WO2022114152A1 - サーチュイン６活性化剤 - Google Patents

サーチュイン６活性化剤 Download PDF

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Publication number
WO2022114152A1
WO2022114152A1 PCT/JP2021/043488 JP2021043488W WO2022114152A1 WO 2022114152 A1 WO2022114152 A1 WO 2022114152A1 JP 2021043488 W JP2021043488 W JP 2021043488W WO 2022114152 A1 WO2022114152 A1 WO 2022114152A1
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WO
WIPO (PCT)
Prior art keywords
urolithin
sirtuin
activator
sirt6
present disclosure
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2021/043488
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English (en)
French (fr)
Japanese (ja)
Inventor
浩明 山本
喜範 片倉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daicel Corp
Kyushu University NUC
Original Assignee
Daicel Corp
Kyushu University NUC
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Publication date
Application filed by Daicel Corp, Kyushu University NUC filed Critical Daicel Corp
Priority to US18/038,821 priority Critical patent/US20240000747A1/en
Priority to JP2022565469A priority patent/JPWO2022114152A1/ja
Publication of WO2022114152A1 publication Critical patent/WO2022114152A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair

Definitions

  • SIRT1-7 are known as mammalian homologues of yeast Sir2, among which SIRT6 is localized in the cell nucleus (for example, human keratinized cells and cutaneous fibroblasts), and the SIRT6 protein translated from the SIRT6 gene is It has been reported that it is useful as an early indicator marker of aging (Non-Patent Document 1).
  • SIRT6 activators have been reported for the purpose of enhancing the action and effect of SIRT6.
  • a peptide consisting of carnosine and / or anserine (Patent Document 1) and the amino acid sequence of GAGVSAE-NH 2 (Patent Document 2) has been reported.
  • SIRT6 activators reported so far, for example, in the case of carnosine, ⁇ -alanine that can cause numbness is generated during digestion, and in the case of anserine, a peculiar unpleasant odor (fishy odor) derived from the raw material is generated. ), And in the case of a specific peptide, it cannot be taken orally. Therefore, it is desired that there is another new option as an active ingredient capable of activating SIRT6.
  • the present inventor confirmed the SIRT6 gene activity enhancing effect on urolithin A, punicalin, precarazine, and caffestol, which are known as components capable of enhancing SIRT1 gene activity. It was found that urolithin has an effect of enhancing the activity of the sirtuin 6 gene, whereas no enhancing effect was observed. This disclosure has been completed by further studies based on this finding.
  • Item 7. A treatment or preventive agent for white hair containing urolithin as an active ingredient.
  • Item 8. Use of urolithin for the production of sirtuin 6 activator.
  • Item 9. A method for treating or preventing hair loss, which comprises a step of administering a therapeutic or prophylactically effective amount of urolithin to a subject of a disease or condition in which hair loss occurs, or a subject at risk of hair loss due to genetic or physical factors.
  • Item 10. A method for treating or preventing white hair, which comprises a step of administering a therapeutically or prophylactically effective amount of urolithin to a subject having gray hair or a subject having a risk of graying due to genetic or physical factors.
  • urolithin A is preferably mentioned from the viewpoint of obtaining an even more excellent sirtuin 6 gene activity enhancing effect.
  • the method for synthesizing urolithin is not particularly limited, and examples thereof include chemical synthesis and microbiological synthesis.
  • 2-bromo-5-methoxybenzoic acid is used as a starting material, converted to 2-bromo-5-hydroxybenzoic acid by demethylation, and further reacted with resorcinol to cause urolithin A. There is a method to obtain.
  • An example of a method for microbiologically synthesizing urolithin is a method in which a urolithin-producing microorganism is fermented to produce urolithin from ellagic acid in a medium containing ellagic acid, and the produced urolithins are recovered to obtain urolithin. Be done.
  • the microorganisms producing urolithins are not particularly limited, but Bacteroides spp., Gordonibacter spp. Are preferred, and Bacteroides uniformis spp., Gordonibacter urolithinfaciens spp. Examples include Bacteroides uniformis HGB5B146 (NITE BP-02193) strain, Gordonibacter urolithinfaciens DSM27213 strain, and Gordonibacter pamelaeae DSM19378 strain.
  • the content of urolithin is not particularly limited as long as it is an amount that enables administration or ingestion of an effective amount that enhances the activity of the sirtuin 6 gene in vivo.
  • the content of urolithin can be appropriately adjusted according to the intended use, dosage form, administration form, etc., and as a specific example, 0.01 to 50% by weight, The amount is preferably 0.1 to 20% by weight.
  • sirtuin 6 activator of the present disclosure is used for activating sirtuin 6 (SIRT6).
  • SIRT6 means enhancing the activity of the SIRT6 gene, not limited to either in vivo or in vitro, and more specifically, enhancing the transcription or expression of the SIRT6 gene.
  • the presence or absence and degree of SIRT6 activation action can be evaluated by constructing a system using the promoter region (SEQ ID NO: 1) of the SIRT6 gene.
  • the sirtuin 6 activator in one embodiment of the present disclosure is used for treating or preventing hair loss, for suppressing hair follicle stem cell aging, and / or for treating white hair, based on sirtuin 6 activation.
  • it can be used for preventive purposes. That is, in one embodiment of the present disclosure, a treatment or preventive agent for hair loss containing urolithin as an active ingredient, a hair follicle stem cell aging inhibitor containing urolithin as an active ingredient, and a treatment or preventive agent for white hair containing urolithin as an active ingredient are also used.
  • a treatment or preventive agent for hair loss containing urolithin as an active ingredient a hair follicle stem cell aging inhibitor containing urolithin as an active ingredient
  • a treatment or preventive agent for white hair containing urolithin as an active ingredient are also used. Provided.
