WO2021133014A1 - Composition containing dmt-tic peptide derivative for preventing or treating hair loss - Google Patents
Composition containing dmt-tic peptide derivative for preventing or treating hair loss Download PDFInfo
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- WO2021133014A1 WO2021133014A1 PCT/KR2020/018823 KR2020018823W WO2021133014A1 WO 2021133014 A1 WO2021133014 A1 WO 2021133014A1 KR 2020018823 W KR2020018823 W KR 2020018823W WO 2021133014 A1 WO2021133014 A1 WO 2021133014A1
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- Prior art keywords
- hair
- hair loss
- formula
- compound
- preventing
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
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- A—HUMAN NECESSITIES
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- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A—HUMAN NECESSITIES
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- A61Q7/00—Preparations for affecting hair growth
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2250/30—Other Organic compounds
Definitions
- the present invention relates to a composition for preventing, treating or improving hair loss comprising a Dmt-Tic peptide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the compound of the present invention promotes hair growth by converting the resting state of the hair growth cycle to the anagen phase by proliferating dermal papilla cells and/or lateral hair root sheath cells.
- Human hair is an aggregate of about 100,000 individual hairs, and hair is produced by hair follicles.
- the hair follicle serves as a repository of stem cells capable of generating all the cell lines needed to reconstruct the hair follicle itself, the epithelium and the sebaceous glands.
- Hair follicles contain dermal papilla cells and dermal sheath cells derived from the mesenchyme, and also inner root sheaths and outer root sheaths derived from the epithelium. It also contains the epithelial cells of the root sheaths, the matrix, and the hair shaft.
- dermal papilla cells are the core cells responsible for the development and growth of hair, and are located at the bottom of the hair root, which is the subcutaneous root of the hair.
- dermal papilla cells are collected from the scalp and transplanted after culturing, new hair grows.
- dermal papilla cells there are several difficulties in using dermal papilla cells as a treatment for hair loss.
- there is a limit in that the hair regeneration ability is significantly reduced when a lot of culture.
- Hair goes through a three-stage cycle of anagen, catagen, and telogen, where it grows, maintains, and falls out.
- the growth period which is the period of hair growth
- overall hair follicle cell apoptosis apoptosis
- hair follicles are reduced in catagen, which is a stage in which the next growth phase is prepared for an average of 3 months (telogen).
- the hair falls out after passing through, and the reason the length of the hair is different depending on the part is that the duration of the growth phase, which is a unique characteristic of the hair follicle, is different for each part.
- AGA androgenetic alopecia
- DHT dehydrotestosterone
- AR androgen receptor
- Hair loss in androgenetic androgenetic alopecia is dependent on dihydrotestosterone (DHT), and DKK1 (Dickkopf-1), which inhibits hair follicle growth, is secreted from dermal papilla (DP) cells of hair follicles by DHT, thereby affecting the growth of hair follicles. It causes male pattern hair loss by inhibiting the growth of outer root sheath (ORS) cells, which play an important role.
- DHT dihydrotestosterone
- DKK1 Dickkopf-1
- Finasteride and dutasteride are 5 ⁇ -reductase inhibitors that inhibit the conversion of testosterone to 5 ⁇ -DHT.
- this product exhibits side effects such as decreased libido, erectile dysfunction, and loss of driving and performance.
- minoxidil the mechanism has not yet been fully elucidated, but it is a potassium channel opener that hyperpolarizes cell membranes, and through vasodilation and potassium channel opening, provides oxygen, blood, nutrients, etc.
- G protein-coupled receptor has a structure that spans the cytoplasmic surface and the outer cell surface of the cell membrane or the cell membrane of an intracellular organ and passes through the membrane 7 times. There are about 800 to 1000 receptor types in the living body, and they catalyze almost all physiological reactions in the living body.
- the signaling system of GPCR has been elucidated as a result of many studies. When a ligand or receptor agonist binds to a receptor, the structure of the receptor changes. The restructured receptor associates with the G protein, and this contact divides the G protein into a G ⁇ and G ⁇ -G ⁇ duplex structure. Each divided substance catalyzes the reaction of secondary messengers within a cell or organ, and various cellular reactions occur by such a chain reaction.
- An antagonist, a type of receptor agonist stabilizes the inactivated form of the GPCR.
- WO 03/062261 discloses a structure and a method for preparing a novel DMT-TIC peptidic derivative, and mentions a method for using it as an antagonist and/or agonist of ⁇ -opioid or ⁇ -opioid receptor. .
- no research has been conducted on the relationship between the DMT-TIC peptide derivative and hair loss so far.
- Patent Document 1 International Publication WO 03/062261 (2003.07.31.)
- the present invention aims to provide a composition capable of preventing, treating or improving hair loss by inducing the growth phase of the hair growth cycle through proliferation of dermal papilla cells and/or outer root sheath cells to promote hair thickness and length growth. do it with
- the present invention provides a composition for preventing, treating or improving hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient.
- R is selected from the group consisting of the following substituents:
- the composition may be a pharmaceutical composition, a cosmetic composition or a food composition.
- the compound of formula (I) or a pharmaceutically acceptable salt thereof converts the resting state of the hair growth cycle to the anagen phase through proliferation of dermal papilla cells and/or outer hair root sheath cells, so that the hair can grow thicker and longer. It can be used to prevent, treat or improve hair loss.
- composition of the present invention promotes hair thickness and length growth by inducing the growth phase of the hair growth cycle through proliferation of dermal papilla cells and/or outer root sheath cells, so it can be usefully used for preventing, treating or improving hair loss due to various causes. and may suggest a new direction for future research for preventing, treating, or improving hair loss.
- FIG. 1 and 2 are graphs showing the results of proliferation of dermal papilla cells (DPC) and outer root sheath cells (ORS) of hair follicles according to treatment with the compound of Formula II, respectively.
- DPC dermal papilla cells
- ORS outer root sheath cells
- FIG 3 and 4 show the migration ability of outer root sheath cells (ORS) of hair follicles by treatment with the compound of Formula II.
- ORS outer root sheath cells
- 5 is a photograph of the length of the mustache hair follicle before and after culturing according to the treatment of the compound of Formula II.
- FIG. 6 is a graph showing the hair length of mustache hair follicles before and after culture according to the treatment of the compound of Formula II.
- the present invention is characterized in that it was discovered for the first time that the compound of formula (I) prevents or treats hair loss or promotes hair growth.
- the present invention provides a pharmaceutical composition for preventing or treating hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient.
- R is selected from the group consisting of the following substituents.
- R is In this case, * represents the stereocenter of the chiral carbon, and the substituent may represent R-type or S-type optical activity. More preferably, the stereocenter * in R has an S-shaped stereostructure.
- the compound of formula (I) is a compound having the structure of formula (II):
- the present invention provides a pharmaceutical composition for preventing or treating hair loss comprising the compound of Formula II or a pharmaceutically acceptable salt thereof as an active ingredient.
