preferably a C16 amide group, i.e., a palmitamide group;

[0028] R 2 is C 1 -C 6 A chain alkyl group of C 1 -C 6 Ring-shaped alkyl group, C 2 -C 6 and combinations thereof,

[0029] R 3、 R 4 and R 5 are the same or different, and each independently C 7 -C 12 phenylalkyl group, pyridinylmethyl group, indolylmethyl group, and benzodioxolomethyl group.

[0030] The phenylalkyl group may be unsubstituted or may be substituted with a hydroxy group, a trifluoromethyl group (CF 3 ), halogen group, cyano group, nitro group, C 1 -C 6 A chain alkyl group of C 1 -C 6 and combinations thereof.

[0031] In one embodiment of the present invention, the R 2 teeth, [ka] and combinations thereof, but are not limited thereto.

[0032] In another embodiment of the present invention, the R 3 , R 4 , and R 5 are the same or different from each other, and each independently: [ka] and combinations thereof, but are not limited thereto.

[0033] In another embodiment of the present invention, the peptoid derivative may be one or more selected from the group consisting of peptoid derivatives represented by the following formulas [Chemical Formula 1-1] to [Chemical Formula 1-27], but is not limited thereto (Table 1). [Table 1]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040] [Table 1] JPEG2025501479000006.jpg188149 JPEG2025501479000007.jpg183149 JPEG2025501479000008.jpg183149 JPEG2025501479000009.jpg183149 JPEG2025501479000010.jpg178149 JPEG2025501479000011.jpg119149

[0041]

[0042] The present invention also provides a composition for increasing the expression of adiponectin, which comprises the peptoid derivative as an active ingredient.

[0043]

[0044] The present invention also provides a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, which contains the peptoid derivative as an active ingredient.

[0045] The present invention also provides a method for preventing or treating one or more diseases selected from the group consisting of inflammatory skin diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising the step of administering the peptoid derivative to an individual.

[0046] The present invention also provides use of the peptoid derivative for the manufacture of a medicament for the prevention or treatment of one or more selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer.

[0047] The present invention also provides a cosmetic composition for preventing or improving one or more conditions selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, which contains the peptoid derivative as an active ingredient.

[0048] The present invention also provides a food composition for preventing or improving one or more conditions selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, which contains the peptoid derivative as an active ingredient.

[0049]

[0050] The present invention also provides a pharmaceutical composition for preventing or improving one or more problems selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, which contains the peptoid derivative as an active ingredient.

[0051] The present invention also provides a method for preventing or improving one or more selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, comprising the step of administering the peptoid derivative to an individual.

[0052] The present invention also provides a use of the peptoid derivative for the manufacture of a medicament for preventing or improving one or more selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing.

[0053] The present invention also provides a cosmetic composition for preventing or improving one or more problems selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, which contains the peptoid derivative as an active ingredient.

[0054] The present invention also provides a food composition for preventing or improving one or more conditions selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, which contains the peptoid derivative as an active ingredient. Effect of the Invention

[0055] The peptoid derivative of one embodiment of the present invention is a partially modified adiponectin receptor peptide, and has higher stability and superior p-AMPK activity than existing adiponectin receptor peptides, and has the advantages of being advantageous for drug formulation due to its improved physical properties and activity.

[0056] Therefore, the peptoid derivatives of the present invention can be used to prevent or treat skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, or cancer, and to prevent or improve aging, sensitive skin, wrinkles, or moisturization.

[0057] The effects of the peptoid derivative according to one embodiment of the present invention are not limited to those mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description below. [Brief description of the drawings]

[0058] [Figure 1] 1 is a graph showing the effect of the peptoid derivatives (DS-13 to DS-16) of the present invention represented by [Chemical Formula 1-1] and [Chemical Formula 1-4] on the AMPK phosphorylation activity in mouse adipocytes, where V is a vehicle treated with DMSO, and P5 is a positive control APN5 peptide having the sequence NH2-GLYYF-OH.

[0059] [Diagram 2] 2 is a graph showing the effect of the peptoid derivatives (DS-21 to DS-24) of the present invention represented by [Chemical Formula 1-5] to [Chemical Formula 1-8] on the AMPK phosphorylation activity in mouse adipocytes, where V is a vehicle treated with DMSO, and P5 is a positive control APN5 peptide having the sequence NH2-GLYYF-OH.

[0060] [Diagram 3] 3 is a graph showing the effect of the peptoid derivatives (DS-25, DS-26) of the present invention represented by [Chemical Formula 1-9] to [Chemical Formula 1-10] on the AMPK phosphorylation activity in mouse adipocytes, where V is a vehicle treated with DMSO, and P5 is a positive control APN5 peptide having the sequence NH2-GLYYF-OH.

[0061] [Figure 4]4 is a graph showing the effect of the peptoid derivatives (DS-31 to DS-34) of the present invention represented by [Chemical Formula 1-11] to [Chemical Formula 1-14] on phosphorylation activity in mouse adipocytes, where V is a vehicle treated with DMSO, and P5 is a positive control APN5 peptide having the sequence NH2-GLYYF-OH.

[0062] [Diagram 5] 5 is a graph showing the effect of the peptoid derivatives (DS-46, DS-47) of the present invention represented by [Chemical Formula 1-15] to [Chemical Formula 1-16] on AMPK phosphorylation activity in mouse adipocytes, where V is a vehicle treated with DMSO, and P5 is a positive control APN5 peptide having the sequence NH2-GLYYF-OH.

