KR20230088621A - Novel peptide derivatives from adiponectin and use thereof - Google Patents

Abstract

The present invention relates to novel adiponectin-derived peptide derivatives, wherein the peptide derivatives are partially modified adiponectin receptor peptides, has higher stability and superior p-AMPK activity than existing adiponectin receptor peptides, and has improved physical properties and activity, making it advantageous for drug formulation. Therefore, the peptide derivatives of the present invention can be used for preventing or treating skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, or cancer, and preventing or treating aging, sensitive skin, wrinkles, or for moisturizing.

Description

Novel peptide derivatives from adiponectin and use thereof {Novel peptide derivatives from adiponectin and use thereof}

The present invention relates to novel adiponectin-derived peptide derivatives and uses thereof.

Skin aging is often caused by external and internal processes associated with an increase in skin wrinkles, sagging, and sagging, and is generally referred to as 'photoaging' because external aging is mainly caused by repeated exposure to ultraviolet rays (UV). Naturally aged skin is smooth, pale and has fine wrinkles, but photoaged skin has thick skin wrinkles and causes pigmentation and telangiectasia.

Subcutaneous fat plays an important role in maintaining energy homeostasis by secreting hormones and adipokines that control the metabolism of other tissues. Recently, ultraviolet rays, an environmental factor that causes various diseases such as photoaging, inflammation, immunosuppression, and cancer, reduce the fat content of human subcutaneous adipose tissue, and adiponectin, a fat-derived product, is reduced in aged skin. MMP-1 It is known that an increase and a decrease in collagen are induced.

There are about 1.3 million or more hairs in the human body, and 100,000 to 150,000 hairs on the head, and each hair has a different cycle: anagen (the active growth phase), catagen (the apoptotic regression phase), and telogen (the apoptotic regression phase). , the resting phase), growth, maintenance and shedding. This cycle is repeated over 3 to 6 years, and as a result, an average of 50 to 100 hairs per day are normally lost. In general, 'hair loss' refers to a state in which there is less or no hair or hair than normal due to some cause.

Today, the causes of hair loss include internal factors such as the action of male hormones or external factors such as mental stress in daily life and accumulation of lipid peroxide in the scalp, and it is known that these factors are complexly involved to show hair loss symptoms. . In recent years, not only male pattern baldness, but also a growing number of female hair loss population due to changes in diet and increased stress due to social environment, etc., and the number of people suffering from abnormal symptoms of the scalp and hair is increasing, and the age It is getting lower.

Hair restorers currently on the market have problems such as lack of clear effects and side effects, and need to be taken continuously, causing side effects such as decreased sexual function, allergies, and depression.

Metabolic disease refers to a syndrome in which risk factors such as obesity, diabetes, hypertension, arteriosclerosis, and nonalcoholic fatty liver disease (NAFLD) appear together due to accumulation of excess nutrients and lack of exercise in the body, 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 addition, according to the ATP of the US National Cholesterol Education Program (NCEP) announced in 2001, abdominal obesity with a waist circumference of 40 inches (102 cm) for men and 35 inches (88 cm) for women, and triglycerides of 150 mg/ Three out of five risk factors: dL or higher, HDL cholesterol lower than 40 mg/dL in men and 50 mg/dL in women, blood pressure higher than 130/85 mmHg, and fasting glucose higher than 110 mg/dL. In case of abnormality, it is judged as a metabolic disease. In the case of Asians, when the waist circumference is 90 for men or 80 for women, it is slightly adjusted only for abdominal obesity. There is also a recent study report that shows symptoms of metabolic syndrome.

On the other hand, adiponectin is a type of adipokine, a protein hormone specifically secreted by adipocytes. It enhances insulin function and inhibits insulin resistance, thereby blocking inflammation and preventing fat from accumulating in blood vessels, resulting in high blood sugar levels. , It is known to play an important role in controlling cardiovascular diseases such as hyperinsulinemia, obesity, and atherosclerosis. In addition, adiponectin has the function of inhibiting cancer cell metastasis and inflammatory response, and promotes not only the proliferation of keratinocytes but also the expression of filaggrin, hyaluronic acid and extracellular matrix in the skin, thereby inhibiting wound healing and fibrosis. It can perform functions such as skin wrinkle improvement and moisturizing.

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. A hexamer and a 400 kDa polymer complex (HMW complex) are the main oligomers, and the polymer complex is known to be more active than the LMW complex.

The development of peptides modified from adiponectin known to have various physiological activities has been the target of many domestic and foreign researchers and pharmaceutical companies, but the possibility of final success is relatively low due to difficulties in forming polymers in the body.

Under this background, the present inventors developed a short peptide derivative that can be applied to the skin by improving the physical properties and activity of existing adiponectin-derived peptides, which are difficult to formulate due to their poor solubility, and confirmed their adiponectin expression increase, hair growth promotion, and neutral fat inhibition effects. completed the present invention.

An object of the present invention is to provide novel peptide derivatives.

Another object of the present invention is to provide a composition for increasing the expression of adiponectin comprising the peptide derivative as an active ingredient.

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, comprising the peptide derivative as an active ingredient.

Another object of the present invention is to provide a cosmetic composition for preventing or improving skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, or cancer comprising the peptide derivative as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for preventing or improving aging, sensitive skin, wrinkles, or moisturizing, containing the peptide derivative as an active ingredient.

Another object of the present invention is to provide a cosmetic composition for preventing or improving aging, sensitive skin, wrinkles, or moisturizing, containing the peptide derivative as an active ingredient.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

In order to solve the above problems, the present invention provides a peptide derivative represented by the following [Formula 1].

[Formula 1]

In the above [Formula 1],

R ₁ is selected from the group consisting of an amino group (NH ₂ ), an acetylamino group (Ac-NH), NH ₂ -(CH ₂ CH ₂ O) _m -CH ₂ CONH, a C ₁₅ -C ₂₀ amide group, and combinations thereof Any one or more selected, wherein m may be an integer of 1 to 5, preferably 3, and the amide group is preferably a C ₁₆ amide group, that is, a palmitamide group, ,

R ₂ is an amino group or a hydroxyl group (OH);

R ₃ is hydrogen (H);

R ₄ is selected from the group consisting of a C ₁ -C ₆ chain alkyl group, a C ₂ -C ₆ alkyl carboxyl group, a C ₁ -C ₆ alkylamide group, an imidazoylmethyl group, and combinations thereof more than one of the

R ₅ and R ₆ are the same as or different from each other, and are each independently a benzyl group, a phenylethyl group, or an indolylmethyl group, and the benzyl group is unsubstituted or a hydroxy group, a trifluoromethyl group (CF ₃ ), a halogen group, At least one selected from the group consisting of a cyano group, a nitro group, a C ₁ -C ₆ chain-type alkyl group, a C ₁ -C ₆ alkoxy group, and combinations thereof,

R ₇ is a benzyl group or a C ₁ -C ₆ alkylamino group, and the benzyl group is unsubstituted or a hydroxy group, a halogen group, a cyano group, a nitro group, a C ₁ -C ₆ chain alkyl group, or a C ₁ -C ₆ alkoxy group. group, and any one or more selected from the group consisting of combinations thereof;

R ₃ and R ₇ are connected to each other to form a C ₁₅ -C ₂₀ heterocycloalkene group;

R ₈ , R ₉ , and R ₁₀ are the same as or different from each other, and are each independently hydrogen or a C ₁ -C ₆ alkyl group;

n can be 0 or 1;

When n is 0, R ₄ is a C ₂ -C ₆ alkylcarboxyl group, R ₅ , R ₆ , and R ₇ may be a benzyl group;

provided that R ₁ is NH ₂ , R ₂ is OH, R ₃ is hydrogen, R ₄ is an isobutyl group, both R ₅ and R ₆ are a hydroxybenzyl group, and R ₇ is an unsubstituted benzyl group; , R ₈ , R ₉ , and R ₁₀ are all hydrogen, except when n is 1. That is, NH2-GLYYF-OH known as APN5 peptide is excluded.

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, 및 이들의 조합으로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.As an embodiment of the present invention, the R ₄ is

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, And may be any one or more selected from the group consisting of combinations thereof, but is not limited thereto.

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, 및 이들의 조합으로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.As another embodiment of the present invention, the R ₅ and R ₆ are the same as or different from each other, and each independently

,

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, And may be any one or more selected from the group consisting of combinations thereof, but is not limited thereto.

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, 및 이들의 조합으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것일 수 있으나, 이에 제한되는 것은 아니다.As another embodiment of the present invention, the C ₁₅ -C ₂₀ heterocycloalkene group

,

,

,

, And may be any one or more selected from the group consisting of combinations thereof, but is not limited thereto.