- the compound of formula II is "(3S)-3-[[(3S)-2-[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-3 ,4-dihydro-1H-isoquinoline-3-carbonyl]amino]-3-(1H-benzimidazol-2-yl)propanoic acid” and is referred to as “H-Dmt-Tic-NH- CH(CH 2 -COOH)-Bid”.
- Dmt refers to 2',6'-dimethyl-L-tyrosine and "Tic” refers to 1,2,3,4-tetra Refers to hydroisoquinoline-3-carboxylic acid (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), "Bid” is 1H-benzimidazol-2-yl (1H-benzimidazol-2-yl ) refers to
- salt refers to a salt according to one aspect of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound.
- the salt is not particularly limited as long as it is pharmaceutically acceptable, and for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid , benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and the like can be used.
- “Hair loss” of the present invention refers to a state in which there is no hair in the site where hair should normally exist, and includes alopecia areata, hereditary androgen hair loss, telogen hair loss, traumatic hair loss, hair growth wall, pressure hair loss, It may be, but is not limited to, genital hair loss, alopecia pityis, syphilitic hair loss, seborrheic hair loss, symptomatic hair loss, scarring hair loss, or congenital hair loss.
- the compound of the present invention promotes the proliferation of dermal papilla cells and/or outer hair root sheath cells to induce hair growth, thereby preventing or treating hair loss.
- Treatment of the present invention is to improve hair loss symptoms by delaying or stopping hair loss by administration of the composition of the present invention, or to beneficially change hair loss symptoms such as hair growth and hair growth promotion, such as lengthening or increasing the number of hair means all actions.
- the pharmaceutical composition of the present invention may be administered parenterally or orally according to a desired method, and the dosage may vary depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of disease, etc. Its scope is diverse.
- the therapeutically effective amount of the composition may vary depending on the administration method, the target site, and the condition of the patient.
- the pharmaceutical composition of the present invention is an oral dosage form such as powders, granules, tablets, soft or hard capsules, suspensions, emulsions, syrups, and aerosols, ointments, creams, etc., according to a conventional method, respectively.
- oral dosage form such as powders, granules, tablets, soft or hard capsules, suspensions, emulsions, syrups, and aerosols, ointments, creams, etc.
- suppositories, injections, and sterile injection solutions may be formulated and used in any form suitable for pharmaceutical preparations.
- excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, diluents, etc. commonly used for the formulation.
- excipients that may be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate , cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, mineral oil, and the like may be used, but is not limited thereto.
- lubricants such as magnesium stearate and talc may also be used.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories.
- Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
- As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
- the present invention also provides a cosmetic composition for preventing or improving hair loss comprising the compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient.
- the cosmetic composition may be, for example, a cosmetic for hair, the formulation thereof is not particularly limited, and may be appropriately selected according to the purpose.
- the cosmetic composition is formulated as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation and spray.
- a cleaning agent such as shampoo, conditioner, and body cleanser
- hair dressing agent such as hair tonic, gel or mousse
- a cosmetic composition for hair such as a hair conditioner or hair dye.
- the cosmetic composition may contain various suitable bases and additives as necessary, and the types and amounts of these components can be easily selected by the inventor. It may contain acceptable additives as necessary, for example, may further include components such as preservatives, pigments, and additives conventional in the art.
- the present invention also provides a food composition for preventing or improving hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient, for example, a health functional food.
- a health functional food means a food manufactured and processed using raw materials or ingredients useful for the human body, and “functionality” means a health purpose such as regulating nutrients or physiological action with respect to the structure and function of the human body. It means to consume for the purpose of obtaining a useful effect.
- the formulation of the food composition is not particularly limited, but, for example, may be formulated as tablets, granules, powders, liquids such as drinks, caramel, gels, bars, and the like.
- the food composition of each dosage form can be formulated without difficulty by those skilled in the art without difficulty depending on the dosage form or purpose of use of ingredients commonly used in the field.
- DPC dermal papilla cells
- ORS lateral root sheath cells
- DPC dermal papilla cells
- ORS outer root sheath cells
- each of 2 x 10 3 dermal papilla cells and outer hair root sheath cells was inoculated in a separate 96-well plate, and 24 hours later, the compound of Formula II was treated at a concentration of 1 nM to 10 ⁇ M for 72 hours. Thereafter, the medium was removed and the cells were treated with 10% CCK-8 solution for 2 hours using a CCK-8 assay kit (Dojindo, Japan), and then the absorbance was measured at 450 nm to determine the number of cells.
- the compound of the present invention is effective for the proliferation of dermal papilla cells and outer root sheath cells of hair follicles.
- the outer hair root sheath cells were inoculated at a concentration of 5 ⁇ 10 5 in a 60 mm culture dish. After overnight incubation, a blue (1000 ⁇ L) tip was used to scratch the bottom of the dish. After treatment with the compound of formula II (1 ⁇ M), it was further cultured for 48 hours. Cell migration ability was confirmed by measuring the distance the cells on both sides moved toward the middle position of the scratch.
- the compound of the present invention is effective for hair growth in actual hair follicles.
Abstract
The present invention relates to a composition for preventing, treating, or ameliorating hair loss, wherein the composition contains a Dmt-Tic peptide derivative, or a pharmaceutically acceptable salt thereof. The compound according to the present invention causes dermal papilla cells and/or outer root sheath cells to proliferate, such that the hair growth cycle moves from the telogen phase to the anagen phase, thereby promoting hair growth.
Description
본 발명은 Dmt-Tic 펩티드성 유도체 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 포함하는 탈모 예방, 치료 또는 개선용 조성물에 관한 것이다. 본 발명의 화합물은 모유두 세포 및/또는 외측 모근초 세포를 증식시킴으로서 모발 성장 주기의 휴지기 상태를 성장기로 전환시켜 모발의 성장을 촉진시킨다.The present invention relates to a composition for preventing, treating or improving hair loss comprising a Dmt-Tic peptide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. The compound of the present invention promotes hair growth by converting the resting state of the hair growth cycle to the anagen phase by proliferating dermal papilla cells and/or lateral hair root sheath cells.