[0063] [Figure 6] 6 is a graph showing the effect of the peptoid derivatives (DS-64 to DS-67) of the present invention represented by [Chemical Formula 1-17] to [Chemical Formula 1-20] on the AMPK phosphorylation activity in mouse adipocytes, where V is a vehicle treated with DMSO, and P5 is a positive control APN5 peptide having the sequence NH2-GLYYF-OH.

[0064] [Figure 7] 7 is a graph showing the effect of the peptoid derivative (DS-71) of the present invention represented by [Chemical Formula 1-21] on the AMPK phosphorylation activity in mouse adipocytes, where V is the vehicle treated with DMSO, and P5 is the positive control APN5 peptide having the sequence NH2-GLYYF-OH.

[0065] [Figure 8]8 is a graph showing the effect of the peptoid derivatives (DS-80 to DS-84) of the present invention represented by [Chemical Formula 1-22] to [Chemical Formula 1-26] on the AMPK phosphorylation activity in mouse adipocytes, where V is a vehicle treated with DMSO, and P5 is a positive control APN5 peptide having the sequence NH2-GLYYF-OH.

[0066] [Figure 9] FIG. 9 shows whether the AMPK phosphorylation activity increased by the peptoid derivatives (DS-15, DS-16, DS-25, DS-47) of the present invention represented by [Chemical Formula 1-3], [Chemical Formula 1-4], [Chemical Formula 1-9] and [Chemical Formula 1-16] is decreased by adiponectin receptor 1 knockdown. Here, NC is scrambled siRNA, R1 is adiponectin receptor 1 siRNA, V is treated with DMSO as a vehicle, P5 is APN5 peptide as a positive control group, and has the NH2-GLYYF-OH sequence. DS-43 is adiponectin receptor 1 agonist, adiporon.

[0067] [Figure 10] Figure 10 shows the cytotoxicity of the peptoid derivative of the present invention represented by [Chemical Formula 1-4] against four types of cell lines (3T3-L1 adipocytes, RD muscle cells, keratinocytes, and fibroblasts), where Veh is the vehicle treated with DMSO.

[0068] [Figure 11]Figure 11 shows the cytotoxicity of the peptoid derivative of the present invention represented by [Chemical Formula 1-9] against four types of cell lines (3T3-L1 adipocytes, RD muscle cells, keratinocytes, and fibroblasts), where Veh is the vehicle treated with DMSO.

[0069] [Figure 12] FIG. 12 shows whether the peptoid derivatives of the present invention represented by [Chemical Formula 1-4] and [Chemical Formula 1-9] increase the AMPK phosphorylation activity in a concentration-dependent manner.

[0070] [Figure 13] 13 shows the hair growth efficacy of the peptoid derivatives of the present invention represented by [Chemical Formula 1-4] and [Chemical Formula 1-9], where V is a vehicle, EtOH:polyethylene glycol=30:70, v / v, P5 is a positive control APN5 peptide having the sequence NH2-GLYYF-OH, and Mnx is a positive control minoxidil, which is known as a hair growth agent.

[0071] [Figure 14] 14 shows the efficacy of the peptoid derivatives of the present invention represented by [Chemical Formula 1-4] and [Chemical Formula 1-9] in improving skin aging. Here, Veh is the vehicle treated with DMSO, and P5 is the APN5 peptide as a positive control.

[0072] [Figure 15A] FIG. 15A shows the neutral fat removal efficacy of the peptoid derivatives of the present invention represented by [Chemical Formula 1-9], [Chemical Formula 1-16], [Chemical Formula 1-4], and [Chemical Formula 1-21]. [Figure 15B]15B shows the differentiation and neutral fat suppression effects of the peptoid derivatives of the present invention represented by [Formula 1-4] and [Formula 1-9]. Here, V is treated with DMSO as a vehicle, P5 is APN5 peptide with the sequence NH2-GLYYF-OH as a positive control, ND is cultured in a non-differentiation medium, and D is cultured in a differentiation medium.

[0073] [Figure 16] 16 shows the efficacy of the peptoid derivatives of the present invention represented by [Chemical Formula 1-4] and [Chemical Formula 1-9] in improving sensitive skin, where Veh is a vehicle treated with DMSO, LA is lactic acid, and P5 is APN5 peptide as a positive control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] The present invention relates to the synthesis of novel peptoid derivatives based on adiponectin-derived peptide APN5, more particularly to peptoids in which some amino acids have been modified to improve the physical properties and activity of existing adiponectin peptides. The peptoid derivatives of the present invention have improved properties and efficacy, such as activity, and are advantageous for formulation into pharmaceuticals.

[0075]

[0076] Here, the present invention provides a peptoid derivative represented by the following [Chemical Formula 1]. [Chemical formula 1]

[0077] [ka]

[0078] In the above [Chemical Formula 1],

[0079] R 1 is an amino group (NH 2 ), acetylamino group (Ac-NH), NH 2 -(CH 2 CH 2 O) m -CH 2 CONH,C. 15 -C 20 and combinations thereof, wherein m may be an integer of 1 to 5;

[0080] R 2 is C 1 -C 6 A chain alkyl group of C 1 -C 6 Ring-shaped alkyl group, C 2 -C 6 and combinations thereof,

[0081] R 3、 R 4 and R 5 are the same or different, and each independently C 7 -C 12 phenylalkyl group, pyridinylmethyl group, indolylmethyl group, and benzodioxolomethyl group.

[0082] The phenylalkyl group may be unsubstituted or may be substituted with a hydroxy group, a trifluoromethyl group (CF 3 ), halogen group, cyano group, nitro group, C 1 -C 6 A chain alkyl group of C 1 -C 6 and combinations thereof.