As another embodiment of the present invention, the peptide derivative may be any one or more selected from the group consisting of peptide derivatives represented by the following [Formula 1-1] to [Formula 1-56], but is not limited thereto ( Table 1).

compound number chemical formula number chemical formula DS-1 1-1

DS-2 1-2

DS-3 1-3

DS-4 1-4

DS-5 1-5

DS-6 1-6

DS-7 1-7

DS-8 1-8

DS-9 1-9

DS-10 1-10

DS-11 1-11

DS-12 1-12

DS-17 1-13

DS-18 1-14

DS-19 1-15

DS-20 1-16

DS-27 1-17

DS-28 1-18

DS-29 1-19

DS-30 1-20

DS-35 1-21

DS-36 1-22

DS-37 1-23

DS-38 1-24

DS-39 1-25

DS-40 1-26

DS-41 1-27

DS-42 1-28

DS-44 1-29

DS-45 1-30

DS-48 1-31

DS-49 1-32

DS-50 1-33

DS-51 1-34

DS-52 1-35

DS-53 1-36

DS-54 1-37

DS-55 1-38

DS-56 1-39

DS-57 1-40

DS-58 1-41

DS-59 1-42

DS-60 1-43

DS-61 1-44

DS-62 1-45

DS-63 1-46

DS-68 1-47

DS-70 1-48

DS-72 1-49

DS-73 1-50

DS-74 1-51

DS-75 1-52

DS-76 1-53

DS-77 1-54

DS-78 1-55

DS-79 1-56

As another embodiment of the present invention, the peptide derivative may be a modified one or more peptide sequences selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 16, but is not limited thereto (Table 2).

sequence number peptide sequence compound number chemical formula number One DYYF DS-27 1-17 DS-28 1-18 DS-29 1-19 DS-30 1-20 2 GDFYF DS-58 1-41 3 GDYFF DS-70 1-48 4 GDYYF DS-5 1-5 DS-6 1-6 DS-7 1-7 DS-8 1-8 DS-40 1-26 DS-41 1-27 DS-68 1-47 DS-78 1-55 DS-79 1-56 5 GDYYK DS-35 1-21 DS-36 1-22 6 GDYYY DS-76 1-53 DS-77 1-54 7 GEYYK DS-37 1-23 DS-38 1-24 8 GHYYF DS-44 1-29 DS-45 1-30 9 GIFYF DS-20 1-16 10 GIWYF DS-18 1-14 11 GIYYF DS-1 1-1 DS-2 1-2 DS-3 1-3 DS-4 1-4 12 GLFYF DS-19 1-15 DS-50 1-33 DS-51 1-34 DS-52 1-35 DS-53 1-36 DS-54 1-37 DS-57 1-40 13 GLWYF DS-17 1-13 14 GLYFF DS-59 1-42 DS-60 1-43 DS-61 1-44 DS-62 1-45 DS-63 1-46 15 GLYYF DS-39 1-25 DS-42 1-28 DS-48 1-31 DS-49 1-32 DS-55 1-38 DS-56 1-39 16 GNYYF DS-9 1-9 DS-10 1-10 DS-11 1-11 DS-12 1-12

In addition, the present invention provides a composition for increasing the expression of adiponectin comprising the peptide derivative as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for preventing or treating any one or more selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising the peptide derivative as an active ingredient.

In addition, the present invention provides a method for preventing or treating one or more selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising administering the peptide derivative to a subject.

In addition, the present invention provides the use of the peptide derivative for the preparation of a drug for preventing or treating any one or more selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer.

In addition, the present invention provides a cosmetic composition for preventing or improving any one or more selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising the peptide derivative as an active ingredient.

In addition, the present invention provides a food composition for preventing or improving any one or more selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising the peptide derivative as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for preventing or improving any one or more selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, containing the peptide derivative as an active ingredient.

In addition, the present invention provides at least one prevention or improvement method selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, which includes administering the peptide derivative to a subject.

In addition, the present invention provides the use of the peptide derivative for the preparation of any one or more preventive or ameliorative agents selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing.

In addition, the present invention provides a cosmetic composition for preventing or improving any one or more selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, containing the peptide derivative as an active ingredient.

In addition, the present invention provides a food composition for preventing or improving any one or more selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, containing the peptide derivative as an active ingredient.

The peptide derivative according to an embodiment of the present invention is a partially modified adiponectin receptor peptide, has higher stability and excellent p-AMPK activity than existing adiponectin receptor peptides, and is advantageous in drug formulation due to improved physical properties and activity there is

Therefore, the peptide derivatives of the present invention can be used for prevention or treatment of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, or cancer, prevention or improvement of aging, sensitive skin, wrinkles, or moisturizing.

Effects of the peptide derivative according to an 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.

1 is a graph showing the effect of the peptide derivatives (DS-1 to DS-10) of the present invention represented by [Formula 1-1] to [Formula 1-10] on AMPK phosphorylation activity in mouse adipocytes. At this time, V is DMSO treated as a vehicle, and P5 is an APN5 peptide as a positive control group and has an NH2-GLYYF-OH sequence.
2 is a graph showing the effect of the peptide derivatives (DS-11, DS-12) of the present invention represented by [Formula 1-11] and [Formula 1-12] on AMPK phosphorylation activity in mouse adipocytes. At this time, V is DMSO treated as a vehicle, and P5 is an APN5 peptide as a positive control group and has an NH2-GLYYF-OH sequence.
3 is a graph showing the effect of the peptide derivatives (DS-17 to DS-20) of the present invention represented by [Formula 1-13] to [Formula 1-16] on AMPK phosphorylation activity in mouse adipocytes. At this time, V is DMSO treated as a vehicle, and P5 is an APN5 peptide as a positive control group and has an NH2-GLYYF-OH sequence.
4 is a graph showing the effect of the peptide derivatives (DS-27 to DS-30) of the present invention represented by [Formula 1-17] to [Formula 1-20] on AMPK phosphorylation activity in mouse adipocytes. At this time, V is DMSO treated as a vehicle, and P5 is an APN5 peptide as a positive control group and has an NH2-GLYYF-OH sequence.
5 is a graph showing the effect of the peptide derivatives (DS-35 to DS-38) of the present invention represented by [Formula 1-21] to [Formula 1-24] on AMPK phosphorylation activity in mouse adipocytes. At this time, V is DMSO treated as a vehicle, and P5 is an APN5 peptide as a positive control group and has an NH2-GLYYF-OH sequence.
Figure 6 shows the effect of the peptide derivatives (DS-39 to DS-42, DS-44, DS-45) of the present invention represented by [Formula 1-25] to [Formula 1-30] on AMPK phosphorylation activity in mouse adipocytes. The impact is shown graphically. At this time, V is DMSO treated as a vehicle, and P5 is an APN5 peptide as a positive control group and has an NH2-GLYYF-OH sequence.
7 is a graph showing the effect of the peptide derivatives (DS-48 to DS-56) of the present invention represented by [Formula 1-31] to [Formula 1-39] on AMPK phosphorylation activity in mouse adipocytes. At this time, V is DMSO treated as a vehicle, and P5 is an APN5 peptide as a positive control group and has an NH2-GLYYF-OH sequence.
8 is a graph showing the effect of the peptide derivatives (DS-57 to DS-63) of the present invention represented by [Formula 1-40] to [Formula 1-46] on AMPK phosphorylation activity in mouse adipocytes. At this time, V is DMSO treated as a vehicle, and P5 is an APN5 peptide as a positive control group and has an NH2-GLYYF-OH sequence.
9 shows the AMPK phosphorylation activity of the peptide derivatives (DS-68, DS-70, DS-72 to DS-75) of the present invention represented by [Formula 1-47] to [Formula 1-52] in these mouse adipocytes. The impact is shown graphically. At this time, V is DMSO treated as a vehicle, and P5 is an APN5 peptide as a positive control group and has an NH2-GLYYF-OH sequence.
10 is a graph showing the effect of the peptide derivatives (DS-76 to DS-79) of the present invention represented by [Formula 1-53] to [Formula 1-56] on AMPK phosphorylation activity in mouse adipocytes. At this time, V is DMSO treated as a vehicle, and P5 is an APN5 peptide as a positive control group and has an NH2-GLYYF-OH sequence.
11 shows [Formula 1-4], [Formula 1-5], [Formula 1-6], [Formula 1-8], [Formula 1-9], [Formula 1-18], and [Formula 1- 35], the AMPK phosphorylation activity increased by the peptide derivatives of the present invention (DS-4, DS-5, DS-6, DS-8, DS-28, DS-43, DS-52) (adiponectin receptor 1) It indicates whether or not it decreases upon knockdown. At this time, NC is scrambled siRNA and R1 is adiponectin receptor 1 siRNA. V is DMSO treated as a vehicle, P5 is an APN5 peptide as a positive control, and has an NH2-GLYYF-OH sequence. DS-43 is an adiporon, an agonist of the adiponectin receptor 1.
12 shows [Formula 1-2], [Formula 1-7], [Formula 1-13], [Formula 1-14], [Formula 1-17], [Formula 1-19], [Formula 1-31 ], and the peptide derivatives of the present invention represented by [Formula 1-34] (DS-2, DS-7, DS-17, DS-18, DS-27, DS-29, DS-48, DS-51) It is shown whether the AMPK phosphorylation activity, which was increased by , is decreased upon adiponectin receptor 1 knockdown. At this time, NC is scrambled siRNA and R1 is adiponectin receptor 1 siRNA. V is DMSO treated as a vehicle, P5 is an APN5 peptide as a positive control, and has an NH2-GLYYF-OH sequence. DS-43 is an adiporon, an agonist of the adiponectin receptor 1.
Figure 13 confirms the cytotoxicity of the peptide derivatives of the present invention represented by [Formula 1-6] against four cell lines (3T3-L1 adipocytes, RD muscle cells, keratinocytes, and fibroblasts). At this time, Veh is DMSO treated as a vehicle.
14 confirms the cytotoxicity of the peptide derivatives of the present invention represented by [Formula 1-8] against four cell lines (3T3-L1 adipocytes, RD muscle cells, keratinocytes, and fibroblasts). At this time, Veh is DMSO treated as a vehicle.
15 confirms the cytotoxicity of the peptide derivatives of the present invention represented by [Formula 1-18] against four cell lines (3T3-L1 adipocytes, RD muscle cells, keratinocytes, and fibroblasts). At this time, Veh is DMSO treated as a vehicle.
16 confirms the cytotoxicity of the peptide derivatives of the present invention represented by [Formula 1-31] against four cell lines (3T3-L1 adipocytes, RD muscle cells, keratinocytes, and fibroblasts). At this time, Veh is DMSO treated as a vehicle.
17 shows whether the peptide derivatives of the present invention represented by [Formula 1-6], [Formula 1-18], and [Formula 1-31] increase AMPK phosphorylation activity in a concentration-dependent manner.
18 shows the hair growth efficacy of the peptide derivatives of the present invention represented by [Formula 1-8], [Formula 1-18], and [Formula 1-31]. At this time, V is EtOH: polyethylene glycol = 30: 70, v / v as a vehicle, P5 is an APN5 peptide as a positive control, has an NH2-GLYYF-OH sequence, and Mnx is a positive control known as a hair growth agent. It is minoxidil.
19 shows the skin aging improvement efficacy of the peptide derivatives of the present invention represented by [Formula 1-8], [Formula 1-18], and [Formula 1-31]. At this time, Veh is DMSO treated as a vehicle, and P5 is an APN5 peptide as a positive control.
20a shows [Formula 1-8], [Formula 1-5], [Formula 1-6], [Formula 1-18], [Formula 1-2], [Formula 1-7], [Formula 1-31 ], and [Formula 1-50] shows the neutral fat removal efficacy of the peptide derivative of the present invention. Figure 20b shows the differentiation and neutral fat inhibition efficacy of the peptide derivatives of the present invention represented by [Formula 1-6], [Formula 1-8], [Formula 1-18], and [Formula 1-31]. At this time, V is DMSO treated as a vehicle, and P5 is an APN5 peptide as a positive control group and has an NH2-GLYYF-OH sequence. ND was cultured in non-differentiation medium and D was cultured in differentiation medium.
21 shows the sensitivity skin improvement efficacy of the peptide derivatives of the present invention represented by [Formula 1-8], [Formula 1-18], and [Formula 1-31]. At this time, Veh is DMSO treated as a vehicle, LA is lactic acid, and P5 is an APN5 peptide as a positive control.