인간의 머리카락은 약 100,000개의 개별 모발의 집합체이며, 모발은 모낭(hair follicle)에 의해 생성된다. 모낭은 모낭 자신, 상피 및 피지선을 재구성하는 데 필요한 모든 세포주를 생성할 수 있는 줄기세포의 저장소 역할을 한다. 모낭은 간엽(mesenchyme)에서 유도된 모유두 세포(dermal papilla cells)와 결직초세포(dermal sheath cells)를 포함하고 있으며, 또한, 상피로부터 유래된 내측 모근초(inner root sheaths)와 외측 모근초(outer root sheaths)의 상피 세포(epithelial cells), 매트릭스(matrix), 모간(hair shaft)도 포함하고 있다. 특히 모유두 세포는 모발의 발생과 성장을 담당하는 핵심 세포로, 모발의 피하에 있는 뿌리인 모근의 가장 밑부분에 위치한다. 실제로 두피에서 모유두 세포를 채집해 배양 후 이식할 경우 모발이 새로 자라난다. 하지만 모유두 세포를 탈모 치료제로 사용하기에는 여러 어려움이 존재한다. 우선 두피로부터의 분리가 어렵고, 배양 조건이 까다로우며 충분한 양의 세포를 배양하는 것이 어렵다. 또한 많이 배양할 경우 모발 재생 능력이 현저히 저하되는 한계가 있다. Human hair is an aggregate of about 100,000 individual hairs, and hair is produced by hair follicles. The hair follicle serves as a repository of stem cells capable of generating all the cell lines needed to reconstruct the hair follicle itself, the epithelium and the sebaceous glands. Hair follicles contain dermal papilla cells and dermal sheath cells derived from the mesenchyme, and also inner root sheaths and outer root sheaths derived from the epithelium. It also contains the epithelial cells of the root sheaths, the matrix, and the hair shaft. In particular, dermal papilla cells are the core cells responsible for the development and growth of hair, and are located at the bottom of the hair root, which is the subcutaneous root of the hair. In fact, when dermal papilla cells are collected from the scalp and transplanted after culturing, new hair grows. However, there are several difficulties in using dermal papilla cells as a treatment for hair loss. First, it is difficult to separate from the scalp, the culture conditions are difficult, and it is difficult to culture a sufficient amount of cells. In addition, there is a limit in that the hair regeneration ability is significantly reduced when a lot of culture.
모발은 성장기(anagen), 퇴화기(catagen) 및 휴지기(telogen)의 3단계 주기를 거쳐 성장, 유지 및 탈락된다. 모발이 자라는 기간인 성장기에는 성인의 경우, 하루 평균 0.3mm 정도의 모발이 자라며, 한 달에 1cm 정도 성장하고, 통상 3년 내지 7년간 지속되는 것으로 알려져 있다. 일반적으로 성장기 후 10일 내지 14일 동안 전반적인 모낭세포의 세포사멸(apoptosis)이 일어나면서 모낭이 축소되는 단계인 퇴화기(catagen), 평균 3개월의 다음 성장기를 준비하는 단계인 휴지기(telogen)를 거쳐 모발이 빠지게 되며, 부위에 따라 모발의 길이가 다른 이유는 각각의 부위에 따라서 모낭의 고유한 특징인 성장기의 지속기간이 서로 다르기 때문이다.Hair goes through a three-stage cycle of anagen, catagen, and telogen, where it grows, maintains, and falls out. In the growth period, which is the period of hair growth, in the case of adults, hair grows on average about 0.3 mm per day, grows about 1 cm per month, and it is known that it usually lasts for 3 to 7 years. In general, for 10 to 14 days after the growth phase, overall hair follicle cell apoptosis (apoptosis) occurs and hair follicles are reduced in catagen, which is a stage in which the next growth phase is prepared for an average of 3 months (telogen). The hair falls out after passing through, and the reason the length of the hair is different depending on the part is that the duration of the growth phase, which is a unique characteristic of the hair follicle, is different for each part.
이와 같이 사람의 모발은 일정한 모발 성장주기(hair growth cycle)를 가지고 있기 때문에 항상 일정한 수의 모발을 유지하게 된다. 그러나 탈모가 진행되면 모근에 존재하는 모유두가 작아지고, 모유두가 작아지면 머리털의 굵기가 가늘어지고, 동시에 모발 성장주기도 짧아진다. 따라서 탈모가 진행되면 머리털은 매우 가늘어지며 모발 성장주기는 더욱 짧아져 조금 자란 후 빠지게 된다. As described above, since human hair has a constant hair growth cycle, a constant number of hairs is always maintained. However, as hair loss progresses, the dermal papilla present in the hair root becomes smaller, and when the dermal papilla becomes smaller, the thickness of the hair becomes thinner, and the hair growth cycle is shortened at the same time. Therefore, as hair loss progresses, the hair becomes very thin, and the hair growth cycle becomes shorter and falls out after a little growth.
탈모의 원인으로는 유전적인 원인, 남성호르몬의 작용뿐만 아니라 내분비 질환, 영양 결핍, 약물 사용, 출산, 발열, 수술 등의 심한 신체적, 정신적 스트레스 등의 요인들이 복합적으로 작용하는 것으로 알려져 있다. 최근에는 남성형 탈모뿐만 아니라 식생활의 변화, 사회 환경 등에 의한 스트레스의 증가로 인해 여성의 탈모 인구도 증가하고 있는 추세이며, 연령 또한 낮아지고 있다.It is known that factors such as genetic causes and the action of male hormones, as well as endocrine diseases, nutritional deficiency, drug use, childbirth, fever, and severe physical and mental stress such as surgery, are the causes of hair loss. Recently, as well as male pattern hair loss, due to the increase in stress caused by changes in diet, social environment, etc., the female hair loss population is also increasing, and the age is also decreasing.
특히 남성형 탈모(AGA: androgenetic alopecia)는 탈모의 대표적 질환으로 안드로겐성 탈모증, 유전성 안드로겐성 탈모증, 남성형 탈모증이라고 하며, 유전과 남성호르몬인 안드로겐(androgen)에 의해 모발이 빠지는 대표적 탈모 질환이다. 병리적 기전은 체내에 있는 남성호르몬인 테스토스테론(testosterone)이 모낭에 있는 5α-환원효소(5-α reductase, 5-AR)에 의해서 남성형 탈모의 원인이 되는 디하이드로테스토스테론(dehydrotestosterone, DHT)으로 전환되어 안드로겐 수용체(AR)와 결합하여 모낭(hair follicle)에 단백질 합성 물질을 저해하고 모유두(dermal papilla)의 축소를 유발시켜 탈모를 일으킨다. 남성형 안드로겐성 탈모증에서의 탈모는 디하이드로테스토스테론(DHT)에 의존적이며, DHT에 의해 모낭의 모유두(dermal papilla, DP) 세포로부터 모낭 성장을 억제하는 DKK1(Dickkopf-1)가 분비되어 모낭의 성장에 중요한 역할을 하는 외측 모근초(Outer root sheath, ORS) 세포의 성장을 억제함으로써 남성형 탈모을 유발하게 된다.In particular, androgenetic alopecia (AGA) is a representative disease of hair loss and is called androgenetic alopecia, hereditary androgenetic alopecia, and androgenetic alopecia. The pathological mechanism is that testosterone, a male hormone in the body, is converted into dehydrotestosterone (DHT), the cause of male pattern hair loss, by 5α-reductase (5-AR) in hair follicles. It binds to androgen receptor (AR), inhibits protein synthesis in hair follicles, and induces shrinkage of dermal papilla, causing hair loss. Hair loss in androgenetic androgenetic alopecia is dependent on dihydrotestosterone (DHT), and DKK1 (Dickkopf-1), which inhibits hair follicle growth, is secreted from dermal papilla (DP) cells of hair follicles by DHT, thereby affecting the growth of hair follicles. It causes male pattern hair loss by inhibiting the growth of outer root sheath (ORS) cells, which play an important role.