[0083]

[0084] In the present invention, the term "substitution" refers to a reaction in which an atom or an atomic group contained in a molecule of a compound is replaced with another atom or an atomic group.

[0085] In the present invention, the term "chain" refers to a molecule having a chain structure, which is a chemical structure in which carbon atoms are linked in a chain, and may be a straight chain or a branched structure.

[0086] In the present invention, the term "ring type" refers to a structure in which both ends of a chain formed by a skeleton of an organic compound are connected to form a ring.

[0087] In the present invention, the term "chain or ring-shaped alkyl group" means a monovalent linear, branched or ring-shaped saturated hydrocarbon residue consisting solely of carbon and hydrogen atoms, having 1 to 12 carbon atoms. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0088] In the present invention, the term "halogen group" may be an element belonging to group 17 of the periodic table, such as fluorine (F), chloride (Cl), bromine (Br), or iodine (I).

[0089] In the present invention, the term "alkoxy group" refers to an atomic group CHO- formed by bonding an oxygen source to an alkyl group, and examples of such alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, or butoxy.

[0090] In the present invention, the term "peptoid" refers to a peptide analogue having an oligomeric form of N-alkylated glycine. Peptoids have a form in which a substituent (R) is attached to an amine and has no chiral center or amide hydrogen. Unlike peptides, such peptoids are unnatural and are not easily decomposed by protease, and therefore have excellent stability in vivo. Therefore, peptoids can overcome the disadvantage of peptides, which are easily decomposed in vivo.

[0091]

[0092] The present invention also provides a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, which contains the peptoid derivative as an active ingredient.

[0093] The present invention also provides a pharmaceutical composition for preventing or improving one or more problems selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, which contains the peptoid derivative as an active ingredient.

[0094] In the present invention, the term "prevention" refers to any action that inhibits or delays the occurrence, spread or recurrence of the disease by administering the composition of the invention, and "treatment" refers to any action that improves or alters the symptoms of the disease by administering the composition of the invention.

[0095] In the present invention, the term "amelioration" refers to any action that at least reduces the parameters related to the treated condition, such as the severity of the symptoms, or reverses or favorably alters the disease.

[0096] In the present invention, the term "pharmaceutical composition" means a product manufactured for the purpose of preventing or treating the above-mentioned disease, and may be formulated into various forms by a conventional method for use. For example, it may be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, and syrups, and may be formulated into external preparations, suppositories, and sterile injection solutions for use.

[0097] In the present invention, "containing as an effective component" means that the corresponding component is contained in an amount necessary or sufficient to realize a desired biological effect. In practical application, the amount contained as an active component is determined in consideration of the amount required to treat the target disease and not causing other toxicity, and may vary depending on various factors such as the disease or pathological condition to be treated, the form of the composition to be administered, the size of the subject, or the severity of the disease or pathological condition. A person skilled in the art to which the present invention pertains can empirically determine the effective amount of an individual composition without excessive testing.

[0098] Furthermore, the pharmaceutical composition of the present invention may further contain one or more pharma- ceutically acceptable carriers in addition to the above-described active ingredients depending on the dosage form.

[0099] The pharma- ceutically acceptable carrier may be a mixture of one or more of saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and its components, and may further contain other common additives such as antioxidants, buffers, bacteriostatic agents, etc., as necessary. In addition, diluents, dispersants, surfactants, binders, and lubricants may be added to the formulation to form an injection form such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules, or tablets. Furthermore, the formulation may be suitably prepared according to each disease or component, using a method appropriate in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA).

[0100] The composition of the present invention can be administered orally or parenterally in a pharma- ceutical effective amount according to the intended method. The term "pharma- ceutical effective amount" as used herein means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment and that does not cause side effects, and the effective dose level may be determined by factors including the patient's health condition, severity, drug activity, drug sensitivity, administration method, administration time, administration route, and excretion rate, treatment period, co-administered or concomitant drugs, and other factors known in the medical field.

[0101] In the present invention, "inflammatory skin disease" refers to inflammation occurring in the outer layer of the skin which induces symptoms such as itching, blistering, redness, swelling, and often oozing, scabbing, and peeling, and non-limiting examples include psoriasis, atopic dermatitis, eczema, contact dermatitis, erythroderma, lichen simplex chronicus, nummular dermatitis, seborrheic dermatitis, and stasis dermatitis.

[0102] In the present invention, the term "metabolic disease" refers to a syndrome in which risk factors such as obesity, diabetes, hypertension, arteriosclerosis, nonalcoholic fatty liver disease (NAFLD), etc. occur together due to excessive nutrient accumulation in the body and lack of exercise, and non-limiting examples include diabetes, hypertension, hyperlipidemia, cardiovascular and cerebrovascular diseases, thrombosis, dyslipidemia, stroke, arteriosclerosis, hyperinsulinemia, etc., but are not limited thereto.

[0103]

[0104] The present invention also provides a method for preventing or treating one or more diseases selected from the group consisting of inflammatory skin diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising the step of administering the peptoid derivative to an individual.

[0105] The present invention also provides a method for preventing or improving one or more selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, comprising the step of administering the peptoid derivative to an individual.

[0106] In the present invention, the term "individual" is not limited to any mammal, such as livestock or human, in which the prevention, treatment, and / or diagnosis of the disease is required, but may preferably be a human.

