Novel adiponectin-derived peptoid derivatives and their uses

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 novel adiponectin-derived peptoid derivatives and uses thereof. [Background technology]

[0002] Skin aging is generally caused by both external and internal processes, such as increased wrinkling and sagging of the skin. External aging is commonly called "photoaging" because it is primarily caused by repeated exposure to ultraviolet rays (UV). While naturally aged skin is smooth, pale, and has fine lines, 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 shown that ultraviolet radiation, 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 fat-derived product, decreases in aging skin, inducing an increase in MMP-1 and a decrease in collagen.

[0004]

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

[0006] Currently, it is known that 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 that hair loss symptoms occur due to the complex interaction of these 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, increased stress caused by social environments, etc., and the number of people suffering from abnormal scalp and hair symptoms as described above is gradually increasing, and the age of those suffering is also getting younger.

[0007] Currently available hair growth drugs have the problems of lacking clear effects and side effects, needing to be taken continuously, and inducing side effects such as decreased sexual function, allergies, and depression.

[0008]

[0009] Metabolic disease is a syndrome in which risk factors such as obesity, diabetes, high blood pressure, arteriosclerosis, and nonalcoholic fatty liver disease (NAFLD) occur together due to excessive 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. According to the ATP published by the US National Cholesterol Education Program (NCEP) in 2001, a patient is diagnosed with metabolic disease if they have three or more of the following five risk factors: abdominal obesity with a waist circumference of 40 inches (102 cm) or more for men and 35 inches (88 cm) for women; triglycerides of 150 mg / dL or more; HDL cholesterol of 40 mg / dL 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. Recent research has shown that when these standards are applied, approximately 25% of the Korean population shows symptoms of metabolic syndrome.

[0010]

[0011] Adiponectin, a type of adipokine, a protein hormone secreted specifically by fat cells, is known to play an important role in regulating cardiovascular diseases such as hyperglycemia, hyperinsulinism, obesity, and arteriosclerosis by enhancing insulin function and suppressing insulin resistance, blocking inflammation and preventing fat accumulation in blood vessels. Adiponectin also inhibits cancer cell metastasis and inflammatory responses, and promotes not only keratinocyte proliferation but also the expression of filaggrin, hyaluronic acid, and extracellular matrix in the skin, thereby healing wounds, inhibiting fibrosis, improving skin wrinkles, and moisturizing the skin.

[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 overseas, 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 with modified backbones that are more resistant to proteolysis. While these peptides have better pharmacokinetic properties than existing peptides, some have been reported to be cytotoxic.

[0015]

[0016] Under these circumstances, the present inventors developed short adiponectin-derived peptoids that have high physiological activity without cytotoxicity, and confirmed their effects of increasing adiponectin expression, promoting hair growth, and suppressing triglycerides, 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 containing the peptoid derivative as an active ingredient for preventing or ameliorating inflammatory skin diseases, wounds, hair loss, fibrosis, metabolic diseases, or cancer.

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

[0023] However, the technical problems that the present invention aims to achieve are not limited to those 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 solve the above problems, the present invention provides a peptoid derivative represented by the following [Chemical Formula 1]. [Chemical formula 1]

[0025] [ka]

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

[0027] R1 is an amino group (NH2), an acetylamino group (Ac-NH), or NH2-(CH2CH2O) m -CH2CONH, C 15 -C 20and combinations thereof, wherein m may be an integer of 1 to 5, preferably 3, and the amide group may preferably be a C16 amide group, i.e., a palmitamide group;

[0028] R2 is at least one selected from the group consisting of a C1-C6 chain alkyl group, a C1-C6 ring alkyl group, a C2-C6 alkylcarboxyl group, and combinations thereof;

[0029] R 3、 R4 and R5 are the same or different and each independently represent a C7-C 12 phenylalkyl group, pyridinylmethyl group, indolylmethyl group, benzodioxolomethyl group,

[0030] The phenylalkyl group may be unsubstituted or may be any one or more selected from the group consisting of a hydroxy group, a trifluoromethyl group (CF), a halogen group, a cyano group, a nitro group, a C1-C6 chain alkyl group, a C1-C6 alkoxy group, and combinations thereof.

[0031] In one embodiment of the present invention, R2 is [ka] and combinations thereof, but is not limited thereto.

[0032] In another embodiment of the present invention, R3, R4, and R5 are the same or different and each independently represent: [ka] and combinations thereof, but is not limited thereto.