현재 국내에서 가장 빈번하게 쓰이는 탈모 치료제로는 피나스테라이드(finasteride; 상품명 Propecia®), 두타스테라이드(dutasteride; 상품명 Avodart®), 미녹시딜(minoxidil; 상품명 마이녹실® 또는 Rogaine®) 등이 있다. 피나스테라이드와 두타스테라이드는 5α-환원효소 억제제(5α-reductase inhibitor)로 남성호르몬(testosterone)이 5α-DHT로 전환되는 것을 억제한다. 그러나 이 제품은 성욕감퇴, 발기부전, 운전 및 수행능력 상실 등의 부작용을 나타낸다. 한편 미녹시딜의 경우 아직까지 그 기전이 완벽히 밝혀지지 않았으나, 세포막을 과분극(hyperpolarization)시키는 칼륨 채널 개방제(potassium chaennel opener)로서, 혈관 확장 및 칼륨 채널 개방을 통해, 모낭에 산소, 혈액, 영양소 등의 공급을 증가시켜 모낭을 건강하게 하는 것으로 여겨지고 있다. 그러나 이 제품 역시 도포 부위의 가려움, 홍반, 피부 자극, 눈의 자극 등의 부작용이 나타나며, 머리 이외에 다른 신체 부위에서의 원치 않는 모발의 성장이 관찰되기도 한다. 또한 최근 중증 탈모 환자들을 대상으로 모발 이식술이 시도되고 있지만, 고가의 비용과 시술 후 부작용이 한계로 지적되고 있다.Currently, the most frequently used hair loss treatments in Korea include finasteride (trade name: Propecia®), dutasteride (trade name: Avodart®), and minoxidil (minoxidil; trade name: Minoxidil® or Rogaine®). Finasteride and dutasteride are 5α-reductase inhibitors that inhibit the conversion of testosterone to 5α-DHT. However, this product exhibits side effects such as decreased libido, erectile dysfunction, and loss of driving and performance. Meanwhile, in the case of minoxidil, the mechanism has not yet been fully elucidated, but it is a potassium channel opener that hyperpolarizes cell membranes, and through vasodilation and potassium channel opening, provides oxygen, blood, nutrients, etc. to the hair follicles. It is believed to make hair follicles healthy by increasing supply. However, this product also has side effects such as itching, erythema, skin irritation, eye irritation, etc. at the application site, and unwanted hair growth in other parts of the body other than the head is also observed. In addition, although hair transplantation has been recently attempted for patients with severe hair loss, high cost and side effects after the procedure are pointed out as limitations.
G 단백질 연결 수용체(G protein-coupled receptor: GPCR)는 세포막 또는 세포 내 기관의 세포막에서 세포질 면과 세포 외면에 걸쳐있고 막을 7번 통과하는 구조를 갖는다. 생체 내에는 800~1000개 정도의 수용체 종류가 존재하고, 생체 내의 거의 모든 생리적 반응을 촉매한다. GPCR의 신호전달체계는 많은 연구의 결과로서 밝혀져 있다. 리간드 또는 수용체 작용제(agonist)가 수용체에 결합하게 되면 수용체의 구조가 바뀌게 된다. 구조가 바뀐 수용체는 G 단백질과 연결되고 이러한 접촉에 의해 G 단백질은 Gα 와 Gβ-Gγ 이중체 구조로 나뉜다. 각기 나뉜 물질은 세포 또는 기관 내의 2차 메신저의 반응을 촉매하고 그러한 연쇄적인 반응에 의해 다양한 세포 반응이 일어나게 된다. 수용체 작용제의 일종인 길항제(antagonist)는 GPCR의 비활성화된 형태를 안정화시킨다.G protein-coupled receptor (GPCR) has a structure that spans the cytoplasmic surface and the outer cell surface of the cell membrane or the cell membrane of an intracellular organ and passes through the membrane 7 times. There are about 800 to 1000 receptor types in the living body, and they catalyze almost all physiological reactions in the living body. The signaling system of GPCR has been elucidated as a result of many studies. When a ligand or receptor agonist binds to a receptor, the structure of the receptor changes. The restructured receptor associates with the G protein, and this contact divides the G protein into a Gα and Gβ-Gγ duplex structure. Each divided substance catalyzes the reaction of secondary messengers within a cell or organ, and various cellular reactions occur by such a chain reaction. An antagonist, a type of receptor agonist, stabilizes the inactivated form of the GPCR.
국제공개공보 WO 03/062261에서는 신규한 DMT-TIC 펩티드성 유도체의 구조 및 제조 방법을 개시하고 있고, 이를 δ-opioid 또는 μ-opioid 수용체의 길항제 및/또는 작용제로 사용하는 방법에 대해 언급하고 있다. 그러나 현재까지 DMT-TIC 펩티드성 유도체와 탈모의 관련성에 대한 연구는 진행된 바가 없다.International Publication No. WO 03/062261 discloses a structure and a method for preparing a novel DMT-TIC peptidic derivative, and mentions a method for using it as an antagonist and/or agonist of δ-opioid or μ-opioid receptor. . However, no research has been conducted on the relationship between the DMT-TIC peptide derivative and hair loss so far.
[선행기술문헌][Prior art literature]
[특허문헌][Patent Literature]
(특허문헌 1) 국제공개공보 WO 03/062261 (2003.07.31.)(Patent Document 1) International Publication WO 03/062261 (2003.07.31.)
본 발명은 모유두 세포 및/또는 외측 모근초 세포의 증식을 통한 모발 성장주기의 성장기 돌입을 유도하여 모발의 굵기 및 길이 성장을 촉진시킴으로서 탈모를 예방, 치료 또는 개선할 수 있는 조성물을 제공하는 것을 목적으로 한다.The present invention aims to provide a composition capable of preventing, treating or improving hair loss by inducing the growth phase of the hair growth cycle through proliferation of dermal papilla cells and/or outer root sheath cells to promote hair thickness and length growth. do it with
본 발명은 하기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 포함하는 탈모 예방, 치료 또는 개선용 조성물을 제공한다. The present invention provides a composition for preventing, treating or improving hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 I][Formula I]
상기 식에서,In the above formula,
R은 하기 치환기로 이루어지는 군으로부터 선택된 것이다:R is selected from the group consisting of the following substituents:
상기 조성물은 약학 조성물, 화장료 조성물 또는 식품 조성물일 수 있다.The composition may be a pharmaceutical composition, a cosmetic composition or a food composition.