[0107] The term "administration" in the present invention means providing a predetermined substance to a patient by any suitable method, and the pharmaceutical composition of the present invention is formulated into various forms for administration to an individual, and a representative dosage form for parenteral administration is an injection dosage form, which is preferably an isotonic aqueous solution or suspension. The injection dosage form can be prepared by a technique well known in the art using a suitable dispersing or wetting agent and suspending agent. For example, each component can be dissolved in saline or a buffer solution to be formulated for injection. In addition, dosage forms for oral administration include, for example, ingestible tablets, buccal tablets, troches, capsules, erythritol, suspensions, syrups, and wafers, and these dosage forms may contain diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine) and lubricants (e.g., silica, talc, stearic acid, and its magnesium or calcium salts and / or polyethylene glycol) in addition to the active ingredient. The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and may further contain disintegrants, absorbents, colorants, flavorings and / or sweeteners, such as starch, agar, alginic acid or its sodium salt. The dosage forms may be manufactured by conventional mixing, granulating or coating methods.

[0108] In addition, the pharmaceutical composition of the present invention may further contain auxiliary substances such as preservatives, hydrating agents, emulsifiers, salts for adjusting osmotic pressure or buffers, and other therapeutically useful substances, and can be formulated by a conventional method.

[0109] The pharmaceutical composition of the present invention may be administered via various routes including oral, transdermal, subcutaneous, intravenous, intranasal, intraperitoneal, or intramuscular, and the dosage of the active ingredient may be appropriately selected depending on various factors such as the administration route, the age, sex, weight, and severity of the patient, etc. The composition of the present invention may also be administered in conjunction with a known compound that can enhance the desired effect.

[0110]

[0111] The present invention also provides a cosmetic composition for preventing or improving one or more conditions selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, which contains the peptoid derivative as an active ingredient.

[0112] The present invention also provides a cosmetic composition for preventing or improving one or more problems selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, which contains the peptoid derivative as an active ingredient.

[0113] The cosmetic composition contains, for example, the peptoid derivative or a cosmetically acceptable salt thereof as an active ingredient, and can be prepared in the form of a basic cosmetic composition (skin lotion, cream, essence, face wash such as cleansing foam and cleansing water, pack, body oil), color cosmetic composition (foundation, lipstick, mascara, makeup base), hair product composition (shampoo, rinse, hair conditioner, hair gel), soap, etc. together with a dermatologically acceptable excipient.

[0114] The excipients may include, for example, skin softeners, skin penetration enhancers, colorants, fragrances, emulsifiers, thickeners and solvents, and more specifically, include, but are not limited to, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, anhydrous skim milk, glycerol, propylene, glycol, water, ethanol, etc.

[0115]

[0116] The present invention also provides a food composition for preventing or improving one or more conditions selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, which contains the peptoid derivative as an active ingredient.

[0117] The present invention also provides a food composition for preventing or improving one or more conditions selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, which contains the peptoid derivative as an active ingredient.

[0118] The food composition contains, for example, the peptoid derivative or a pharma- ceutically acceptable salt thereof as an active ingredient, and when the peptoid derivative is used as an additive for the food composition, it can be added as it is or together with other foods or food ingredients, and can be used appropriately by a conventional method. In general, when producing a food or drink, the composition of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less, based on the raw materials. However, in the case of long-term intake for the purpose of health and hygiene or health regulation, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than the above range. That is, the amount of the active ingredient to be mixed can be determined appropriately depending on the purpose of use, such as prevention, health, or treatment.

[0119] The dosage form of the food composition may be any of powder, granule, capsule, tablet, and capsule forms, as well as general food or drink forms.

[0120] The food of the present invention can be produced by a method commonly used in the art, and may be produced by adding raw materials and ingredients commonly added in the art. Specifically, the food may include proteins, carbohydrates, fats, nutrients, seasonings, and flavorings, and examples of the carbohydrates include, but are not limited to, glucose, fructose, maltose, sucrose, oligosaccharides, dextrin, cyclodextrin, xylitol, sorbitol, erythritol, saccharin, or synthetic flavorings.

[0121]

[0122] The terms used in the embodiments are used for the purpose of explanation and are not to be construed as being limiting. A singular expression includes a plural expression unless it has a clearly different meaning in the context. In this specification, the terms "include" or "have" indicate the presence of features, numbers, steps, operations, components, parts, or combinations thereof described in the specification, and should be understood as not precluding the presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0123] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which the present invention belongs. Commonly used predefined terms should be interpreted as having a meaning consistent with the meaning they have in the context of the relevant art, and should not be interpreted as ideal or overly formal unless expressly defined in this specification.

[0124] In addition, terms such as first, second, A, B, (a), (b), etc. may be used to describe components of the embodiment. Such terms are used to distinguish the components from other components, and do not limit the nature, order, or sequence of the components. When a component is described as being "coupled," "coupled," or "connected" to another component, it should be understood that the component may be directly coupled or connected to the different component, but additional components may be "coupled," "coupled," or "connected" between each component.

[0125]

[0126] Hereinafter, the embodiments will be described in detail with reference to the accompanying drawings. However, since the embodiments can be modified in various ways, the scope of the patent application is not limited or restricted by the embodiments. It should be understood that all modifications, equivalents, or alternatives to the embodiments are included in the scope of the patent.

[0127] In addition, in the description with reference to the accompanying drawings, the same reference numerals will be given to the same components regardless of the reference numerals, and duplicated descriptions thereof will be omitted. In the description of the embodiments, if a detailed description of related known technology is determined to unnecessarily obscure the gist of the embodiments, the detailed description thereof will be omitted.

[0128]

[0129] The present invention can be modified in various ways and can have various embodiments, and the following specific embodiments are illustrated in the drawings and described in detail in the detailed description. However, this is not intended to limit the present invention to the specific embodiments, and it should be understood that the present invention includes all modifications, equivalents, or alternatives within the spirit and technical scope of the present invention. In the description of the present invention, if a detailed description of related publicly known technology is deemed to obscure the gist of the present invention, the detailed description will be omitted.