The present invention relates to the synthesis of a novel peptide derivative having an adiponectin-derived peptide APN5 as a parent, and more particularly, to a peptide in which some amino acids are modified to improve the physical properties and activity of an existing adiponectin peptide. The peptide derivatives of the present invention are advantageous in drug formulation because of their improved physical properties and activity.

Accordingly, the present invention provides a peptide derivative represented by the following [Formula 1].

[Formula 1]

In the above [Formula 1],

R ₁ is selected from the group consisting of an amino group (NH ₂ ), an acetylamino group (Ac-NH), NH ₂ -(CH ₂ CH ₂ O) _m -CH ₂ CONH, a C ₁₅ -C ₂₀ amide group, and combinations thereof Any one or more selected, wherein m may be an integer from 1 to 5,

R ₂ is an amino group or a hydroxyl group (OH);

R ₃ is hydrogen (H);

R ₄ is selected from the group consisting of a C ₁ -C ₆ chain alkyl group, a C ₂ -C ₆ alkyl carboxyl group, a C ₁ -C ₆ alkylamide group, an imidazoylmethyl group, and combinations thereof more than one of the

R ₅ and R ₆ are the same as or different from each other, and are each independently a benzyl group, a phenylethyl group, or an indolylmethyl group, and the benzyl group is unsubstituted or a hydroxy group, a trifluoromethyl group (CF ₃ ), a halogen group, At least one selected from the group consisting of a cyano group, a nitro group, a C ₁ -C ₆ chain-type alkyl group, a C ₁ -C ₆ alkoxy group, and combinations thereof,

R ₇ is a benzyl group or a C ₁ -C ₆ alkylamino group, and the benzyl group is unsubstituted or a hydroxy group, a halogen group, a cyano group, a nitro group, a C ₁ -C ₆ chain alkyl group, or a C ₁ -C ₆ alkoxy group. group, and any one or more selected from the group consisting of combinations thereof;

R ₃ and R ₇ are connected to each other to form a C ₁₅ -C ₂₀ heterocycloalkene group;

R ₈ , R ₉ , and R ₁₀ are the same as or different from each other, and are each independently hydrogen or a C ₁ -C ₆ alkyl group;

n may be 0 or 1.

In the present invention, the term “substitution” is a reaction in which an atom or group of atoms included in a molecule of a compound is replaced with another atom or group of atoms.

In the present invention, the term "chain" refers to a molecule having a chain-like structure, and the chain-like structure is a chemical structure in which carbon atoms are connected in a chain shape, and there are straight chain shapes and branched ones.

In the present invention, the term "cyclic" refers to a structure in which both ends linked in the backbone of an organic compound are connected to form a ring.

In the present invention, the term "chain or cyclic alkyl group" means a monovalent linear or branched or cyclic saturated hydrocarbon residue having 1 to 12 carbon atoms and consisting only of carbon and hydrogen 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, and the like. Not limited.

In the present invention, the term “halogen group” refers to elements belonging to group 17 of the periodic table, and may be fluorine (F), chloride (Cl), bromine (Br), or iodine (I).

In the present invention, the term “alkoxy group” refers to an atomic group CnH2n+1O- formed by bonding an oxygen atom to an alkyl group, and examples of such alkoxy groups include methoxy, ethoxy, propoxy, or phthaloxy. Not limited.

In the present invention, the term “cycloalkene group”, also referred to as a cyclic alkene group, refers to a cyclic group in which all ring members are carbon and have at least one double bond (but are not aromatic). The term “heterocycloalkene group” refers to a cycloalkene group each containing at least one heteroatom of N, O, or S. Each of the cycloalkene group or heterocycloalkene group includes at least one ring structure, and may be, for example, a single ring, a double ring, or a triple ring.

In addition, the present invention provides a pharmaceutical composition for preventing or treating any one or more selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising the peptide derivative as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for preventing or improving any one or more selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, containing the peptide derivative as an active ingredient.

In the present invention, the term "prevention" refers to any action that inhibits or delays the occurrence, spread or recurrence of the disease by administration of the composition of the present invention, and "treatment" refers to the treatment of the disease by administration of the composition of the present invention. It means any action that improves or beneficially changes the condition.

In the present invention, the term "improvement" refers to any action that at least reduces a parameter related to the condition being treated, eg, the severity of a symptom, or that is beneficially altered so that the disease is improved.

As used herein, the term "pharmaceutical composition" means prepared for the purpose of preventing or treating the above diseases, and may be formulated and used in various forms according to conventional methods. For example, it can be formulated into oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions and syrups, and can be formulated and used in the form of external preparations, suppositories and sterile injection solutions.

In the present invention, "included as an active ingredient" means that the component is included in an amount necessary or sufficient to realize a desired biological effect. The amount can be determined in consideration of other non-toxic factors, and can vary depending on various factors such as, for example, the disease or condition being treated, the type of composition to be administered, the size of the subject, or the severity of the disease or condition. Effective amounts of individual compositions can be determined empirically without undue experimentation by those skilled in the art to which the present invention pertains.