[0033] In another embodiment of the present invention, the peptoid derivative may be at least one 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] JPEG0007799063000005.jpg188149 JPEG0007799063000006.jpg183149 JPEG0007799063000007.jpg183149 JPEG0007799063000008.jpg183149 JPEG0007799063000009.jpg178149 JPEG0007799063000010.jpg119149

[0041]

[0042] The present invention also provides a composition for increasing adiponectin expression, 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 conditions 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 conditions 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 conditions 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 any 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 conditions 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. [Effects of the Invention]

[0055] The peptoid derivative according to 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 advantage 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 for the prevention or treatment of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, or cancer, and for the prevention or improvement of aging, sensitive skin, wrinkles, or moisturizing.

[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 following description. [Brief explanation 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 AMPK phosphorylation activity in mouse adipocytes, where V is a vehicle treated with DMSO, and P5 is a positive control APN5 peptide with the sequence NH2-GLYYF-OH.

[0059] [Figure 2] Figure 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 AMPK phosphorylation activity in mouse adipocytes, where V is the vehicle treated with DMSO, and P5 is the positive control APN5 peptide with the sequence NH2-GLYYF-OH.

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

[0062] [Figure 5]5 is a graph showing the effect of the peptoid derivatives (DS-46 and 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 the vehicle treated with DMSO, and P5 is the positive control APN5 peptide with 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 AMPK phosphorylation activity in mouse adipocytes, where V is the vehicle treated with DMSO, and P5 is the positive control APN5 peptide with 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 AMPK phosphorylation activity in mouse adipocytes, where V is the vehicle treated with DMSO, and P5 is the positive control APN5 peptide with 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 AMPK phosphorylation activity in mouse adipocytes, where V is the vehicle treated with DMSO, and P5 is the positive control APN5 peptide with the sequence NH2-GLYYF-OH.

[0066] [Figure 9]Figure 9 shows whether the AMPK phosphorylation activity increased by the peptoid derivatives (DS-15, DS-16, DS-25, and 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 reduced by adiponectin receptor 1 knockdown. Here, NC is scrambled siRNA, and R1 is adiponectin receptor 1 siRNA. V is a DMSO-treated vehicle, and P5 is the APN5 peptide with the NH2-GLYYF-OH sequence as a positive control. DS-43 is adiponectin receptor 1 agonist, adiporon.

[0067] [Figure 10] Figure 10 shows the cytotoxicity of the peptoid derivatives of the present invention represented by [Chemical Formulas 1-4] against four cell lines (3T3-L1 adipocytes, RD muscle cells, keratinocytes, and fibroblasts). Here, Veh indicates 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 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 an APN5 peptide having the sequence NH2-GLYYF-OH as a positive control, and Mnx is minoxidil, a known hair growth agent, as a positive control.

[0071] [Figure 14] Figure 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] Figure 15B shows the differentiation and triglyceride suppression effects of the peptoid derivatives of the present invention represented by [Chemical Formula 1-4] and [Chemical Formula 1-9]. Here, V is a vehicle treated with DMSO, P5 is a positive control APN5 peptide with the sequence NH2-GLYYF-OH, ND is a culture in a non-differentiation medium, and D is a culture 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 the vehicle treated with DMSO, LA is lactic acid, and P5 is the APN5 peptide as a positive control. DETAILED DESCRIPTION OF THE INVENTION

[0074] The present invention relates to the synthesis of novel peptoid derivatives based on the adiponectin-derived peptide APN5, and 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 activity, making them advantageous for drug formulation.

[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] R1 is an amino group (NH2), an acetylamino group (Ac-NH), or NH2-(CH2CH2O) m -CH2CONH, C 15 -C 20 and combinations thereof, wherein m may be an integer of 1 to 5;

[0080] R2 is at least one selected from the group consisting of a C1-C6 chain alkyl group, a C1-C6 ring alkyl group, a C2-C6 alkylcarboxyl group, and combinations thereof;

[0081] R 3、 R4 and R5 are the same or different and each independently represent a C7-C 12phenylalkyl group, pyridinylmethyl group, indolylmethyl group, benzodioxolomethyl group,

[0082] The phenylalkyl group is unsubstituted or is at least one selected from the group consisting of a hydroxy group, a trifluoromethyl group (CF), a halogen group, a cyano group, a nitro group, a C1-C6 chain alkyl group, a C1-C6 alkoxy group, 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 connected in a chain, and can 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 CH0- 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 structure in which the substituent (R) is attached to an amine and lacks a chiral center and amide hydrogen. Unlike peptides, peptoids are unnatural and therefore not easily degraded by protease enzymes, resulting in excellent in vivo stability. Therefore, peptoids can overcome the disadvantage of peptides, which are easily degraded 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 conditions 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" means any action that inhibits or delays the occurrence, spread, or recurrence of the disease by administering the composition of the present invention, and "treatment" means any action that improves or alters the symptoms of the disease by administering the composition of the present invention.