[0130] [Mode for carrying out the invention] Embodiment 1. Production of the peptoid derivatives of the present invention

[0131] The method for preparing the peptoid derivatives of the present invention is diagrammed in Scheme 1 below. [Reaction Scheme 1]

[0132] [ka]

[0133] Peptoids can be easily synthesized using solid-phase synthesis. Using polymer beads having amine or hydroxyl groups as starting materials, peptoid residues can be easily introduced through a two-step reaction of bromoacetylation and amine substitution using a primary amine. By repeating this process, peptoid oligomers can be efficiently synthesized. The peptoid derivatives according to one embodiment of the present invention were synthesized on resin beads by manual synthesis using a solid-phase submonomer protocol and by a microwave-assisted method.

[0134] Microwave synthesis was performed using a microwave oven (Whirlpool, 700 W, 2450 Hz). C-terminal amide peptoids were synthesized using Fmoc-Rink amid MBHA resin (0.89 mmol / g, Novabiochem®, San Diego, CA, USA) on resin beads. All microwave heating reactions were performed at atmospheric pressure, and half-scale resin beads (100 mg, 89 μmol) were used in the initial reaction. To remove the Fmoc protecting group from the resin, the Fmoc-Rink amid MBHA resin was reacted with 1 mL of dimethylformamide (DMF) containing 20% ​​(v / v) piperidine at room temperature for 10 minutes each, twice, and then the resin beads were washed with dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM), and finally dimethylformamide (DMF), repeating the washing process twice each. For bromoacetylation, bromoacetic acid (2M, 890uL) dissolved in DMSO and N,N'-diisopropylcarbodiimide (2M, 890uL) were added. The reaction solution was stirred and irradiated twice for 15 seconds using a microwave (700W, 10% power) at room temperature. After the reaction, the resin beads were washed by repeating the washing process twice each using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM), and finally dimethylformamide (DMF).

[0135] For the amine substitution reaction, the primary amine (2M, 20eq) was dissolved in dimethylformamide (DMF) and then stirred and irradiated twice for 15 seconds using a microwave (700W, 10% power) at room temperature. After the reaction, the resin beads were washed using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM), and finally dimethylformamide (DMF) by repeating the above process twice each. The second residue and polymer peptoid were synthesized by repeating the above process.

[0136] The peptoid residue Ngly was synthesized by peptide synthesis using 1-hydroxybenzotriazole (HOBt), N-[(dimethylamino-)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), N,N-diisopropylethylamine (DIEA) and Fmoc-Gly-OH in dimethylformamide (DMF) for 2 hours.

[0137]

[0138] On the other hand, when the N-terminus was protected with PEG or PAL, the synthesis was carried out as follows.

[0139] To synthesize peptoids protected with (PEG)3(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetic acid) or PAL(Palmitic acid) from the N-terminal unprotected peptoids synthesized by the above-mentioned peptoid synthesis method, 1-hydroxybenzotriazole (HOBt), N-[(dimethylamino-)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), N,N-diisopropylethylamine (DIEA) and PEG(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetic acid) or PAL(Palmitic acid) were reacted and stirred in dimethylformamide (DMF) for 2 hours. The reacted resin was washed twice with dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM), and finally dimethylformamide (DMF) to complete the washing process.

[0140]

[0141] To separate the completed peptoid from the resin, a separation solution (TFA:H 2 After stirring at room temperature for 2 hours at 0:TIPS=95:2.5:2.5), the peptoid solution separated from the resin was distilled under reduced pressure to remove the solvent. The peptoid compound from which the solvent was removed was purified using high performance liquid chromatography (Prep-HPLC, Gilson), and peptides with a purity of 98% or more were obtained using RP-HPLC and LC-MS for purity confirmation and analysis (Methods Enzymol.267, 437-447 1996, Org Lett.2002, 14;423:4057-9).

[0142]

[0143] The sequences and molecular weights of the peptoid derivatives according to one embodiment of the present invention are shown in Table 2 below. [Table 2]

[0144] [Table 2]

[0145]

[0146] In Table 2, each monomer residue constituting the peptoid derivative of the present invention may have the following structure.

[0147] [ka]

[0148]

[0149] Test Example 1. Verification of AMPK phosphorylation activity in vitro

[0150] The effect of the peptoid derivative of the present invention on adiponectin expression and receptor activity in mouse adipocytes, the main site of adiponectin production, was confirmed. Mouse adipocyte cell line 3T3-L1 was treated with the peptoid derivative of the present invention at a concentration of 10 μM, cultured for 24 hours, and then cells were obtained. Proteins were then extracted, and the effect on AMPK phosphorylation, which is responsible for the main downstream signaling of adiponectin, was confirmed by Western blot.

[0151] As a result, the peptoid derivatives of the present invention increased the AMPK phosphorylation activity related to the activity of the adiponectin receptor in mouse adipocytes (Figures 1 to 8), and in particular, the peptoid derivatives represented by [Chemical Formula 1-3], [Chemical Formula 1-4], [Chemical Formula 1-9], and [Chemical Formula 1-16] were confirmed to have a significant effect of increasing AMPK phosphorylation activity compared to APN5, a conventionally known adiponectin-derived peptide (Table 3). [Table 3]

[0152] [Table 3]

[0153]

[0154] Test Example 2: Verification of loss of AMPK phosphorylation activity after in vitro adiponectin receptor 1 knockdown

[0155] In order to verify whether the peptoid derivatives of the present invention bind to adiponectin receptor 1, a mouse adipocyte cell line, 3T3-L1, was knocked down by treating with siRNA of adiponectin receptor 1, and treated with the peptoid derivatives of the present invention at a concentration of 10 μM, respectively, and cultured for 24 hours, and then the cells were obtained. Proteins were then extracted, and it was confirmed by Western blotting whether the AMPK phosphorylation activity increased by the peptoid derivatives disappeared.