In addition, the pharmaceutical composition of the present invention may include one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients according to each formulation.

The pharmaceutically acceptable carrier may be saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and a mixture of one or more of these components, and, if necessary, antioxidants, buffers, bacteriostatic agents Other common additives such as may be further included. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to prepare formulations for injections such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets. Furthermore, it may be preferably formulated according to each disease or component by using an appropriate method in the art or by using a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA).

The composition of the present invention can be administered orally or parenterally in a pharmaceutically effective amount according to the desired method, and the term "pharmaceutically effective amount" of the present invention is a disease at a reasonable benefit/risk ratio applicable to medical treatment. The effective dose level is the patient's health condition, severity, drug activity, drug sensitivity, administration method, administration time, administration route and excretion rate, treatment It may depend on factors including duration, combination or drugs used concurrently and other factors well known in the medical arts.

In the present invention, "skin inflammatory disease" refers to inflammation occurring in the outer layer of the skin, which often causes itching, blisters, redness, swelling, as well as exudation, scabs, and peeling, including but not limited to psoriasis, atopic dermatitis, eczema, Contact dermatitis, erythroderma, lichen simplex chronic, nummular dermatitis, seborrheic dermatitis, stasis dermatitis, etc., but are not limited thereto.

In the present invention, "metabolic disease" is a syndrome that occurs together with risk factors such as obesity, diabetes, hypertension, arteriosclerosis, nonalcoholic fatty liver disease (NAFLD) due to accumulation of excess nutrients and lack of exercise in the body. As non-limiting examples, there are diabetes, hypertension, hyperlipidemia, cardiovascular and cerebrovascular disease, thrombosis, dyslipidemia, stroke, arteriosclerosis, hyperinsulinemia, etc., but are not limited thereto.

In addition, the present invention provides a method for preventing or treating one or more selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising administering the peptide derivative to a subject.

In addition, the present invention provides at least one prevention or improvement method selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, which includes administering the peptide derivative to a subject.

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

The term "administration" of the present invention means providing a predetermined substance to a patient by any suitable method, and the pharmaceutical composition of the present invention may be formulated in various forms for administration to a subject, and parenteral administration Representative of the dosage form is an injectable dosage form, preferably an isotonic aqueous solution or suspension. Formulations for injection may be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. For example, it may be formulated for injection by dissolving each component in saline or a buffer solution. In addition, dosage forms for oral administration include, for example, ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. , sucrose, mannitol, sorbitol, cellulose and/or glycine) and lubricants (eg silica, talc, stearic acid and magnesium or calcium salts thereof and/or polyethylene glycol). The tablet may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally starch, agar, alginic acid or Disintegrants such as sodium salts, absorbents, colorants, flavors and/or sweeteners may further be included. The formulation may be prepared by conventional mixing, granulating or coating methods.

In addition, the pharmaceutical composition of the present invention may further include adjuvants such as preservatives, hydrating agents, emulsification accelerators, salts or buffers for osmotic pressure control, and other therapeutically useful substances, and may be formulated according to conventional methods. .

The pharmaceutical composition according to the present invention can be administered through various routes including oral, transdermal, subcutaneous, intravenous, intranasal, intraperitoneal, or intramuscular, and the dosage of the active ingredient depends on the route of administration, the patient's age, gender, It can be appropriately selected according to various factors such as body weight and severity of the patient. In addition, the composition of the present invention can be administered in parallel with a known compound capable of increasing the desired effect.

In addition, the present invention provides a cosmetic composition for preventing or improving any one or more selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising the peptide derivative as an active ingredient.

In addition, the present invention provides a cosmetic composition for preventing or improving any one or more selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, containing the peptide derivative as an active ingredient.

The cosmetic composition includes, for example, the peptide derivative or a cosmetically acceptable salt thereof as an active ingredient, and a basic cosmetic composition (toilet water, cream, essence, cleansing foam and cleansing water) together with dermatologically acceptable excipients The same face wash, pack, body oil), color cosmetic composition (foundation, lipstick, mascara, makeup base), hair product composition (shampoo, rinse, hair conditioner, hair gel) and soap can be prepared in the form of.

The excipients may include, for example, skin softeners, skin penetration enhancers, colorants, fragrances, emulsifiers, thickeners and solvents, and more specifically, 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, ethanol, and the like, but are not limited thereto.

In addition, the present invention provides a food composition for preventing or improving any one or more selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising the peptide derivative as an active ingredient.

In addition, the present invention provides a food composition for preventing or improving any one or more selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, containing the peptide derivative as an active ingredient.

The food composition includes, for example, the peptide derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and when the peptide derivative is used as an additive in a food composition, it is added as it is or together with other food or food ingredients It can be used, and it can be used suitably according to a conventional method. In general, 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 material during production of food or beverage. However, in the case of long-term intake for the purpose of health and hygiene or health control, it may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range. That is, the mixing amount of the active ingredient can be appropriately determined according to each purpose of use, such as prevention, health, or treatment.

The formulation of the food composition may be in the form of a powder, granule, pill, tablet, or capsule, as well as a general food or beverage form.

The food of the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and ingredients commonly added in the art during the preparation. Specifically, it may include proteins, carbohydrates, fats, nutrients, seasonings, and flavoring agents, and examples of the carbohydrates include glucose, fructose, maltose, sucrose, oligosaccharides, dextrins, cyclodextrins, xylitol, sorbitol, and erythrocytes. trolls, saccharin, or synthetic flavors, but are not limited thereto.

Terms used in the examples are used only for the purpose of explanation and should not be construed as limiting. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, terms such as "include" or "have" are intended to designate that there is a feature, number, step, operation, component, part, or combination thereof described in the specification, but one or more other features It should be understood that the presence or addition of numbers, steps, operations, components, parts, or combinations thereof is not precluded.

Unless defined otherwise, 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 embodiment belongs. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related art, and unless explicitly defined in the present application, they should not be interpreted in an ideal or excessively formal meaning. don't

In describing the components of the embodiment, terms such as first, second, A, B, (a), and (b) may be used. These terms are only used to distinguish the component from other components, and the nature, order, or order of the corresponding component is not limited by the term. When an element is described as being “connected,” “coupled to,” or “connected” to another element, that element may be directly connected or connected to the other element, but there may be another element between the elements. It should be understood that may be "connected", "coupled" or "connected".

Hereinafter, embodiments will be described in detail with reference to the accompanying drawings. However, since various changes can be made to the embodiments, the scope of the patent application is not limited or limited by these embodiments. It should be understood that all changes, equivalents or substitutes to the embodiments are included within the scope of rights.

In addition, in the description with reference to the accompanying drawings, the same reference numerals are given to the same components regardless of reference numerals, and overlapping descriptions thereof will be omitted. In describing the embodiment, if it is determined that a detailed description of a related known technology may unnecessarily obscure the gist of the embodiment, the detailed description will be omitted.

The present invention can apply various transformations and can have various embodiments. Hereinafter, specific embodiments will be illustrated in the drawings and described in detail in the detailed description. However, it should be understood that this is not intended to limit the present invention to specific embodiments, and includes all transformations, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the present invention, if it is determined that a detailed description of related known technologies may obscure the gist of the present invention, the detailed description will be omitted.

Example 1. Preparation of Peptide Derivatives of the Invention

The peptide derivative of the present invention was prepared using a conventional amino acid synthesis method (Umbarger. H. E., Ann. Rev. Biochem. 1978, 47, 533-606).

The start of the C-terminus is to prepare a peptide with a general C-terminus having a COOH carboxy group terminal using Wang resin (100-200 mesh, Novabiochem ^® , CAS No: 65307-53-1) and Rink amide AM resin (100-200 mesh). mesh, Novabiochem ^® , CAS No: 65307-53-1) was used to prepare a peptide whose C-terminus is CONH ₂ amide-terminus.