[0095] In the present invention, the term "amelioration" refers to any action that at least reduces the parameters related to the condition being treated, 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 substance prepared for the purpose of preventing or treating the above-mentioned diseases, and may be formulated into various forms by a conventional method for use. For example, it can be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, and syrups, and it can also be formulated into external preparations, suppositories, and sterile injection solutions for use.

[0097] In the present invention, "containing an effective component" means that the component is contained in an amount necessary or sufficient to achieve a desired biological effect. In practical application, the amount of the active component is determined taking into consideration the amount required to treat the target disease without causing other toxicity, and may vary depending on various factors such as the disease or condition being treated, the form of the composition to be administered, the size of the subject, or the severity of the disease or condition. A person skilled in the art to which the present invention pertains can empirically determine the effective amount of a particular composition without excessive testing.

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

[0099] The pharmaceutically acceptable carrier may be saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more of these components, and may further contain other common additives such as antioxidants, buffers, bacteriostatic agents, etc., as necessary. Diluents, dispersants, surfactants, binders, and lubricants may also be added to form the solution into an injectable dosage form such as an aqueous solution, suspension, or emulsion, or into pills, capsules, granules, or tablets. Furthermore, suitable formulations may be prepared according to the disease or ingredients, using a method appropriate to the art or a method disclosed in Remington's Pharmaceutical Sciences (Mack Publishing Company, Easton PA).

[0100] The composition of the present invention can be administered orally or parenterally in a pharmaceutically effective amount depending on the intended method. The term "pharmaceutically 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 which does not cause side effects. The effective dose level may be determined based on factors including the patient's health condition, severity, drug activity, drug sensitivity, administration method, administration time, administration route, and excretion rate, treatment period, concomitant or concurrently used 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 causes itching, blisters, 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. Non-limiting examples include diabetes, hypertension, hyperlipidemia, cardio-cerebrovascular disease, 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 conditions 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 conditions 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 need of prevention, treatment, and / or diagnosis of the disease, but may preferably be a human.

[0107] The term "administration" as used herein means providing a predetermined substance to a patient by any suitable method. The pharmaceutical compositions of the present invention can be formulated into various forms for administration to an individual. A typical dosage form for parenteral administration is an injectable dosage form, preferably an isotonic aqueous solution or suspension. Injectable dosage forms can be prepared by techniques well known in the art using appropriate dispersing or wetting agents and suspending agents. For example, each component can be dissolved in saline or a buffer solution to form a dosage form for injection. Oral dosage forms include, for example, ingestible tablets, buccal tablets, troches, capsules, erythritol, suspensions, syrups, and wafers. These dosage forms may contain, in addition to the active ingredient, 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). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and may optionally further contain disintegrants, absorbents, colorants, flavorings and / or sweeteners such as starch, agar, alginic acid or its sodium salt. The dosage forms may be produced by conventional mixing, granulating or coating methods.

[0108] 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 can be administered via various routes, including oral, transdermal, subcutaneous, intravenous, intranasal, intraperitoneal, or intramuscular, and the dosage of the active ingredient can be appropriately selected depending on various factors such as the administration route, the age, sex, and weight of the patient, and the severity of the patient's condition, etc. The composition of the present invention can 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 conditions 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 may contain, for example, the peptoid derivative or a cosmetically acceptable salt thereof as an active ingredient, and may be prepared together with a dermatologically acceptable excipient in the form of a basic cosmetic composition (skin lotion, cream, essence, facial cleanser 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.

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

[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 pharmaceutically acceptable salt thereof as an active ingredient. When the peptoid derivative is used as an additive in a food composition, it can be added directly or in combination with other foods or food ingredients, and can be used appropriately in a conventional manner. Generally, 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, when taking the composition for long-term purposes such as health and hygiene or health regulation, the amount may be less than the above range, and since there are no safety issues, the active ingredient may be used in an amount greater than the above range. That is, the amount of the active ingredient to be added can be determined appropriately depending on the intended use, such as prevention, health, or treatment.