[0156] As a result, it was confirmed that the peptoid derivatives of the present invention, including [Chemical Formula 1-3], [Chemical Formula 1-4] to [Chemical Formula 1-9], and [Chemical Formula 1-16], reduce AMPK phosphorylation activity after knockdown of adiponectin receptor 1 (Figure 9).

[0157] Adiponectin acts by binding to the adiponectin receptor, and when the adiponectin receptor is activated, it is known to increase the phosphorylation of AMPK and the activity of PPARα / PPARγ, which are downstream signaling pathways (Crystal structures of the human adiponectin receptors. Nature. 2015 Apr16;5207547:312-6.doi:10.1038 / nature14301). In addition, the expression of adiponectin and its receptors is reduced in photoaged skin and skin exposed to UV rays. It is known that such reduced expression of adiponectin can regulate the expression of MMP-1 and procollagen, which are regulators of skin aging, and alter the extracellular matrix, thereby worsening photoaging (UV-induced inhibition of adipokine production in subcutaneous fat aggravates dermal matrix degradation in human skin. 2016. Scientific Reports. 10; 6: 25616. doi:10.1038 / srep25616).

[0158] Therefore, it is suggested that the peptoid derivatives of the present invention increase the activity of AMPK phosphorylation related to the activity of adiponectin receptors, and therefore play a major role in preventing skin aging by increasing the expression of adiponectin in the body.

[0159]

[0160] Test Example 3: Verification of in vitro cytotoxicity

[0161] Four types of cell lines (3T3-L1 adipocytes, RD muscle cells, keratinocytes, and fibroblasts) were used, and each cell was cultured in a 24-well plate at 5 × 10 cells per well. 4After dispensing into 100 pieces, the cells were cultured for 24 hours under the culture conditions of each cell. The medium was discarded and washed with PBS, and then replaced with new medium not containing 10% FBS, and treated with the peptoid derivative of the present invention at each concentration (0, 0.1, 1, 10, 100, 500 μM) and cultured for 24 hours. The medium was again carefully removed and washed with PBS, and the MTT reagent was added according to the manufacturer's method, and after reacting at room temperature for 30 minutes, the absorbance was measured at 450 nm.

[0162] As a result, it was confirmed that the peptoid derivatives of the present invention, including [Chemical Formula 1-4] and [Chemical Formula 1-9], were non-toxic in multiple cell lines (FIGS. 10 and 11).

[0163]

[0164] Test Example 4. Verification of concentration dependency of in vitro AMPK phosphorylation activity

[0165] The mouse adipocyte cell line 3T3-L1 was treated with a series of concentrations of the peptoid derivatives of the present invention (0, 0.01, 0.1, 1, 10, 100 μM) and cultured for 24 hours, after which the cells were harvested. Proteins were then extracted and the concentration-dependent effect of the peptoid derivatives on AMPK phosphorylation was examined by Western blotting.

[0166] As a result, it was confirmed that the peptoid derivatives of the present invention, including [Chemical Formula 1-4] and [Chemical Formula 1-9], increased the AMPK phosphorylation activity in a concentration-dependent manner (FIG. 12).

[0167]

[0168] Test Example 5. Solubility test

[0169] PRISMA HT solution was diluted with distilled water at a ratio of 1:40 and adjusted to pH 7.4 to be used as a test buffer. In addition, reference substances (Diclofenac stock 50 mM, Phenazopyridine stock 25 mM) used for accuracy in general solubility tests and the peptoid derivative of the present invention (50 mM) as a test substance were prepared in DMSO and used as a test standard solution.

[0170] The test material was diluted with 10mL of isopropyl alcohol to prepare a blank sample. In addition, 75mL of the test solution was mixed with 70mL of isopropyl alcohol to prepare a blank sample, and 5mL of the test material diluted with isopropyl alcohol was added to the blank sample. After mixing the diluted samples, the absorbance was measured and used as the initial test value. For the solubility test, 1mL of the test solution was mixed with 10mL of DMSO test standard solution and reacted at room temperature for 24 hours. After that, the sample was filtered using a filter plate to remove precipitates, and 75mL of isopropyl alcohol was added to 74mL of the filtered sample, and the absorbance was measured and used as the sample value.

[0171] The solubility values ​​of the test substances were analyzed using MSOL Explorer (Solubility Explorer program) after measuring the absorbance of each sample using a microplate reader. The average and standard deviation of three replicates (n=3) were calculated using an Excel program.

[0172] As a result, the peptoid derivatives of the present invention showed excellent solubility in DMSO (Table 4).

[0173] [Table 4]

[0174]

[0175] Test Example 6. Plasma stability test

[0176] The peptoid derivative of the present invention was added to two types of plasma (human and rat) at a concentration of 1 μM, and then placed in each tube and incubated at 37° C. for a period of time (0, 30, 60, 120, 240 min). After each period, the tube containing the plasma was taken out, and an acetonitrile solution containing an internal standard (chlorpropamide) was added, vortexed for 5 minutes, centrifuged (14,000 rpm, 4° C.) for 5 minutes, and the supernatant was injected into an LC-MS / MS system to analyze the drug at each period of time, thereby evaluating the plasma stability of the peptoid derivative. Here, procaine and enalapril were used as reference substances used for accuracy in general plasma stability tests.