Example 1.1. When the N-terminus is an amino group and the C-terminus is a carboxy group

To prepare a peptide consisting of a carboxyl group at the C-terminus, Wang resin (100 mg, 0.5 - 1.3 mmol/g) dried using a polypropylene syringe from Torviq was mixed in dichloromethane (DCM) solvent. After stirring for 60 minutes, the first step reaction was started by removing the solvent. The reaction of the first step is hydroxybenzotriazole (1-Hydroxybenzotriazole, HOBt), diisopropylcarbodiimide (N,N'-Diisopropylcarbodiimide, DIC), 4-dimethylaminopyridine (4-Dimethylaminopiridine, DMAP) and the first amino acid The residue, Fmoc-Phe-OH, was stirred for 2 hours in the solvent of dichloromethane (DCM) and dimethylformamide (DMF) in a 3: 2 ratio, and then dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM) Then, the resin was washed by repeating the washing process twice each using dimethylformamide (DMF). In the second step, the peptide monomer synthesis was performed twice for 10 minutes each at room temperature using 1 mL of dimethylformamide (DMF) to which 20% (v/v) piperidine was added for the Fmoc protecting group removal reaction. After that, the resin was washed by repeating the above washing process twice each using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM) and finally dimethylformamide (DMF), and then hydroxybenzotriazole ( 1-Hydroxybenzotriazole, HOBt), N-[(dimethylamino-)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexa Reaction of fluorophosphate N-oxide (HATU), N,N-diisopropylethylamine (DIEA) and Fmoc-Tyr(OtBu)-OH in dimethylformamide (DMF) solvent for 2 hours Stirring was completed. The reaction-completed resin was completed by repeating the washing process twice each using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM), and finally dimethylformamide (DMF). The synthesis of peptide monomers in the following steps was also performed through the same process as in the second monomer synthesis step. The peptide, which has completed step-by-step monomer synthesis, is finally a reaction to remove the Fmoc protecting group of the last peptide of the resin. After reacting twice per minute, the washing process was repeated twice each using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM) and finally dimethylformamide (DMF) to complete the reaction. The peptide was purified using high performance liquid chromatography (Prep-HPLC, Gilson) with a gradient solvent composition of acetonitrile and water. For purity confirmation and analysis, RP-HPLC and LC-MS were used to obtain peptides with a purity of 98% or more.

Example 1.2. When the N-terminus is an amino group and the C-terminus is an amide group

To prepare a peptide consisting of an amide group at the C-terminus, the dried Rink amide AM resin (100 mg, 0.9 mmol/g) was mixed with dimethylformamide (DMF) using a polypropylene syringe from Torviq. After stirring in a solvent for 60 minutes, the solvent is removed to initiate the first step reaction. For the Fmoc protecting group removal reaction from the resin, Fmoc-Rink amid MBHA resin was reacted twice for 10 minutes each at room temperature using 1 mL of dimethylformamide (DMF) with 20% (v/v) piperidine added. After that, the washing process was repeated twice each using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM), and finally dimethylformamide (DMF) to wash the resin and introduce the first amino acid residue For hydroxybenzotriazole (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-Phe-OH in dimethylformamide (DMF) solvent The reaction was stirred for 2 hours under the condition of completion. The reaction-completed resin was completed by repeating the washing process twice each using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM), and finally dimethylformamide (DMF). In the second step of peptide monomer synthesis, 1 mL of dimethylformamide (DMF) to which 20% (v/v) piperidine was added was used to remove the Fmoc protecting group, and the reaction was carried out twice for 10 minutes at room temperature. After that, the resin was washed by repeating the above washing process twice each using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM) and finally dimethylformamide (DMF), and then hydroxybenzotriazole ( 1-Hydroxybenzotriazole, HOBt), N-[(dimethylamino-)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexa Reaction of fluorophosphate N-oxide (HATU), N,N-diisopropylethylamine (DIEA) and Fmoc-Tyr(OtBu)-OH in dimethylformamide (DMF) solvent for 2 hours Stirring was completed. The reaction-completed resin was completed by repeating the washing process twice each using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM), and finally dimethylformamide (DMF). The peptide monomer synthesis of the following steps was also synthesized through the same process as the above monomer synthesis step. Finally, for the Fmoc protective group removal reaction of the last peptide of the resin, 1 mL of dimethylformamide (DMF) to which 20% (v/v) piperidine was added was used to react twice for 10 minutes each at room temperature. Using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM) and finally dimethylformamide (DMF), the washing process was repeated twice each to complete. The peptide was purified using high performance liquid chromatography (Prep-HPLC, Gilson) with a gradient solvent composition of acetonitrile and water. For purity confirmation and analysis, RP-HPLC and LC-MS were used to obtain peptides with a purity of 98% or more.

Example 1.3. Acetylprotection of the N-terminus

Example 1.1. Alternatively, acetic anhydride and N,N-diisopropylethylamine (DIEA) were added to the N-terminal unprotected peptide synthesized in 1.2 for 2 hours in a dimethylformamide (DMF) solvent. Reaction stirring was completed. After the reaction is completed, the washing process is repeated twice each using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM) and finally dimethylformamide (DMF) to protect the N-terminus with an acetyl group peptide was synthesized. The peptide was purified using high performance liquid chromatography (Prep-HPLC, Gilson) with a gradient solvent composition of acetonitrile and water. For purity confirmation and analysis, RP-HPLC and LC-MS were used to obtain peptides with a purity of 98% or more.

Example 1.4. PAL protection of the N-terminus

Example 1.1. Alternatively, hydroxybenzotriazole (1-Hydroxybenzotriazole, HOBt), N-[(dimethylamino-)-1H-1 for the synthesis of peptides protected with PAL (Palmitic acid) in the N-terminal unprotected peptide synthesized in 1.2 ,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), N,N-diisopropylethylamine (N,N-diisopropylethylamine, DIEA) and PEG (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetic acid) or PAL (Palmitic acid) in dimethylformamide (DMF) solvent for 2 hours Reaction stirring was completed. The reaction-completed resin was completed by repeating the washing process twice each using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM), and finally dimethylformamide (DMF).

The crude peptide obtained by the above method was added with a solution of trifluoroacetic acid (TFA):H ₂ O:triisopropylsilane (TIPS) (95:2.5:2.5 vol./vol.) as a separation solution, and 2 After reacting for 3 hours to remove the protecting group and separating the peptide from the resin, the peptide was precipitated with cold diethyl ether. The peptide was purified using high performance liquid chromatography (Prep-HPLC, Gilson) with a gradient solvent composition of acetonitrile and water. For purity confirmation and analysis, RP-HPLC and LC-MS were used to obtain peptides with a purity of 98% or more.

Example 1.5. PEG protection at the N-terminus

Example 1.1. Alternatively, hydroxybenzotriazole for the synthesis of peptides protected with (PEG)3 (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetic acid) to the N-terminal unprotected peptide synthesized in 1.2 (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) was stirred for 2 hours in the presence of a dimethylformamide (DMF) solvent. The reaction-completed resin was completed by repeating the washing process twice each using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM), and finally dimethylformamide (DMF).

The crude peptide obtained by the above method was added with a solution of trifluoroacetic acid (TFA):H ₂ O:triisopropylsilane (TIPS) (95:2.5:2.5 vol./vol.) as a separation solution, and 2 After reacting for 3 hours to remove the protecting group and separating the peptide from the resin, the peptide was precipitated with cold diethyl ether. The peptide was purified using high performance liquid chromatography (Prep-HPLC, Gilson) with a gradient solvent composition of acetonitrile and water. For purity confirmation and analysis, RP-HPLC and LC-MS were used to obtain peptides with a purity of 98% or more.

Example 1.6. Cyclic Peptide Synthesis

Peptides were synthesized by the method of Example 1.2 by the method of preparing a peptide consisting of an amide group terminal at the C-terminus. For the first and last amino acids, linear peptide synthesis was performed in the same manner as in Example 1.2 using Fmoc-Allyl-Gly-OH, and then the N-terminal Fmoc-protected resin was prepared in dichloromethane (DCM) solvent LiCl (0.4 M) dissolved in dimethylformamide (DMF) and Grubbs' catalyst were added and reacted at 100 °C for 1 to 2 hours using a microwave (2.5 GHz, 300 W). The reaction-completed resin was completed by repeating the washing process twice each using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM), and finally dimethylformamide (DMF). Finally, for the Fmoc protective group removal reaction of the last peptide of the resin, 1 mL of dimethylformamide (DMF) to which 20% (v/v) piperidine was added was used to react twice for 10 minutes each at room temperature. Using dimethylformamide (DMF), methyl alcohol (MeOH), dichloromethane (DCM) and finally dimethylformamide (DMF), the washing process was repeated twice each to complete. The crude peptide obtained by the above method was added with a solution of trifluoroacetic acid (TFA):H2O:triisopropylsilane (TIPS) (95:2.5:2.5 vol./vol.) as a separation solution, and 2 to 3 After reacting for an hour to remove the protecting group and separating the peptide from the resin, the peptide was precipitated with cold diethyl ether. The peptide was purified using high performance liquid chromatography (Prep-HPLC, Gilson) with a gradient solvent composition of acetonitrile and water. For purity confirmation and analysis, RP-HPLC and LC-MS were used to obtain peptides with a purity of 98% or more (J. Pept. Sci. 2007; 13: 280-285).