일 실시태양에서, 상기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염은 모유두 세포 및/또는 외측 모근초 세포의 증식을 통해 모발 성장주기의 휴지기 상태를 성장기로 전환시켜 모발이 보다 굵고 길게 성장할 수 있도록 하여 탈모 예방, 치료 또는 개선에 사용될 수 있다.In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof converts the resting state of the hair growth cycle to the anagen phase through proliferation of dermal papilla cells and/or outer hair root sheath cells, so that the hair can grow thicker and longer. It can be used to prevent, treat or improve hair loss.
본 발명의 조성물은 모유두 세포 및/또는 외측 모근초 세포의 증식을 통해 모발 성장주기의 성장기 돌입을 유도하여 모발의 굵기 및 길이 성장을 촉진시키므로 다양한 원인에 의한 탈모 예방, 치료 또는 개선에 유용하게 사용될 수 있으며, 향후 탈모 예방, 치료 또는 개선을 위한 연구에 새로운 방향을 제시할 수 있다.The composition of the present invention promotes hair thickness and length growth by inducing the growth phase of the hair growth cycle through proliferation of dermal papilla cells and/or outer root sheath cells, so it can be usefully used for preventing, treating or improving hair loss due to various causes. and may suggest a new direction for future research for preventing, treating, or improving hair loss.
도 1 및 2는 각각 화학식 II의 화합물의 처리에 따른 모낭의 모유두 세포(DPC) 및 외측 모근초 세포(ORS)의 증식 결과를 나타낸 그래프이다. 1 and 2 are graphs showing the results of proliferation of dermal papilla cells (DPC) and outer root sheath cells (ORS) of hair follicles according to treatment with the compound of Formula II, respectively.
도 3 및 4는 화학식 II의 화합물의 처리에 의한 모낭의 외측 모근초 세포(ORS)의 이동능을 보여준다. 3 and 4 show the migration ability of outer root sheath cells (ORS) of hair follicles by treatment with the compound of Formula II.
도 5는 화학식 II의 화합물의 처리에 따른 배양 전, 후의 콧수염 모낭의 모발 길이를 촬영한 사진이다.5 is a photograph of the length of the mustache hair follicle before and after culturing according to the treatment of the compound of Formula II.
도 6은 화학식 II의 화합물의 처리에 따른 배양 전, 후의 콧수염 모낭의 모발 길이를 나타낸 그래프이다.6 is a graph showing the hair length of mustache hair follicles before and after culture according to the treatment of the compound of Formula II.
이하, 첨부한 도면을 참조하여 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본원의 실시태양 및 실시예를 상세히 설명한다. 그러나 본원은 여러 가지 형태로 구현될 수 있으며 여기에서 설명하는 실시태양 및 실시예에 한정되지 않는다. Hereinafter, with reference to the accompanying drawings, embodiments and examples of the present invention will be described in detail so that those of ordinary skill in the art to which the present invention pertains can easily carry out. However, the present application may be embodied in various forms and is not limited to the embodiments and examples described herein.
본원 명세서 전체에서, 어떤 부분이 어떤 구성 요소를 "포함" 한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.Throughout this specification, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.
당업계에서 사용되는 관습에 따라, 본원의 화학식에 사용된"
"은 잔기 또는 치환기 "R"이 골격 구조에 부착되어 있는 것을 나타내는데 사용된다.In accordance with the convention used in the art, "used in the formulas herein" "A" is used to indicate that a moiety or substituent "R" is attached to the backbone structure.
본 발명은 화학식 I의 화합물이 탈모 예방 또는 치료, 또는 발모를 촉진함을 최초로 발견한 것을 특징으로 한다. 일 실시태양에서, 본 발명은 하기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 포함하는 탈모의 예방 또는 치료용 약학 조성물을 제공한다.The present invention is characterized in that it was discovered for the first time that the compound of formula (I) prevents or treats hair loss or promotes hair growth. In one embodiment, the present invention provides a pharmaceutical composition for preventing or treating hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 식에서,In the above formula,
R은 하기 치환기로 이루어지는 군으로부터 선택된 것이다.R is selected from the group consisting of the following substituents.
바람직한 실시태양에서, R은
일 수 있으며, 이 때 *는 키랄 탄소의 입체중심을 나타내며, 상기 치환기는 R-형 또는 S-형의 광학 활성을 나타낼 수 있다. 더욱 바람직하게는, 상기 R에서 입체중심 *는 S형의 입체구조를 갖는다. In a preferred embodiment, R is In this case, * represents the stereocenter of the chiral carbon, and the substituent may represent R-type or S-type optical activity. More preferably, the stereocenter * in R has an S-shaped stereostructure.
또다른 실시태양에서, 상기 화학식 I의 화합물은 하기 화학식 II의 구조를 갖는 화합물이다.In another embodiment, the compound of formula (I) is a compound having the structure of formula (II):
[화학식 II][Formula II]
이에 따라 본 발명은 화학식 II의 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 포함하는 탈모 예방 또는 치료용 약학 조성물을 제공한다. 화학식 II의 화합물은 "(3S)-3-[[(3S)-2-[(2S)-2-아미노-3-(4-히드록시-2,6-디메틸페닐)프로파노일]-3,4-디히드로-1H-이소퀴놀린-3-카르보닐]아미노]-3-(1H-벤즈이미다졸-2-일)프로판산"의 화학명으로 지칭되며, "H-Dmt-Tic-NH-CH(CH
2-COOH)-Bid"로 불리기도 한다. 본원에 사용된 용어 "Dmt"는 2',6'-디메틸-L-티로신(2',6'-dimethyl-L-tyrosine)을 지칭하고, "Tic"는 1,2,3,4-테트라히드로이소퀴놀린-3-카르복실산(1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid)를 지칭하며, "Bid"는 1H-벤즈이미다졸-2-일(1H-benzimidazol-2-yl)을 지칭한다.Accordingly, the present invention provides a pharmaceutical composition for preventing or treating hair loss comprising the compound of Formula II or a pharmaceutically acceptable salt thereof as an active ingredient. The compound of formula II is "(3S)-3-[[(3S)-2-[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-3 ,4-dihydro-1H-isoquinoline-3-carbonyl]amino]-3-(1H-benzimidazol-2-yl)propanoic acid” and is referred to as “H-Dmt-Tic-NH- CH(CH 2 -COOH)-Bid". As used herein, the term "Dmt" refers to 2',6'-dimethyl-L-tyrosine and "Tic" refers to 1,2,3,4-tetra Refers to hydroisoquinoline-3-carboxylic acid (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), "Bid" is 1H-benzimidazol-2-yl (1H-benzimidazol-2-yl ) refers to
본 명세서에서 "약학적으로 허용가능한 염"은 약학적으로 허용가능하고 모 화합물(parent compound)의 바람직한 약리 활성을 갖는 본 발명의 일측면에 따른 염을 의미한다. 상기 염으로는 약학적으로 허용되는 것이면 특별히 한정되지 않으며, 예를 들어 염산, 황산, 질산, 인산, 불화수소산, 브롬화수소산, 포름산 아세트산, 타르타르산, 젖산, 시트르산, 푸마르산, 말레산, 숙신산, 메탄술폰산, 벤젠술폰산, 톨루엔술폰산, 나프탈렌술폰산 등을 사용할 수 있다. As used herein, "pharmaceutically acceptable salt" refers to a salt according to one aspect of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. The salt is not particularly limited as long as it is pharmaceutically acceptable, and for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid , benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and the like can be used.