  • the specific application target of the treatment or preventive agent for hair loss in one embodiment of the present disclosure is a subject of a disease or condition in which hair loss is actually occurring, or a subject at risk of hair loss due to genetic factors or physical factors. All you need is.
  • alopecia other than male pattern baldness can be mentioned, and specific examples thereof include female pattern baldness and alopecia areata.
  • alopecia areata risk genotype (specifically, T allogene of SNP rs142896308 present in CCHCR1 gene), chemotherapeutic treatment, vitamin A excess disease, malnutrition (for example, iron) Deficiency, zinc deficiency, etc.), stress (specifically, physical or mental stress associated with high fever, surgery, illness, weight loss, pregnancy, etc.) and the like.
  • Specific application targets of the hair follicle stem cell aging inhibitor and the treatment or preventive agent for white hair in one embodiment of the present disclosure include a subject in which hair follicle stem cell aging or white hair is actually occurring, or a genetic factor or physical. Any subject may be used as long as it has a risk of aging or graying of hair follicle stem cells depending on the factors. For example, as the risk of aging or graying of hair follicle stem cells due to genetic factors, the T allele of SNP rs12203592 present in the intron 4 of the graying risk genotype (specifically, the interferon regulator 4 gene (IRF4)) ) Is owned.
  • examples of the risk of aging or graying of hair follicle stem cells due to physical factors include poor blood circulation in the scalp (for example, reddish scalp), mental stress, and the like.
  • the sirtuin 6 activator in one embodiment of the present disclosure is oral or parenteral (eg, transdermal, transmucosal (nasal, transintestinal, etc.), transvascular (transtrans)) to a subject for which SIRT6 activation is desirable. It can be administered or ingested by intra-arterial or transvenous).
  • the dose or ingestion of the sirtuin 6 activator of the present disclosure to a subject in which activation of SIRT6 is desirable may be determined by a person skilled in the art depending on the age, weight, gender, applicable disease or condition of the subject. It is set appropriately.
  • the dose or intake of the sirtuin 6 activator in one embodiment of the present disclosure may be, for example, 0.1 to 10,000 mg / day, preferably 0.1 to 10,000 mg / day, as the dose or intake of the active ingredient urolithin. 1 to 100 mg / day can be mentioned, and these daily doses or intakes can be administered or ingested at one time or in a plurality of times (for example, 2 to 3 times).
  • the dosage form of the sirtuin 6 activator of the present disclosure is not particularly limited.
  • the dosage form of the sirtuin 6 activator in one embodiment of the present disclosure may be solid, semi-solid, or liquid, and the type of active ingredient, the use of the sirtuin 6 activator, and the use of the sirtuin 6 activator. / Or can be appropriately set by those skilled in the art according to the administration method and the like.
  • the sirtuin 6 activator in one embodiment of the present disclosure can be used as a constituent component of, for example, pharmaceuticals, quasi-drugs, cosmetics, foods and the like.
  • pharmaceuticals for example, pharmaceuticals, quasi-drugs, cosmetics, foods and the like.
  • other ingredients those skilled in the art can appropriately select ingredients generally used in pharmaceutical products, quasi-drugs, cosmetics, and foods.
  • Specific examples of other ingredients include pharmaceutically, food-based, or cosmetically acceptable excipients, disintegrants, diluents, lubricants, flavoring agents, colorants, sweeteners, etc.
  • the thirtuin 6 activator in one embodiment of the present disclosure is used as a constituent of a drug, non-pharmaceutical product, cosmetics, or food
  • the form of the drug, non-pharmaceutical product, cosmetics, or food is oral.
  • tablets, capsules, powders, granules, fine granules, sustained-release agents, solutions, syrups, jelly emulsions, etc. are included, and for those intended for parenteral administration, Examples thereof include injections, ointments, lotions, emulsions, creams, powders and the like.
  • the sirtuin 6 activator in one embodiment of the present disclosure is used as a constituent of a food
  • the types of the food include general foods and drinks, health functional foods (foods for specified health use, nutritional functional foods, supplements). Etc.), foods for the sick, etc.
  • SIRT6p-NheI GCTAGCCCTCGACTGCCCCACGGGAA: SEQ ID NO: 3
  • KOD FX TOYOBO
  • PCR was performed under 40 cycles of reaction conditions, with 94 ° C. for 2 minutes, 98 ° C. for 10 seconds, and 68 ° C. for 1 minute as one cycle.
  • the SIRT6 promoter fragment obtained by PCR was TA cloned into pGEM-T Easy Vector (Promega). In addition, the base sequence was confirmed by sequencing.
  • the SIRT6 promoter fragment incorporated into the pGEM-T Easy vector was excised by the restriction enzymes AseI and NheI digestion, and the CMV promoter of EGFP-C3 (manufactured by Takara Bio Inc.) was inserted into the site removed by the AseI and NheI digestion, and pSIRT6p- Obtained EGFP.
  • Caco-2-SIRT6p-EGFP cells were seeded in 96-well plates at 0.6 ⁇ 10 4 cells / well. The next day, 10 ⁇ M of test ingredient (urolithin A, punicalin, precarazine, or cafestol) or control (PBS) was added to each well. Two days after the addition, the culture was aspirated, then 100 ⁇ L of 4% paraformaldehyde was added to each well and allowed to stand at room temperature for 10 minutes.
  • test ingredient urolithin A, punicalin, precarazine, or cafestol
  • PBS control
  • FIG. 1 The obtained results (effect of SIRT6 on promoter activity when the test component is added to Caco-2-SIRT6p-EGFP cells) are shown in FIG.
  • the vertical axis represents the relative SIRT6 promoter activity, and the higher the value, the stronger the promoter activity.
  • punicalin, precarazine, and cafestol which are known to have a sirtuin 1 gene enhancing effect, have little or no SIRT6 promoter enhancing activity, whereas urolithin A has a strong SIRT6 promoter enhancing activity. was confirmed.
  • SEQ ID Nos: 2 and 3 are primers.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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  • Polymers & Plastics (AREA)
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PCT/JP2021/043488 2020-11-26 2021-11-26 サーチュイン６活性化剤 Ceased WO2022114152A1 (ja)