The sequence and molecular weight of the peptide derivative according to an embodiment of the present invention are shown in Table 3 below.

compound number chemical formula number order measured molecular weight
[M+H] ⁺ DS-1 1-1 NH2-GlYYF-OH 662.25 DS-2 1-2 AcNH-GlYYF-OH 661.25 DS-3 1-3 NH2-GlYYF-NH2 703.24 DS-4 1-4 AcNH-GlYYF-NH2 664.17 DS-5 1-5 NH2-GDYYF-OH 706.19 DS-6 1-6 AcNH-GDYYF-OH 663.20 DS-7 1-7 NH2-GDYYF-NH2 705.21 DS-8 1-8 AcNH-GDYYF-NH2 663.20 DS-9 1-9 NH2-GNYYF-OH 663.20 DS-10 1-10 AcNH-GNYYF-OH 705.20 DS-11 1-11 NH2-GNYYF-NH2 662.23 DS-12 1-12 Ac-NH-GNYYF-NH2 704.22 DS-17 1-13 NH2-GLWYF-NH2 684.27 DS-18 1-14 NH2-GIWYF-NH2 684.28 DS-19 1-15 NH2-GLFYF-NH2 645.27 DS-20 1-16 NH2-GIFYF-NH2 645.28 DS-27 1-17 NH2-DYYF-OH 607.13 DS-28 1-18 AcNH-DYYF-OH 649.18 DS-29 1-19 NH2-DYYF-NH2 606.20 DS-30 1-20 AcNH-DYYF-NH2 648.25 DS-35 1-21 NH2-GDYYK-NH2 644.18 DS-36 1-22 AcNH-GDYYK-NH2 686.24 DS-37 1-23 NH2-GEYYK-NH2 658.24 DS-38 1-24 AcNH-GEYYK-NH2 700.26 DS-39 1-25 NH2-GLYY(Dmt)F-NH2 689.26 DS-40 1-26 NH2-GDYY(Dmt)F-NH2 691.23 DS-41 1-27 NH2-GDY(Dmt)YF-NH2 691.25 DS-42 1-28 NH2-GLY(Dmt)YF-NH2 689.30 DS-44 1-29 NH2-GHYYF-NH2 685.23 DS-45 1-30 AcNH-GHYYF-NH2 727.26 DS-48 1-31 NH2-GLYYF(N-Me)-NH2 675.29 DS-49 1-32 NH2-GLYYF(homo)-NH2 675.28 DS-50 1-33 NH2-GLF(OMe)YF-NH2 675.28 DS-51 1-34 NH2-GLF(4-F)YF-NH2 663.26 DS-52 1-35 NH2-GLF(4-Cl)YF-NH2 679.23 DS-53 1-36 NH2-GLF(4-CN)YF-NH2 670.27 DS-54 1-37 NH2-GLF(4-NO2)YF-NH2 690.26 DS-55 1-38 NH2-GLYY(N-Me)F-NH2 675.26 DS-56 1-39 NH2-GLY(N-Me)YF-NH2 675.28 DS-57 1-40 NH2-GLF(4-Cl)YF(homo)-NH2 693.24 DS-58 1-41 NH2-GDF(4-Cl)YF-NH2 681.17 DS-59 1-42 NH2-GLYF(OMe)F-NH2 675.27 DS-60 1-43 NH2-GLYF(4-F)F-NH2 663.26 DS-61 1-44 NH2-GLYF(4-Cl)F-NH2 679.24 DS-62 1-45 NH2-GLYF(4-CN)F-NH2 670.26 DS-63 1-46 NH2-GLYF(4-NO2)F-NH2 690.25 DS-68 1-47 NH2-GDYYF(homo)-NH2 677.20 DS-70 1-48 NH2-GDYF(4-Cl)F-NH2 681.15 DS-72 1-49 Cyclic 623.22 DS-73 1-50 Cyclic 637.25 DS-74 1-51 Cyclic 637.24 DS-75 1-52 Cyclic 651.27 DS-76 1-53 AcNH-GDY(N-Me)YY-NH2 735.21 DS-77 1-54 AcNH-GDYYY(N-Me)-NH2 735.30 DS-78 1-55 PAL-NH-GDYYF-NH2 901.45 DS-79 1-56 NH2-(PEG)3-NH-GDYYF-NH2 852.28

In Table 3, each amino acid constituting the peptoid derivative of the present invention may have the following structure.

Experimental Example 1. In vitro ( in vitro ) Verification of AMPK phosphorylation activity

The effects of the peptide derivatives of the present invention on the expression and receptor activity of adiponectin in mouse adipocytes, which are the main site of adiponectin production, were confirmed. 3T3-L1, a mouse adipocyte cell line, was treated with the peptide derivatives of the present invention at a concentration of 10 μM each, and cultured for 24 hours, and then the cells were obtained. Then, the protein was extracted and its effect on AMPK phosphorylation, which is responsible for the main sub-signaling of adiponectin, was confirmed by western blot.

As a result, the peptide derivatives of the present invention increased the AMPK phosphorylation activity associated with the activity of the adiponectin receptor in mouse adipocytes (Figs. 1 to 10), especially [Formula 1-2], [Formula 1-4] to [Formula 1-4] 1-9], [Formula 1-13], [Formula 1-14], [Formula 1-17] to [Formula 1-19], [Formula 1-31], [Formula 1-34], and [Formula 1-34] 1-35] was confirmed to have a remarkable AMPK phosphorylation activity increasing effect compared to APN5, a previously known adiponectin-derived peptide (Table 4).

compound number chemical formula number AMPK phosphorylation activity (fold change) DS-8 1-8 2.6 DS-5 1-5 2.0 DS-6 1-6 1.9 DS-28 1-18 1.9 DS-4 1-4 1.8 DS-9 1-9 1.6 DS-48 1-31 1.5 DS-2 1-2 1.3 DS-7 1-7 1.3 DS-27 1-17 1.3 DS-51 1-34 1.3 DS-17 1-13 1.2 DS-18 1-14 1.2 DS-29 1-19 1.2 DS-52 1-35 1.2 DS-43 adiporon 1.2 APN5 P5 1.0

Experimental Example 2. In vitro ( in vitro ) Verification of loss of AMPK phosphorylation activity after adiponectin receptor 1 knockdown

In order to verify whether the peptide derivative of the present invention binds to adiponectin receptor 1, 3T3-L1, a mouse adipocyte cell line, was knocked down by treating adiponectin receptor 1 siRNA, and 10 μM each of the peptide derivatives of the present invention After treatment with a concentration of and incubated for 24 hours, cells were obtained. Then, proteins were extracted and it was confirmed by Western blot whether the AMPK phosphorylation activity, which had been increased by the peptide derivative, was lost.

As a result, [Formula 1-2], [Formula 1-5] to [Formula 1-8], [Formula 1-13], [Formula 1-14], [Formula 1-17] to [Formula 1-19] It was confirmed that the peptide derivatives of the present invention, including [Formula 1-31], [Formula 1-34], and [Formula 1-35], reduce AMPK phosphorylation activity after knockdown of adiponectin receptor 1 (FIG. 11 and Figure 12).

Adiponectin acts by binding to adiponectin receptors, and when adiponectin receptors are activated, it is known to increase phosphorylation of AMPK and PPARα / PPARγ activity, which are sub-signaling pathways (Crystal structures of the human adiponectin receptors. Nature. 2015 Apr16;520( 7547):312-6.doi: 10.1038/nature14301). In addition, the expression of adiponectin and its receptors is reduced in photoaged skin and skin irradiated with ultraviolet rays, and when the expression of adiponectin is reduced in this way, the expression of skin aging regulators MMP-1 and procollagen is regulated to change the extracellular matrix. It is known that 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).

Therefore, the peptide derivative of the present invention increases AMPK phosphorylation activity associated with the activity of the adiponectin receptor, thus increasing the expression of adiponectin in the body, suggesting that it can play a major role in protecting against skin aging.

Experimental Example 3. In vitro ( in vitro ) cytotoxicity verification

Using 4 cell lines (3T3-L1 adipocytes, RD muscle cells, keratinocytes, fibroblasts), each cell was dispensed in a 24-well plate at 5×10 ⁴ cells per well, and cultured for 24 hours under each cell culture condition. The medium was discarded, washed with PBS, replaced with a new medium without 10% FBS, treated with the peptide derivative of the present invention at different concentrations (0, 0.1, 1, 10, 100, 500 μM) and cultured for 24 hours. After carefully removing the medium and washing with PBS, MTT reagent was added according to the manufacturer's method, followed by reaction at room temperature for 30 minutes, and absorbance was measured at 450 nm.

As a result, it was confirmed that the peptide derivatives of the present invention, including [Formula 1-6], [Formula 1-8], [Formula 1-18], and [Formula 1-31], are not toxic in a number of cell lines ( 13 to 16).