본 발명의 "탈모"는, 그 원인과 무관하게, 정상적으로 모발이 존재해야 할 부위에 모발이 없는 상태를 지칭하며, 원형 탈모, 유전성 안드로겐 탈모, 휴지기 탈모, 외상성 탈모, 발모벽, 압박성 탈모, 생장기 탈모, 비강성 탈모, 매독성 탈모, 지루 탈모, 증후성 탈모, 반흔성 탈모 또는 선천성 탈모일 수 있으나, 이로 제한되지 않는다. "Hair loss" of the present invention, regardless of the cause, refers to a state in which there is no hair in the site where hair should normally exist, and includes alopecia areata, hereditary androgen hair loss, telogen hair loss, traumatic hair loss, hair growth wall, pressure hair loss, It may be, but is not limited to, genital hair loss, alopecia pityis, syphilitic hair loss, seborrheic hair loss, symptomatic hair loss, scarring hair loss, or congenital hair loss.
본 발명의 상기 화합물은 모유두 세포 및/또는 외측 모근초 세포의 증식을 촉진하여 모발의 성장기를 유도함으로써, 탈모 예방 또는 치료 효과를 나타낼 수 있다.The compound of the present invention promotes the proliferation of dermal papilla cells and/or outer hair root sheath cells to induce hair growth, thereby preventing or treating hair loss.
본 발명의 "치료"는, 본 발명 조성물의 투여로 탈모 진행이 지연 또는 멈춰 탈모 증세를 호전시키거나, 모발이 길어지거나 수가 많아지는 등의 발모 및 육모가 촉진되는 등의 탈모 증세를 이롭게 변경하는 모든 행위를 의미한다."Treatment" of the present invention is to improve hair loss symptoms by delaying or stopping hair loss by administration of the composition of the present invention, or to beneficially change hair loss symptoms such as hair growth and hair growth promotion, such as lengthening or increasing the number of hair means all actions.
본 발명의 약학 조성물은 목적하는 방법에 따라 비경구투여 또는 경구 투여할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다. 또한 상기 조성물의 치료적으로 유효한 양은 투여방법, 목적부위, 환자의 상태에 따라 달라질 수 있으며, 인체에 사용시 투여량은 안전성 및 효율성을 함께 고려하여 적정량으로 결정되어야 한다.The pharmaceutical composition of the present invention may be administered parenterally or orally according to a desired method, and the dosage may vary depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of disease, etc. Its scope is diverse. In addition, the therapeutically effective amount of the composition may vary depending on the administration method, the target site, and the condition of the patient.
일 실시태양에서, 본 발명의 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 연질 또는 경질 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 연고, 크림 등의 피부 외용제, 좌제, 주사제 및 멸균주사용액 등을 비롯하여 약제학적 제제에 적합한 어떠한 형태로든 제형화하여 사용될 수 있다. In one embodiment, the pharmaceutical composition of the present invention is an oral dosage form such as powders, granules, tablets, soft or hard capsules, suspensions, emulsions, syrups, and aerosols, ointments, creams, etc., according to a conventional method, respectively. , suppositories, injections, and sterile injection solutions may be formulated and used in any form suitable for pharmaceutical preparations.
상기 제제화를 위해 통상 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제, 희석제 등의 부형제를 추가로 포함할 수 있다. 예를 들어, 본 발명의 약학 조성물에 포함될 수 있는 부형제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 메틸히드록시 벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 사용할 수 있으나, 이에 제한되지 않는다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.It may further include excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, diluents, etc. commonly used for the formulation. For example, excipients that may be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate , cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, mineral oil, and the like may be used, but is not limited thereto. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명은 또한 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 포함하는 탈모 예방 또는 개선용 화장료 조성물을 제공한다. 구체적으로, 화장료 조성물로는 예를 들어, 모발용 화장료일 수 있고, 그 제형은 특별히 제한되지 않으며, 목적하는 바에 따라 적절히 선택할 수 있다.The present invention also provides a cosmetic composition for preventing or improving hair loss comprising the compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the cosmetic composition may be, for example, a cosmetic for hair, the formulation thereof is not particularly limited, and may be appropriately selected according to the purpose.
예를 들면, 상기 화장료 조성물은 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 샴푸, 린스, 바디클렌저 등의 세정료, 헤어토닉, 젤 또는 무스 등의 정발제, 양모제 또는 염모제 등의 모발용 화장료 조성물 일 수 있다.For example, the cosmetic composition is formulated as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation and spray. may be, but is not limited thereto. More specifically, it may be a cleaning agent such as shampoo, conditioner, and body cleanser, hair dressing agent such as hair tonic, gel or mousse, and a cosmetic composition for hair such as a hair conditioner or hair dye.
본 발명의 일 실시태양에서 상기 화장료 조성물은 필요에 따라 적절한 각종의 기제와 첨가제를 함유할 수 있으며, 이들 성분의 종류와 양은 발명자에 의해 용이하게 선정될 수 있다. 필요에 따라 허용 가능한 첨가제를 함유할 수 있으며, 예를 들면, 당업계에 통상적인 방부제, 색소, 첨가제 등의 성분을 추가로 포함할 수 있다.In one embodiment of the present invention, the cosmetic composition may contain various suitable bases and additives as necessary, and the types and amounts of these components can be easily selected by the inventor. It may contain acceptable additives as necessary, for example, may further include components such as preservatives, pigments, and additives conventional in the art.
또다른 실시태양에서, 본 발명은 또한 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 포함하는 탈모 예방 또는 개선용 식품 조성물, 예를 들어, 건강기능식품을 제공한다. 상기 "건강기능식품"은 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다. In another embodiment, the present invention also provides a food composition for preventing or improving hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient, for example, a health functional food. The "health functional food" means a food manufactured and processed using raw materials or ingredients useful for the human body, and "functionality" means a health purpose such as regulating nutrients or physiological action with respect to the structure and function of the human body. It means to consume for the purpose of obtaining a useful effect.