[0119] The dosage form of the food composition may be any of powder, granules, tablets, capsules, as well as general food or drink forms.

[0120] The food product 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 product may include proteins, carbohydrates, fats, nutrients, seasonings, and flavorings. Examples of carbohydrates include, but are not limited to, glucose, fructose, maltodextrose, sucrose, oligosaccharides, dextrin, cyclodextrin, xylitol, sorbitol, erythritol, saccharin, and synthetic flavorings.

[0121]

[0122] The terms used in the embodiments are used for the purpose of explanation and are not to be construed as limiting. A singular expression includes a plural expression unless the context clearly indicates otherwise. 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 possibility of 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 having an ideal or overly formal meaning unless expressly defined herein.

[0124] Furthermore, when describing components of an embodiment, terms such as first, second, A, B, (a), (b), etc. may be used. Such terms are used to distinguish the component 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, embodiments will be described in detail with reference to the accompanying drawings. However, since various modifications can be made to the embodiments, the scope of the patent application is not limited to or restricted by the embodiments. It should be understood that all modifications, equivalents, and alternatives to the embodiments are included in the scope of the patent.

[0127] In addition, when describing the embodiments with reference to the accompanying drawings, the same reference numerals will be used to refer to the same components regardless of the reference numerals, and redundant descriptions thereof will be omitted. In describing 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, and alternatives within the spirit and technical scope of the present invention. In describing the present invention, if a detailed description of related publicly known technology is considered 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 peptoid derivatives of the present invention

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

[0132] [ka]

[0133] Peptoids can be easily synthesized using solid-phase synthesis. Using polymer beads bearing amine or hydroxyl groups as starting materials, peptoid residues can be easily introduced through a two-step reaction: bromoacetylation and amine substitution using a primary amine. Repeating this process allows efficient synthesis of peptoid oligomers. 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, 700W, 2450Hz). C-terminal amide peptoids were synthesized on resin beads using Fmoc-Rink amid MBHA resin (0.89 mmol / g, Novabiochem®, San Diego, CA, USA). All microwave-assisted reactions were performed at atmospheric pressure, and the initial reaction was performed at half-scale using resin beads (100 mg, 89 μmol). To remove the Fmoc protecting group from the resin, the Fmoc-Rink amid MBHA resin was reacted with 1 mL of 20% (v / v) piperidine in dimethylformamide (DMF) at room temperature for 10 minutes each, followed by washing the resin beads twice with dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM), and finally dimethylformamide (DMF). For bromoacetylation, bromoacetic acid (2M, 890 μL) dissolved in DMSO and N,N'-diisopropylcarbodiimide (2M, 890 μL) were added. The reaction solution was stirred and irradiated twice for 15 seconds using a microwave (700 W, 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), repeating the washing process twice each.

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

[0136] The peptoid residue, designated 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), N-terminally unprotected peptoids synthesized by the peptoid synthesis method described above were reacted with 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-(2-aminoethoxy)ethoxy)ethoxy)acetic acid) or PAL (Palmitic acid) in dimethylformamide (DMF) for 2 hours with stirring. 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] The synthesized peptoid was separated from the resin by stirring in a separation solution (TFA:HO:TIPS = 95:2.5:2.5) at room temperature for 2 hours, and then the peptoid solution separated from the resin was distilled under reduced pressure to remove the solvent. The peptoid compound was purified using high-performance liquid chromatography (Prep-HPLC, Gilson) and purified using RP-HPLC and LC-MS to confirm and analyze its purity, yielding peptides with a purity of over 98% (Methods Enzymol. 267, 437-447 1996; Org Lett. 2002, 14;423:4057-9).

[0142]

[0143] The sequences and molecular weights of 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 in vitro AMPK phosphorylation activity

[0150] The effects of the peptoid derivatives of the present invention on adiponectin expression and receptor activity in mouse adipocytes, the main adiponectin-producing cells, were examined. The mouse adipocyte cell line 3T3-L1 was treated with each of the peptoid derivatives of the present invention at a concentration of 10 μM and cultured for 24 hours, after which the cells were harvested. Proteins were then extracted, and the effects on AMPK phosphorylation, which is responsible for the main downstream signaling of adiponectin, were examined by Western blot.