Experimental Example 4. In vitro ( in vitro ) Verification of concentration dependence of AMPK phosphorylation activity

3T3-L1, a mouse adipocyte cell line, was treated with a series of concentrations (0, 0.01, 0.1, 1, 10, 100 μM) of the peptide derivative of the present invention and cultured for 24 hours, and then the cells were obtained. Then, the protein was extracted and the effect of the peptide derivative on AMPK phosphorylation in a concentration-dependent manner was confirmed by Western blotting.

As a result, it was confirmed that the peptide derivatives of the present invention, including [Formula 1-6], [Formula 1-18], and [Formula 1-31], increased AMPK phosphorylation activity in a concentration-dependent manner (FIG. 17).

Experimental Example 5. Solubility test

After diluting the PRISMA HT solution in distilled water at a ratio of 1:40, the pH was adjusted to 7.4 and used as a test buffer. In addition, reference substances used for accuracy in general solubility tests (Diclofenac stock 50 mM, Phenazopyridine stock 25 mM) and the peptide derivatives of the present invention (50 mM) as test substances were prepared in DMSO and used as test standard solutions.

10 mL of the prepared test substance was diluted in 190 μL of isopropyl alcohol. In addition, 75 mL of the test solution and 70 mL of isopropyl alcohol were mixed and used as a blank sample, and 5 mL of the test material diluted in isopropyl alcohol was added to the blank sample. After mixing the diluted samples, the absorbance was measured and used as an initial test value. For the solubility test, 1 mL test solution and 10 mL of DMSO test standard solution were mixed and reacted at room temperature for 24 hours. Thereafter, the precipitate was removed using a filter plate, and 75 mL of isopropyl alcohol was added to 74 mL of the filtered sample, and then the absorbance was measured and used as a sample value.

The solubility value of the test substance was analyzed using msol Exploer (Solubility explorer program) after measuring the absorbance of each sample through a microplate reader. The average and standard deviation of the experimental values repeated three times (n = 3) were calculated using the Excel program.

As a result, the peptide derivatives of the present invention showed excellent solubility in DMSO (Table 5).

compound number chemical formula number Average DMSO solubility (μg/ml) DS-2 1-2 348.0 DS-5 1-5 328.0 DS-6 1-6 349.0 DS-8 1-8 349.0 DS-27 1-17 300.0 DS-28 1-18 321.0 DS-29 1-19 300.0 DS-43 adiporon 43.7 DS-48 1-31 334.0 DS-51 1-34 135.5 DS-73 1-50 315.0 APN5 P5 8.2 Diclofenac
(reference) 157.0 Phenazopyridine
(reference) 23.76

Experimental Example 6. Plasma stability test

After adding the peptide derivative of the present invention at a concentration of 1 μM to two types of plasma (Human, Rat) and putting it into each tube, incubation at 37 ° C according to the time (0, 30, 60, 120, 240 minutes) did After each time, the tube containing the plasma was taken out, an acetonitrile solution containing an internal standard (chlorpropamide) was added, vortexing for 5 minutes, and centrifugation (14,000 rpm, 4 ℃) for 5 minutes. Plasma stability of the peptide derivative was evaluated by injecting the supernatant into an LC-MS/MS system and analyzing the drug at each time point. At this time, Procaine and Enalapril were used as reference materials used for accuracy in general plasma stability tests.

After the reaction, the amount of drug remaining in each tube was analyzed by LC-MS/MS using a Shimadzu Nexera XR system and TSQ vantage (Thermo). The HPLC column was Luna C18 column (2.0 × 50 mm, 3 μm particle size; Phenomenex, US), and the mobile phase was distilled water containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B). Data analysis was performed using Xcalibur (version 1.6.1). In the result analysis, each plasma stability for each peptide derivative was expressed as % remaining for each time period for samples that were not cultured.

As a result, it was confirmed that the peptide derivatives of the present invention had excellent plasma stability, and in particular, plasma stability was significantly improved compared to APN5, a previously known adiponectin-derived peptide (Table 6).

compound number chemical formula number Plasma stability (% remaining) Human, 30m Human, 120m Rat, 30m Rat, 120m DS-5 1-5 1.4 < 1 >100 94.1 DS-6 1-6 12.6 1.3 >100 >100 DS-8 1-8 39.8 3.3 >100 96 DS-28 1-18 17.6 3.1 >100 >100 DS-35 1-21 2.9 < 1 99.4 89.4 DS-41 1-27 < 1 < 1 >100 99.6 DS-43 adiporon >100 >100 >100 >100 DS-48 1-31 1.1 < 1 >100 84.9 DS-56 1-39 2.8 < 1 70.9 29.4 DS-73 1-50 94.7 75.2 >100 89.3 APN5 P5 < 1 < 1 83.1 70.5 Procaine
(reference) 2.8
(5min) < 1
(5min) 90.3 57.4 Enalapril
(reference) >100 97.4 27.9 < 1

Experimental Example 7. Metabolic stability test

Three types of liver microsomes (Human, Rat, Mouse, 0.5 mg/ml), 0.1 M phosphate buffer (pH 7.4), and the peptide derivative of the present invention were added at a concentration of 1 μM and incubated at 37°C for 5 minutes in advance. , NADPH Regeneration system solution was added and incubated at 37 ° C for 30 minutes. Then, to terminate the reaction, an acetonitrile solution containing an internal standard (chlorpropamide) was added, centrifuged for 5 minutes (14,000 rpm, 4 ℃), and the supernatant was injected into the LC-MS/MS system to detect the substrate drug. Metabolic stability was evaluated by analyzing. At this time, Verapamil was used as a reference material used for accuracy in general plasma stability tests.

The amount of substrate remaining through 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 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% formic acid (A) and acetonitrile containing 0.1% formic acid (B). TurboSpray Ionization was used as an ion source for MS/MS, and a triple quadruple type mass spectrometer was used. Produced metabolites were quantified using MRM (multiple reaction monitoring) quantitative mode, and Analyst software (version 1.6.1) was used for data analysis.

As a result, it was confirmed that the peptide derivatives of the present invention had excellent metabolic stability, and in particular, metabolic stability was significantly improved compared to APN5, a previously known adiponectin-derived peptide (Table 7).

compound number chemical formula number Metabolic stability (% remaining) Human, 30m Rat, 30m Mouse, 30m DS-5 1-5 62.5 66.4 95.9 DS-6 1-6 88.0 88.1 96.5 DS-8 1-8 93.9 78.2 83.6 DS-28 1-18 93.8 85.8 96.6 DS-35 1-21 >100 95.8 99.2 DS-41 1-27 95.8 75.1 95.2 DS-43 adiporon 54.9 2.3 3.1 DS-48 1-31 21.6 2.8 20.6 DS-56 1-39 53.9 41.1 10.6 DS-73 1-50 71.6 65.7 78 APN5 P5 1.7 1.3 9.5 Verapamil (reference) 13.4 - -

Experimental Example 8. CYP inhibition assay

Human liver microsomes (0.25 mg/ml), 0.1 M phosphate buffer solution (pH 7.4), substrate drug cocktail of 5 drug metabolizing enzymes (Phenacetin 50 μM, S-mephenytoin 100 μM, dextromethorphan 5 μM, midazolam 2.5 μM, diclofenac 10 μM) and the peptide derivative of the present invention were added at concentrations of 0 and 10 μM, respectively, and pre-incubated at 37° C. for 5 minutes, and then NADPH Regeneration system solution was added and incubated at 37° C. for 15 minutes. Then, to terminate the reaction, an acetonitrile solution containing an internal standard (chlorpropamide) was added, centrifuged for 5 minutes (14,000 rpm, 4°C), and the supernatant was injected into the LC-MS/MS system to detect the substrate drug. The drug-metabolizing enzyme inhibitory ability of the peptide derivative was evaluated by simultaneously analyzing metabolites of . At this time, Ketoconazole was used as a reference material used for accuracy when evaluating general drug-metabolizing enzyme inhibitory ability.

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

As a result, the peptide derivatives of the present invention inhibit CYP enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Table 8), suggesting that they do not cause fatal adverse reactions due to drug interactions.

compound number chemical formula number CYP inhibition (% of control activity) CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 DS-5 1-5 83.2 97.3 80.9 85.5 90.9 DS-6 1-6 86.1 >100 70.2 89.1 94.1 DS-8 1-8 95.1 >100 100 >100 >100 DS-28 1-18 81.7 96.9 87.2 86.1 95.5 DS-35 1-21 77.7 93.6 4.1 97.4 >100 DS-41 1-27 82.7 93.6 75.8 09.6 92.3 DS-43 adiporon 91.6 57.8 66.0 30.3 90.3 DS-48 1-31 79.0 85.0 17.0 78.1 24.1 DS-56 1-39 80.5 100.0 73.5 91.6 9.2 DS-73 1-50 82.7 96.5 85.1 85.9 80.5 APN5 P5 88.8 >100 98.5 92.3 82.9 Ketoconazole
(reference) 97.2 >100 >100 >100 26.1

Experimental Example 9. Mouse application hair growth and skin aging improvement efficacy evaluation

After shaving the back of 7-week-old C57BL/6 mice, the peptide 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. A solution corresponding to 200 μl per mouse was uniformly applied to the entire back every day for 35 days.