상기 식품 조성물의 제형은 특별히 한정되지 않으나, 예를 들어, 정제, 과립제, 분말제, 드링크제와 같은 액제, 캐러멜, 겔, 바 등으로 제형화될 수 있다. 각 제형의 식품 조성물은 유효 성분 이외에 해당 분야에서 통상적으로 사용되는성분들을 제형 또는 사용 목적에 따라 당업자가 어려움 없이 적의 선정하여 배합할 수 있다.The formulation of the food composition is not particularly limited, but, for example, may be formulated as tablets, granules, powders, liquids such as drinks, caramel, gels, bars, and the like. In addition to the active ingredient, the food composition of each dosage form can be formulated without difficulty by those skilled in the art without difficulty depending on the dosage form or purpose of use of ingredients commonly used in the field.
이하 실시예를 통하여 본 발명을 더욱 상세하게 설명하고자 하나, 하기의 실시예는 단지 설명의 목적을 위한 것이며 본원 발명의 범위를 한정하고자 하는 것은 아니다.The present invention will be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
[실시예 1] [Example 1]
모낭의 모유두 세포(DPC) 및 외측 모근초 세포(ORS)의 증식 측정Measurement of proliferation of dermal papilla cells (DPC) and lateral root sheath cells (ORS) of hair follicles
본 발명의 화합물이 모낭의 모유두 세포(DPC) 및 외측 모근초 세포(ORS)의 증식에 미치는 영향을 확인하기 위해, 각 세포에 본 발명의 화합물을 처리한 후 세포 증식을 분석하였다. To determine the effect of the compound of the present invention on the proliferation of dermal papilla cells (DPC) and outer root sheath cells (ORS) of hair follicles, cell proliferation was analyzed after each cell was treated with the compound of the present invention.
2 x 10
3개의 모유두 세포 및 외측 모근초 세포 각각을 별도의 96-well 플레이트에 접종하고 24시간 후에 화학식 II의 화합물을 1 nM 내지 10 μM의 농도로 72시간 동안 처리하였다. 그 후, 배지를 제거하고 CCK-8 분석 키트 (Dojindo, Japan)를 사용하여 10% CCK-8 용액을 세포에 2시간 동안 처리한 후, 450 nm에서 흡광도를 측정하여 세포수를 확인하였다.Each of 2 x 10 3 dermal papilla cells and outer hair root sheath cells was inoculated in a separate 96-well plate, and 24 hours later, the compound of Formula II was treated at a concentration of 1 nM to 10 μM for 72 hours. Thereafter, the medium was removed and the cells were treated with 10% CCK-8 solution for 2 hours using a CCK-8 assay kit (Dojindo, Japan), and then the absorbance was measured at 450 nm to determine the number of cells.
그 결과는 도 1 및 2에 나타낸 바와 같이, 모유두 세포 및 외측 모근초 세포에 화학식 II의 화합물을 처리한 경우 이를 처리하지 않은 대조군에 비해 세포 증식이 증가하였다. 특히 1 μM을 처리한 모유두 세포의 증식은 대조군에 비해 약 10% 증가하였고, 특히 1 nM 내지 1 μM을 처리한 외측 모근초 세포의 증식은 대조군에 비해 약 40% 이상 증가하였다. As a result, as shown in FIGS. 1 and 2, when the dermal papilla cells and the outer hair root sheath cells were treated with the compound of Formula II, cell proliferation was increased compared to the control group not treated therewith. In particular, the proliferation of dermal papilla cells treated with 1 μM was increased by about 10% compared to the control group, and in particular, the proliferation of lateral root sheath cells treated with 1 nM to 1 μM was increased by about 40% or more compared to the control group.
이로부터 본 발명의 화합물은 모낭의 모유두 세포 및 외측 모근초 세포의 증식에 효과적임이 확인되었다.From this, it was confirmed that the compound of the present invention is effective for the proliferation of dermal papilla cells and outer root sheath cells of hair follicles.
[실시예 2] [Example 2]
모낭의 외측 모근초 세포의 이동 효과 확인Confirmation of migration effect of outer hair root sheath cells of hair follicles
본 실시예에서는 본 발명의 화합물에 의한 모낭의 외측 모근초 세포(ORS)의 이동 효과를 확인하고자 하였다.In this example, the effect of the compound of the present invention on the migration of outer hair follicle sheath cells (ORS) of hair follicles was confirmed.
60 mm 배양접시에 외측 모근초 세포(ORS)를 5×10
5농도로 접종하였다. 하룻밤 동안 배양한 후 블루(1000 μL)팁을 이용하여 접시 바닥에 스크래치를 내주었다. 화학식 II의 화합물 (1 μM)을 처리한 후 48 시간 동안 추가 배양하였다. 양쪽의 세포들이 스크래치 중간 위치를 향해 이동한 거리를 측정하여, 세포 이주능을 확인하였다.The outer hair root sheath cells (ORS) were inoculated at a concentration of 5×10 5 in a 60 mm culture dish. After overnight incubation, a blue (1000 μL) tip was used to scratch the bottom of the dish. After treatment with the compound of formula II (1 μM), it was further cultured for 48 hours. Cell migration ability was confirmed by measuring the distance the cells on both sides moved toward the middle position of the scratch.
그 결과, 도 3 및 4에 나타난 바와 같이 화학식 II의 화합물 처리군에서 배양한 외측 모근초 세포의 이동이 대조군 대비 월등하게 증가함을 확인할 수 있었다.As a result, as shown in FIGS. 3 and 4 , it was confirmed that the migration of the outer hair root sheath cells cultured in the compound treated group of Formula II was significantly increased compared to the control group.
[실시예 3] [Example 3]
모발 성장 효과 측정Measurement of hair growth effect
본 실시예에서는 본 발명의 화합물의 실제 모낭에서의 모발 성장 효과를 확인하고자 하였다. 이를 위해 콧수염 모낭에 화학식 II의 화합물을 처리하여 성장한 모발의 길이를 측정하였다.In this example, the effect of the compound of the present invention on hair growth in actual hair follicles was confirmed. To this end, the length of hair grown by treating the compound of Formula II in mustache hair follicles was measured.