Priority Applications (2)

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US18/038,821 US20240000747A1 (en) 2020-11-26 2021-11-26 Sirtuin 6 activator
JP2022565469A JPWO2022114152A1 (https=) 2020-11-26 2021-11-26

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JP2020-195763 2020-11-26
JP2020195763 2020-11-26

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023228994A1 (ja) * 2022-05-25 2023-11-30 株式会社ダイセル Ｓｉｒｔ３遺伝子発現増強用組成物
WO2025070552A1 (ja) * 2023-09-29 2025-04-03 株式会社ダイセル ウロリチン類を含有する、肌改善用組成物又は髪改善用組成物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014042261A1 (ja) * 2012-09-13 2014-03-20 森下仁丹株式会社 サーチュイン遺伝子活性増強剤ならびにそれを用いた医薬品、化粧品、および食品
WO2019211294A1 (en) * 2018-04-30 2019-11-07 Amazentis Sa Urolithin a as immune enhancer
WO2020153434A1 (ja) * 2019-01-25 2020-07-30 第一三共株式会社 ピラゾール化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014042261A1 (ja) * 2012-09-13 2014-03-20 森下仁丹株式会社 サーチュイン遺伝子活性増強剤ならびにそれを用いた医薬品、化粧品、および食品
WO2019211294A1 (en) * 2018-04-30 2019-11-07 Amazentis Sa Urolithin a as immune enhancer
WO2020153434A1 (ja) * 2019-01-25 2020-07-30 第一三共株式会社 ピラゾール化合物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023228994A1 (ja) * 2022-05-25 2023-11-30 株式会社ダイセル Ｓｉｒｔ３遺伝子発現増強用組成物
WO2025070552A1 (ja) * 2023-09-29 2025-04-03 株式会社ダイセル ウロリチン類を含有する、肌改善用組成物又は髪改善用組成物

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