In addition, after the last application, skin tissue was extracted to extract mRNA, and the effect on the expression of procollagen, a skin aging factor, was verified by real-time PCR.

As a result, the ratio of the hair growth area among the first hair removal areas was significantly increased in the group treated with the peptide derivative of the present invention. In particular, it was confirmed that the formation of hair follicles was promoted similarly to the group treated with minoxidil used as a positive control group (FIG. 18).

In addition, it was confirmed that procollagen, a skin aging factor, was expressed similarly to or higher than APN5, a previously known adiponectin-derived peptide, in the group treated with the peptide derivative of the present invention (FIG. 19).

Experimental Example 10. Adipocyte triglyceride inhibition effect verification

3T3-L1, a mouse adipocyte cell line, was treated with a differentiation inducing reagent to differentiate into adipocytes, filled with neutral fat, and then treated with a series of concentrations (10, 30 μM) of the peptide derivative of the present invention, cultured for 24 hours, and cells were Obtained and measured the neutral fat content. As a result, it was confirmed that treatment with the peptide derivative of the present invention reduced the neutral fat content in a concentration-dependent manner (FIG. 20a).

Meanwhile, 3T3-L1, a mouse adipocyte cell line, was differentiated into adipocytes by treating the peptide derivative of the present invention with 10 μM of a differentiation inducing reagent before differentiation induction, and then the cells were obtained and the triglyceride content was measured. As a result, it was confirmed that neutral fat accumulation was inhibited when the peptide derivative of the present invention was treated (FIG. 20b).

Experimental Example 11. Muscle Cell Sensitive Skin Improvement Efficacy Verification

After culturing the RD cell line, a human muscle cell line, when the cells are 90% full, the medium is replaced with a serum-free medium, treated with 50 mM of lactic acid (LA), a substance that induces sensitive skin, and 10 μM of the peptide derivative of the present invention, and after 4 hours Cells were harvested, mRNA was extracted, and the effect on the expression of CGRP, a pain mediator neurotransmitter, was observed.

As a result, it was confirmed that when the peptide derivative of the present invention was treated, the expression of pain mediators was significantly reduced compared to when lactic acid was treated, and the level was similar to or lower than when nothing was treated (Fig. 21). That is, it can be seen that the peptide derivative of the present invention can significantly suppress the expression of genes related to skin sensitivity induced by lactic acid.

As described above, although the embodiments have been described with limited drawings, those 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 the method described, and/or the components of the described system, structure, device, circuit, etc. may be combined or combined in a different form than the method described, or other components may be used. Or even if it is replaced or substituted by equivalents, appropriate results can be achieved.

Therefore, other implementations, other embodiments, and equivalents of the claims are within the scope of the following claims.

Claims (11)

A peptide derivative represented by the following [Formula 1]:
[Formula 1]

In the above [Formula 1],
R ₁ is selected from the group consisting of an amino group (NH ₂ ), an acetylamino group (Ac-NH), NH ₂ -(CH ₂ CH ₂ O) _m -CH ₂ CONH, a C ₁₅ -C ₂₀ amide group, and combinations thereof Any one or more selected (where m is an integer from 1 to 5),
R ₂ is an amino group or a hydroxyl group (OH);
R ₃ is hydrogen (H);
R ₄ is selected from the group consisting of a C ₁ -C ₆ chain alkyl group, a C ₂ -C ₆ alkyl carboxyl group, a C ₁ -C ₆ alkylamide group, an imidazoylmethyl group, and combinations thereof more than one of the
R ₅ and R ₆ are the same as or different from each other, and are each independently a benzyl group, a phenylethyl group, or an indolylmethyl group, and the benzyl group is unsubstituted or a hydroxy group, a trifluoromethyl group (CF ₃ ), a halogen group, At least one selected from the group consisting of a cyano group, a nitro group, a C ₁ -C ₆ chain-type alkyl group, a C ₁ -C ₆ alkoxy group, and combinations thereof,
R ₇ is a benzyl group or a C ₁ -C ₆ alkylamino group, and the benzyl group is unsubstituted or a hydroxy group, a halogen group, a cyano group, a nitro group, a C ₁ -C ₆ chain alkyl group, or a C ₁ -C ₆ alkoxy group. group, and any one or more selected from the group consisting of combinations thereof;
R ₃ and R ₇ are connected to each other to form a C ₁₅ -C ₂₀ heterocycloalkene group;
R ₈ , R ₉ , and R ₁₀ are the same as or different from each other, and are each independently hydrogen or a C ₁ -C ₆ alkyl group;
n is 0 or 1;
When n is 0, R ₄ is a C ₂ -C ₆ alkylcarboxyl group, R ₅ , R ₆ , and R ₇ are benzyl groups;
provided that R ₁ is NH ₂ , R ₂ is OH, R ₃ is hydrogen, R ₄ is an isobutyl group, both R ₅ and R ₆ are a hydroxybenzyl group, and R ₇ is an unsubstituted benzyl group; , R ₈ , R ₉ , and R ₁₀ are all hydrogen, except when n is 1.
According to claim 1,
The R ₄ is

,

,

,

,

,

,

, And characterized in that any one or more selected from the group consisting of combinations thereof, a peptide derivative.
According to claim 1,
The R ₅ and R ₆ are the same as or different from each other, and each independently

,

,

,

,

,

,

,

,

,

,

,

, And characterized in that any one or more selected from the group consisting of combinations thereof, a peptide derivative.
According to claim 1,
The C ₁₅ -C ₂₀ heterocycloalkene group

,

,

,

, And characterized in that any one or more selected from the group consisting of combinations thereof, a peptide derivative.
According to claim 1,
The peptide derivative is characterized in that at least one selected from the group consisting of peptide derivatives represented by the following [Formula 1-1] to [Formula 1-56], a peptide derivative:
[Formula 1-1]

;
[Formula 1-2]

;
[Formula 1-3]

;
[Formula 1-4]

;
[Formula 1-5]

;
[Formula 1-6]

;
[Formula 1-7]

;
[Formula 1-8]

;
[Formula 1-9]

;
[Formula 1-10]

;
[Formula 1-11]

;
[Formula 1-12]

;
[Formula 1-13]

;
[Formula 1-14]

;
[Formula 1-15]

;
[Formula 1-16]

;
[Formula 1-17]

;
[Formula 1-18]

;
[Formula 1-19]

;
[Formula 1-20]

;
[Formula 1-21]

;
[Formula 1-22]

;
[Formula 1-23]

;
[Formula 1-24]

;
[Formula 1-25]

;
[Formula 1-26]

;
[Formula 1-27]

;
[Formula 1-28]

;
[Formula 1-29]

;
[Formula 1-30]

;
[Formula 1-31]

;
[Formula 1-32]

;
[Formula 1-33]

;
[Formula 1-34]

;
[Formula 1-35]

;
[Formula 1-36]

;
[Formula 1-37]

;
[Formula 1-38]

;
[Formula 1-39]

;
[Formula 1-40]

;
[Formula 1-41]

;
[Formula 1-42]

;
[Formula 1-43]

;
[Formula 1-44]

;
[Formula 1-45]

;
[Formula 1-46]

;
[Formula 1-47]

;
[Formula 1-48]

;
[Formula 1-49]

;
[Formula 1-50]

;
[Formula 1-51]

;
[Formula 1-52]

;
[Formula 1-53]

;
[Formula 1-54]

;
[Formula 1-55]

; and
[Formula 1-56]

.
According to claim 1,
The peptide derivative is characterized in that any one or more peptide sequences selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 16 are modified.
A composition for increasing the expression of adiponectin comprising the peptide derivative of any one of claims 1 to 6 as an active ingredient.
A pharmaceutical composition for preventing or treating any one or more selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising the peptide derivative of any one of claims 1 to 6 as an active ingredient. .
A cosmetic composition for preventing or improving any one or more selected from the group consisting of skin inflammatory diseases, wounds, hair loss, fibrosis, metabolic diseases, and cancer, comprising the peptide derivative of any one of claims 1 to 6 as an active ingredient.
A pharmaceutical composition for preventing or improving any one or more selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, comprising the peptide derivative of any one of claims 1 to 6 as an active ingredient.
A cosmetic composition for preventing or improving any one or more selected from the group consisting of aging, sensitive skin, wrinkles, and moisturizing, comprising the peptide derivative of any one of claims 1 to 6 as an active ingredient.

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