[0177] The amount of drug remaining in each tube after the reaction was analyzed by LC-MS / MS using a Shimadzu Nexera XR system and a TSQ vantage (Thermo). The HPLC column used was a Luna C18 column (2.0 x 50 mm, 3 μm particle size; Phenomenex, US), and the mobile phase was distilled water containing 0.1% formalic acid (A) and acetonitrile containing 0.1% formalic acid (B). Data analysis was performed using Xcalibur (version 1.6.1). The plasma stability of each peptoid derivative was shown as the % remaining at each time point relative to the unincubated sample.

[0178] As a result, it was confirmed that the peptoid derivatives of the present invention have excellent plasma stability, and in particular, their plasma stability is significantly improved compared to that of APN5, a conventionally known adiponectin-derived peptide (Table 5).

[0179] [Table 5]

[0180]

[0181] Test Example 7. Metabolic stability test

[0182] Three kinds of liver microsomes (human, rat, mouse, 0.5mg / ml), 0.1M phosphate buffer solution (pH7.4), and the peptoid derivative of the present invention at a concentration of 1μM were added and incubated at 37℃ for 5 minutes, and then NADPH Regeneration system solution was added and incubated at 37℃ for 30 minutes. Then, to terminate the reaction, an acetonitrile solution containing an internal standard substance (chlorpropamide) was added, and the mixture was centrifuged (14,000rpm, 4℃) for 5 minutes, and the supernatant was injected into the LC-MS / MS system to analyze the substrate drug and evaluate the metabolic stability. Verapamil was used as a reference substance used for accuracy in general plasma stability tests.

[0183] The amount of substrate remaining after the reaction was analyzed by LC-MS / MS using an Agilent 1290 infinity series pump system (Agilent, USA) and a Triple Quad 5500 LC-MS / MS system (Applied Biosystems, USA). The HPLC column used was a Kinetex C18 column (2.1 × 100 mm, 1.7 μm particle size; Phenomenex, USA), and the mobile phase was distilled water containing 0.1% formalic acid (A) and acetonitrile containing 0.1% formalic acid (B). TurboSpray Ionization was used as the ion source for MS / MS, and the mass analyzer was a Triple quadruple type. The metabolites produced were quantified using the MRM (multiple reaction monitoring) quantitative mode, and data analysis was performed using Analyst software (version 1.6.1).

[0184] As a result, it was confirmed that the peptoid derivatives of the present invention have excellent metabolic stability, and in particular, their metabolic stability is extremely improved compared to that of APN5, a conventionally known adiponectin-derived peptide (Table 6).

[0185] [Table 6]

[0186] Test Example 8. CYP Inhibition Analysis

[0187] Human liver microsomes (0.25mg / ml), 0.1M phosphate buffer solution (pH7.4), a cocktail of five drug-metabolizing enzyme substrates (phenacetin 50μM, S-mephenytoin 100μM, dextromethorphan 5μM, midazolam 2.5μM, diclofenac 10μM), and the peptoid derivative of the present invention were added at 0 and 10μM concentrations, and incubated at 37℃ for 5 minutes, and then NADPH Regeneration system solution was added and incubated at 37℃ for 15 minutes. Then, to terminate the reaction, an acetonitrile solution containing an internal standard (chlorpropamide) was added, and the mixture was centrifuged (14,000rpm, 4℃) for 5 minutes. The supernatant was then injected into an LC-MS / MS system to simultaneously analyze the metabolites of the substrate drugs, thereby evaluating the inhibitory ability of the peptoid derivative against drug-metabolizing enzymes. Ketoconazole was used as a reference substance for accuracy in evaluating the inhibitory ability of general drug-metabolizing enzymes.

[0188] The metabolites of each CYP enzyme-indicating drug produced through the reaction were analyzed by LC-MS / MS using a Shimadzu Nexera XR system and a TSQ vantage (Thermo). The HPLC column used was a Kinetex C18 column (2.1 x 100 mm, 2.6 μm particle size; Phenomenex, USA), and the mobile phase was distilled water containing 0.1% formalic acid (A) and acetonitrile containing 0.1% formalic acid (B). TurboSpray Ionization was used as the ion source for MS / MS, and the mass analyzer was a Triple quadruple type. The metabolites produced were quantified using the MRM (multiple reaction monitoring) quantitative mode, and data analysis was performed using Xcalibur (version 1.6.1).

[0189] As a result, the peptoid derivatives of the present invention inhibit CYP enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Table 7), suggesting that they do not cause fatal abnormal reactions due to drug interactions.

[0190] [Table 7]

[0191]

[0192] Test Example 9. Evaluation of efficacy of application to mice for hair growth and improvement of skin aging

[0193] After shaving the backs of 7-week-old C57BL / 6 mice, the formulations of the peptoid derivatives of the present invention were dissolved in a vehicle (EtOH:polyethylene glycol=30:70, v / v) at a concentration of 0.15 mM and applied to the backs. 200 μl of the corresponding solution per mouse was applied evenly over the entire back every day for 35 days.

[0194] In addition, after the final application, skin tissue was removed and mRNA was extracted, and the effect on the expression of procollagen, a factor in skin aging, was verified using real-time PCR.

[0195] As a result, the ratio of areas where hair had grown back among areas where hair had been removed for the first time was significantly increased in the group treated with the peptoid derivative of the present invention. In particular, it was confirmed that the formation of hair follicles was promoted, similar to the group treated with minoxidil, which was used as a positive control (FIG. 13).