[0151] As a result, the peptoid derivatives of the present invention increased the AMPK phosphorylation activity related to the activation of adiponectin receptors 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] 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 it with siRNA for adiponectin receptor 1, and then treated with each of the peptoid derivatives of the present invention at a concentration of 10 μM. After culturing for 24 hours, the cells were harvested. Proteins were then extracted, and Western blotting was performed to determine whether the increased AMPK phosphorylation activity caused by the peptoid derivatives had 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 adiponectin receptors, and activation of the adiponectin receptors 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). Furthermore, the expression of adiponectin and its receptors is reduced in photoaged skin and skin exposed to UV rays. This reduced expression of adiponectin can worsen photoaging by regulating the expression of MMP-1 and procollagen, which are regulators of skin aging, and altering the extracellular matrix (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, thereby increasing the expression of adiponectin in the body and playing a major role in preventing skin aging.

[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 grown in a 24-well plate at 5 × 10 cells per well. 4The cells were then aliquoted and cultured for 24 hours under the appropriate cell culture conditions. The medium was discarded, washed with PBS, and replaced with fresh medium without 10% FBS. The cells were treated with the peptoid derivatives of the present invention at various concentrations (0, 0.1, 1, 10, 100, and 500 μM) and cultured for 24 hours. The medium was again carefully removed and washed with PBS. MTT reagent was added according to the manufacturer's instructions, and the cells were incubated at room temperature for 30 minutes, after which 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 peptoid derivatives of the present invention at various concentrations (0, 0.01, 0.1, 1, 10, and 100 μM) and cultured for 24 hours. After cell collection, proteins were 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], increase 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 test standard solutions.

[0170] 10 mL of the prepared test substance was diluted with 190 μL of isopropyl alcohol. A blank sample was prepared by mixing 75 mL of test solution with 70 mL of isopropyl alcohol, and 5 mL of the test substance diluted in isopropyl alcohol was added to the blank sample. After mixing the diluted sample, the absorbance was measured and used as the initial test value. For the solubility test, 1 mL of test solution was mixed with 10 mL of DMSO test standard solution and incubated at room temperature for 24 hours. The sample was then used to remove precipitates using a filter plate. 75 mL of isopropyl alcohol was added to 74 mL of the filtered sample, and the absorbance was measured and used as the sample value.

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

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

[0173] [Table 4]

[0174]

[0175] Test Example 6. Plasma stability test

[0176] The peptoid derivatives of the present invention were added to two types of plasma (human and rat) at a concentration of 1 μM, placed in separate tubes, and incubated at 37°C for various time periods (0, 30, 60, 120, and 240 minutes). After each incubation period, the plasma tubes were removed, an acetonitrile solution containing an internal standard (chlorpropamide) was added, vortexed for 5 minutes, and centrifuged (14,000 rpm, 4°C) for 5 minutes. The supernatant was then injected into an LC-MS / MS system to analyze the drug at each time point, thereby assessing the plasma stability of the peptoid derivatives. Procaine and enalapril were used as reference substances to ensure 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 0.1% formic acid in distilled water (A) and 0.1% formic acid in acetonitrile (B). Data analysis was performed using Xcalibur (version 1.6.1). The plasma stability of each peptoid derivative was shown as the percentage 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 APN5, a conventionally known adiponectin-derived peptide (Table 5).

[0179] [Table 5]

[0180]

[0181] Test Example 7. Metabolic stability test

[0182] Three types of liver microsomes (human, rat, mouse, 0.5 mg / ml) were added to 0.1 M phosphate buffer (pH 7.4) and the peptoid derivative of the present invention at a concentration of 1 μM. The mixture was then pre-incubated at 37°C for 5 minutes, followed by the addition of an NADPH regeneration system solution and incubation at 37°C for 30 minutes. To terminate the reaction, an acetonitrile solution containing an internal standard (chlorpropamide) was added, followed by centrifugation (14,000 rpm, 4°C) for 5 minutes. The supernatant was then injected into an LC-MS / MS system to analyze the substrate drug and evaluate metabolic stability. Verapamil was used as a reference substance to ensure 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). The mobile phase was 0.1% formic acid in distilled water (A) and 0.1% formic acid in acetonitrile (B). The MS / MS ion source was TurboSpray ionization, and the mass analyzer was a Triple quadruple type. The metabolites produced were quantified using multiple reaction monitoring (MRM) quantification 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 significantly improved compared to APN5, a conventionally known adiponectin-derived peptide (Table 6).