해부 현미경으로 관찰하며 성장기 콧수염 모낭(anagen vibrissa follicles)을 조심스럽게 분리하였다. 48-well 플레이트의 각 웰에 2 mM L-글루타민, 10 μg/mL 인슐린, 10 ng/mL 하이드로코르티손, 100 U/mL 페니실린 및 혈청 없는 100 μg/mL 스트렙토마이신이 첨가된 윌리엄스 E 배지를 넣고, 각 웰에 분리한 모낭을 하나씩 넣어 37°C, 5% CO
2 항온기에서 배양하였다. 화학식 II의 화합물을 0.1 μM 및 1 μM의 농도로 처리하였다. 72 시간 동안 배양한 후 개별 모낭을 촬영하였다(Edmund Optics Ltd, UK). 모낭으로부터 자라난 콧수염 모발 약 8~10개의 길이를 측정하여 이의 평균값을 구하였다.Observation under a dissecting microscope, anagen vibrissa follicles were carefully isolated. Add Williams E medium supplemented with 2 mM L-glutamine, 10 µg/mL insulin, 10 ng/mL hydrocortisone, 100 U/mL penicillin, and 100 µg/mL streptomycin without serum to each well of a 48-well plate, Separated hair follicles were put into each well and incubated at 37 °C, 5% CO 2 incubator. Compounds of formula II were treated at concentrations of 0.1 μM and 1 μM. After incubation for 72 hours, individual hair follicles were photographed (Edmund Optics Ltd, UK). The length of about 8 to 10 mustache hairs grown from the hair follicles was measured and the average value thereof was obtained.
그 결과는 도 5 및 6에 나타낸 바와 같이, 모낭에 화학식 II의 화합물을 처리한 경우 이를 처리하지 않은 대조군에 비해 콧수염 모발의 길이가 증가하였다. As a result, as shown in FIGS. 5 and 6, when the hair follicles were treated with the compound of Formula II, the length of the mustache hair was increased compared to the control group not treated therewith.
이로부터 본 발명의 화합물은 실제 모낭에서의 모발 성장에 효과적임이 확인되었다.From this, it was confirmed that the compound of the present invention is effective for hair growth in actual hair follicles.
Claims (8)
- 하기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 포함하는 탈모 예방 또는 치료용 약학 조성물:A pharmaceutical composition for preventing or treating hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient:[화학식 I][Formula I]
상기 식에서,In the above formula,R은 하기 치환기로 이루어지는 군으로부터 선택된 것이다:R is selected from the group consisting of the following substituents:
,
,,
,,
,,
,및
and.
. - 제1항에 있어서, R은인 것을 특징으로 하는, 약학 조성물.The method of claim 1, wherein R is
Characterized in that, the pharmaceutical composition. - 제2항에 있어서, R에서 입체중심 *는 S형의 입체구조를 갖는 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 2, wherein the stereocenter * in R has an S-shaped stereostructure.
- 하기 화학식 II의 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 포함하는 탈모 예방 또는 치료용 약학 조성물:A pharmaceutical composition for preventing or treating hair loss comprising a compound of Formula II or a pharmaceutically acceptable salt thereof as an active ingredient:[화학식 II][Formula II]
- 제1항 내지 제4항 중 어느 한 항에 있어서, 상기 탈모는 원형 탈모, 유전성 안드로겐 탈모, 휴지기 탈모, 외상성 탈모, 발모벽, 압박성 탈모, 생장기 탈모, 비강성 탈모, 매독성 탈모, 지루 탈모, 증후성 탈모, 반흔성 탈모 및 선천성 탈모로 이루어진 그룹으로부터 선택된 것인, 약학 조성물.The hair loss according to any one of claims 1 to 4, wherein the hair loss is alopecia areata, hereditary androgenic alopecia, telogen hair loss, traumatic hair loss, hair growth wall, pressure hair loss, anagen phase hair loss, alopecia areata, syphilitic hair loss, seborrheic hair loss , A pharmaceutical composition that is selected from the group consisting of symptomatic alopecia, scarring alopecia and congenital alopecia.
- 제1항 내지 제4항 중 어느 한 항에 있어서, 상기 화합물은 모유두 세포 또는 외측 모근초 세포의 증식을 촉진하여 모발의 성장기를 유도하는 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to any one of claims 1 to 4, wherein the compound promotes proliferation of dermal papilla cells or lateral hair root sheath cells to induce hair growth phase.
- 하기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 포함하는 탈모 예방 또는 개선용 화장료 조성물:A cosmetic composition for preventing or improving hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient:[화학식 I] [Formula I]
상기 식에서,In the above formula,R은 하기 치환기로 이루어지는 군으로부터 선택된 것이다:R is selected from the group consisting of the following substituents:,
,,
,,
,,
,,
,및
and.
. - 하기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 포함하는 탈모 예방 또는 개선용 식품 조성물:A food composition for preventing or improving hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient:[화학식 I][Formula I]
상기 식에서,In the above formula,R은 하기 치환기로 이루어지는 군으로부터 선택된 것이다:R is selected from the group consisting of the following substituents:
,
,,
,,
,,
,및
and.
.
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| KR10-2019-0176082 | 2019-12-27 |
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| WO2003062261A2 (en) * | 2001-12-21 | 2003-07-31 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Dmt-tic di- and tri-peptidic derivatives and related compositions and methods of use |
| WO2008016913A1 (en) * | 2006-07-31 | 2008-02-07 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Biologically potent analogues of the dmt-tic pharmacophore and methods of use |
-
2019
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| WO2003062261A2 (en) * | 2001-12-21 | 2003-07-31 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Dmt-tic di- and tri-peptidic derivatives and related compositions and methods of use |
| WO2008016913A1 (en) * | 2006-07-31 | 2008-02-07 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Biologically potent analogues of the dmt-tic pharmacophore and methods of use |
Non-Patent Citations (3)
| Title |
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| AGUILA B, COULBAULT L, BOULOUARD M, LΙVEILLΙ F, DAVIS A, TΣTH G, BORSODI A, BALBONI G, SALVADORI S, JAUZAC P, ALLOUCHE S: "In vitro and in vivo pharmacological profile of UFP-512, a novel selective δ-opioid receptor agonist; correlations between desensitization and tolerance : UFP-512: a novel DOP receptor agonist", BRITISH JOURNAL OF PHARMACOLOGY, WILEY-BLACKWELL, UK, vol. 152, no. 8, 1 December 2007 (2007-12-01), UK, pages 1312 - 1324, XP055825011, ISSN: 0007-1188, DOI: 10.1038/sj.bjp.0707497 * |
| BALBONI, G. ET AL.: "Evaluation of the Dmt-Tic pharmacophore: conversion of a potent delta-opioid receptor antagonist into a potent delta agonist and ligands with mixed properties.", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 45, no. 3, 1 January 2002 (2002-01-01), pages 713 - 720, XP002247105, ISSN: 0022-2623, DOI: 10.1021/jm010449i * |
| TORTELLY VIOLETA DUARTE, TAYNARA DE MATTOS, LARISSA STARLING DE ALBUQUERQUE FERNANDES, BRUNAO EDUARDO MORAIS NUNES, DANIEL FERMAND: "Low-dose naltrexone: a novel adjunctive treatment in symptomatic alopecias?", DERMATOLOGY ONLINE JOURNAL, 1 January 2019 (2019-01-01), XP055825003, Retrieved from the Internet <URL:https://escholarship.org/uc/item/6j45h81f> * |
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