[0196] It was also confirmed that procollagen, a factor in skin aging, was expressed in a manner similar to or even greater than APN5, a previously known adiponectin-derived peptide, in the group treated with the peptoid derivative of the present invention (Figure 14).

[0197]

[0198] Test Example 10. Verification of the efficacy of neutral fat suppression in adipocytes

[0199] After treating mouse adipocyte cell line 3T3-L1 with differentiation-inducing reagent to differentiate into adipocytes and fill with neutral fat, the cells were treated with a series of concentrations (10, 30 μM) of the peptoid derivatives of the present invention and cultured for 24 hours, and the cells were harvested and the neutral fat content was measured. As a result, it was confirmed that the content of neutral fat produced was reduced in a concentration-dependent manner when the peptoid derivatives of the present invention were treated (FIG. 15A).

[0200] On the other hand, mouse adipocyte cell line 3T3-L1 was differentiated into adipocytes by treating with 10 μM of the peptoid derivative of the present invention together with a differentiation-inducing agent before differentiation induction, and the cells were then isolated and the triglyceride content was measured. As a result, it was confirmed that the accumulation of triglycerides was suppressed when the peptoid derivative of the present invention was treated (FIG. 15B).

[0201]

[0202] Test Example 11. Verification of the efficacy of muscle cells in improving sensitive skin

[0203] After culturing the RD cell line, a human muscle cell line, the medium was replaced with serum-free medium when the cells reached 90% cell volume, and the medium was treated with 50 mM lactic acid (LA), a sensitive skin inducer, and 10 μM of the peptoid derivative of the present invention. After 4 hours, the cells were harvested and mRNA was extracted to observe the effect on the expression of CGRP, a neurotransmitter that mediates pain.

[0204] As a result, it was confirmed that the expression of pain mediators was significantly reduced when treated with the peptoid derivatives of the present invention compared to when treated with lactic acid, and was similar to or lower than when neither treatment was performed (Figure 16), indicating that the peptoid derivatives of the present invention significantly suppress the expression of genes related to skin sensitivity induced by lactic acid.

[0205]

[0206] Although the embodiments of the present invention have been described in detail above with reference to the drawings, the present invention is not limited to the above-described embodiments, and a person having ordinary skill in the art can apply various technical modifications and variations based on the above. For example, the described techniques may be performed in an order different from that described, and / or the components of the described systems, structures, devices, circuits, etc. may be combined or combined in a form different from that described, or may be replaced or substituted by other components or equivalents to achieve appropriate results.

[0207] Accordingly, other implementations, other embodiments, and equivalents of the claims are within the scope of the following claims. [Industrial Applicability]

[0208] The present invention relates to a novel peptoid derivative, which is a partially modified adiponectin receptor peptide and has higher stability and superior p-AMPK activity than existing adiponectin receptor peptides, and has the advantage of being advantageous for drug formulation due to improved physical properties and activity. Therefore, the peptoid derivative of the present invention can be conveniently used in the fields of preventing or treating skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, or cancer, and preventing or improving aging, sensitive skin, wrinkles, or moisturization.

Claims

1. A peptoid derivative represented by the following chemical formula 1. 【Chemistry 1】 In the above [Chemical Formula 1], R １ is an amino group (NH ２ ), acetylamino group (Ac-NH), NH ２ - (CH ２ CH ２ O) ｍ -CH ２ C.O.N.H.,C. １５ -C ２０ and combinations thereof (wherein m is an integer from 1 to 5); R ２ is C １ -C ６ A chain alkyl group of C １ -C ６ Ring-shaped alkyl group of C ２ -C ６ and combinations thereof, R ３、 R ４ and R ５ are the same or different, and each independently represents C ７ -C １２ a phenylalkyl group, a pyridinylmethyl group, an indolylmethyl group, and a benzodioxolomethyl group, The phenylalkyl group may be unsubstituted or may be substituted with a hydroxy group, a trifluoromethyl group (CF ３ ), halogen group, cyano group, nitro group, C １ -C ６ A chain alkyl group of C １ -C ６ and combinations thereof.

2. The R ２ teeth, 【Chemistry 2】 2. The peptoid derivative according to claim 1, which is any one or more selected from the group consisting of:

3. The R ３ , R ４ , and R ５ are the same or different from each other, and each independently: 【Chemistry 3】 2. The peptoid derivative according to claim 1, which is any one or more selected from the group consisting of:

4. The peptoid derivative according to claim 1, which is at least one selected from the group consisting of peptoid derivatives represented by the following [Chemical Formula 1-1] to [Chemical Formula 1-27]. 【Chemistry 4】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

5. A composition for increasing adiponectin expression, comprising the peptoid derivative according to any one of claims 1 to 4 as an active ingredient.

6. A pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising the peptoid derivative according to any one of claims 1 to 4 as an active ingredient.

7. A cosmetic composition for preventing or improving one or more conditions selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising the peptoid derivative according to any one of claims 1 to 4 as an active ingredient.

8. A pharmaceutical composition for preventing or improving one or more conditions selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, comprising the peptoid derivative according to any one of claims 1 to 4 as an active ingredient.

9. A cosmetic composition for preventing or improving one or more of the following: aging, sensitive skin, wrinkles, and moisturizing, comprising the peptoid derivative according to any one of claims 1 to 4 as an active ingredient.

10. A method for preventing or treating one or more conditions selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising a step of administering to an individual the peptoid derivative according to any one of claims 1 to 4.

11. A method for preventing or improving one or more selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, comprising the step of administering to an individual the peptoid derivative according to any one of claims 1 to 4.

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