[0185] [Table 6]

[0186] Test Example 8. CYP Inhibition Analysis

[0187] Human liver microsomes (0.25 mg / ml) were mixed with 0.1 M phosphate buffer (pH 7.4), a cocktail of five drug-metabolizing enzyme substrates (phenacetin 50 μM, S-mephenytoin 100 μM, dextromethorphan 5 μM, midazolam 2.5 μM, diclofenac 10 μM), and the peptoid derivatives of the present invention at 0 and 10 μM concentrations, and then incubated at 37°C for 5 minutes. An NADPH regeneration system solution was then added and incubated at 37°C for 15 minutes. To terminate the reaction, an acetonitrile solution containing an internal standard (chlorpropamide) was added, followed by centrifugation for 5 minutes (14,000 rpm, 4°C). The supernatant was then injected into an LC-MS / MS system to simultaneously analyze the metabolites of the drug substrates, thereby assessing the inhibitory activity of the peptoid derivatives against drug-metabolizing enzymes. Ketoconazole was used as a reference substance to ensure accuracy when assessing the inhibitory activity of common drug-metabolizing enzymes.

[0188] The metabolites of each CYP isoenzyme-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 × 100 mm, 2.6 μm particle size; Phenomenex, USA), and the mobile phase was 0.1% formic acid in distilled water (A) and 0.1% formic acid in acetonitrile (B). The MS / MS ion source was TurboSpray ionization, and the mass analyzer was a Triple Quadrupole type. The metabolites produced were quantified using multiple reaction monitoring (MRM) quantification 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 the efficacy of hair growth and skin aging improvement after application to mice

[0193] After shaving the backs of 7-week-old C57BL / 6 mice, the peptoid derivative formulations 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 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 hair growth sites among the first hair removal sites was significantly increased in the group treated with the peptoid derivative of the present invention. In particular, it was confirmed that hair follicle formation was promoted, similar to the group treated with minoxidil, which was used as a positive control (Figure 13).

[0196] Furthermore, it was confirmed that procollagen, a factor in skin aging, was expressed in a manner similar to or even greater than APN5, a conventionally 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 effect of suppressing neutral fat in adipocytes

[0199] The mouse adipocyte cell line 3T3-L1 was differentiated into adipocytes by treatment with a differentiation-inducing agent, and the cells were filled with triglycerides. After treatment with a series of concentrations (10, 30 μM) of the peptoid derivatives of the present invention and culturing for 24 hours, the cells were harvested and the triglyceride content was measured. As a result, it was confirmed that treatment with the peptoid derivatives of the present invention reduced the triglyceride content in a concentration-dependent manner (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 reagent prior to differentiation induction, and the cells were then isolated and the triglyceride content was measured. As a result, it was confirmed that treatment with the peptoid derivative of the present invention inhibited the accumulation of triglycerides (FIG. 15B).

[0201]

[0202] Test Example 11: Verification of the effectiveness of muscle cells in improving sensitive skin

[0203] After culturing the RD cell line, a human muscle cell line, the medium was changed to serum-free medium when the cells reached 90% fullness, 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 that the levels were similar to or lower than when not treated with either compound (Figure 16).In other words, it was found that the peptoid derivatives of the present invention significantly suppressed 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 skilled 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 substituted or replaced by other components or equivalents, and still 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 novel peptoid derivatives, which are partially modified adiponectin receptor peptides and have higher stability and superior p-AMPK activity than existing adiponectin receptor peptides. The improved physical properties and activity make them suitable for drug formulation. Therefore, the peptoid derivatives of the present invention can be conveniently used in the prevention or treatment of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, or cancer, as well as the prevention or improvement of aging, sensitive skin, wrinkles, or moisturizing.

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 CONH, C. １５ -C ２０ and combinations thereof (where m is an integer of 1 to 5), R ２ is C １ -C ６ a chain alkyl group of C3-C ６ a ring-shaped alkyl group of C ２ -C ６ and any one or more selected from the group consisting of alkyl carboxyl groups of the formula (I) and combinations thereof; R ３、 R ４ and R ５ are the same or different, and each independently represents C ７ -C １２ a phenyl alkyl group, a pyridinylmethyl group, an indolylmethyl group, or a benzodioxolomethyl group, The phenyl alkyl group may be unsubstituted or may be substituted with a hydroxy group, a trifluoromethyl group (CF ３ ), a halogen group, a cyano group, a 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: 【Transformation 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, wherein the peptoid derivative 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】

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 the prevention or treatment of 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 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.

10. Use of a peptoid derivative described in any one of claims 1 to 4 for the manufacture of a pharmaceutical 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.

11. Use of a peptoid derivative described in any one of claims 1 to 4 for the manufacture of a cosmetic preparation for improving one or more of the following selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing.

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