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WO2000047172A1 - Agent de stimulation de la croissance capillaire et recherche systematique de substances ayant cet effet - Google Patents

Agent de stimulation de la croissance capillaire et recherche systematique de substances ayant cet effet Download PDF

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Publication number
WO2000047172A1
WO2000047172A1 PCT/JP2000/000694 JP0000694W WO0047172A1 WO 2000047172 A1 WO2000047172 A1 WO 2000047172A1 JP 0000694 W JP0000694 W JP 0000694W WO 0047172 A1 WO0047172 A1 WO 0047172A1
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WIPO (PCT)
Prior art keywords
adenosine
compound
receptor
hair restorer
action
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
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PCT/JP2000/000694
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English (en)
Japanese (ja)
Inventor
Yutaka Nakaya
Seiji Arase
Koji Imamura
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Taisho Pharmaceutical Co Ltd filed Critical Taisho Pharmaceutical Co Ltd
Priority to AU24591/00A priority Critical patent/AU2459100A/en
Publication of WO2000047172A1 publication Critical patent/WO2000047172A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
    • 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
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/606—Nucleosides; Nucleotides; Nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/70—Biological properties of the composition as a whole

Definitions

  • the present invention relates to a hair restorer, particularly to a hair restorer which can be used as various external preparations and has a novel action mechanism exhibiting excellent efficacy.
  • the present invention also relates to a method for screening a substance having a hair-growth action, and more particularly to a method for screening a hair-growth substance having a novel action mechanism.
  • Such drugs include, for example, vasodilators, male hormone receptor inhibitors, steroid-5-hydroxylase inhibitors, vitamins, immunosuppressants and the like.
  • vasodilators include, for example, vasodilators, male hormone receptor inhibitors, steroid-5-hydroxylase inhibitors, vitamins, immunosuppressants and the like.
  • steroid-5-hydroxylase inhibitors include, for example, steroid-5-hydroxylase inhibitors, vitamins, immunosuppressants and the like.
  • the effectiveness of these drugs as hair restorers is not currently satisfactory.
  • mice such as mice, rats, egrets, and guinea pigs, especially C3H mice and C57BL mice of appropriate age, mainly shaved the back hair, and apply a test substance to determine the degree of hair growth.
  • Method of observing mouse hair, human hair, etc. culturing the obtained hair tissue in organs, adding a test substance to evaluate the degree of growth, or converting the hair tissue to the cellular level.
  • male hormones are involved in the onset of androgenetic hair loss in particular, male hormone receptor inhibition tests and the enzyme steroid-5, an enzyme that converts the male hormone testosterone to dihydrotestosterone, are considered.
  • a test for the inhibition of redakase has also been applied. Disclosure of the invention
  • An object of the present invention is to provide a hair restorer having a superior hair growth effect as compared with a conventional hair restorer.
  • Another object of the present invention is to provide a screening method for providing an excellent hair restorer having a novel action mechanism different from that of a conventional hair restorer.
  • One embodiment of the present invention enhances the action of a compound having a purine receptor stimulating action, a compound having a purine receptor stimulating action after application to a living body, or a compound having a purine receptor stimulating action. It is a hair restorer containing one or more compounds as active ingredients.
  • the “purine receptor stimulating action” refers to an action of stimulating a purine receptor to cause a certain phenomenon to cells, and usually such stimulation is caused by a purine receptor and the purine receptor. It is brought about by interaction with substances that can specifically bind to purine receptors.
  • a compound which releases a compound having a purine receptor stimulating action after being applied to a living body is a compound which has a purinergic receptor stimulating action after application or administration to skin, mucous membrane, body tissue, or the like.
  • a compound having a function of separating and releasing a compound and is usually a compound obtained by subjecting a compound having a purin receptor stimulating action to some chemical modification.
  • Specific examples of the chemical modification include operations such as esterification and amidation.
  • the compound having a purine receptor stimulating action of the present invention includes a compound having a stimulating action on adenosine receptor and / or ATP receptor.
  • Examples of the compound having the adenosine receptor stimulation of the present invention include adenosine, N 6 -cyclohexyl adenosine, N 6 -cyclopentyl adenosine, (R) -N 6 -phenylisopropyl adenosine, and (S) -N 6 -f Enylisoprovir adeno Synth, (R) -phenylisoproviradenosine, N— [R— (2-benzothiazolyl) thio-2-probyl] -1-chloroadenosine, 2-chloro-N6-cyclopentyladenosine, N— (methyl-phenene Til) Adenosine, minoprinii-Rudeoxy N-ethyl ribofuranuroamide, defibuchitide, 5,1-N-ethyl carboxamide adenosine, 2-chloroadenosine, N
  • the compound having the adenosine receptor stimulating action or the compound releasing the compound having the adenosine receptor stimulating action after application to the living body is represented by the following formula 1:
  • n is 0 or 1
  • 1 ⁇ to 11 2 each represent a hydrogen atom or a Ashiru group having 1 to 5 carbon atoms
  • R 3 represents a hydrogen atom or a protecting group. ] It may be the compound shown by these.
  • an uptake inhibitor of the compound having the adenosine receptor stimulating action is preferable.
  • the term “uptake inhibitor” refers to a compound having an action of inhibiting absorption and uptake of a target compound into cells or tissues.
  • the uptake inhibitor Preference is given to diviridamol, diracep, lidofrazine, hexobendine, carbochromene, chromonalic acid, cinepadizide, diazepam, papaverine, 6- (2,1-hydridoxoxynitrobenzyl) thioguanosine, and proventophilin.
  • the compound that enhances the action of the compound having the adenosine receptor stimulating action may be an inactivation inhibitor of the compound having the adenosine receptor stimulating action.
  • the term “inactivation inhibitor” refers to a compound having an action of inhibiting a decrease in a certain property, function or action of a target compound. Therefore, an inactivation inhibitor of a compound having an adenosine receptor stimulating action has a function of preventing a decrease in the adenosine receptor stimulating action of the compound.
  • the inactivation inhibitor of the compound having adenosine receptor stimulating activity 2, -deoxycoformycin and erythro 9_ (2-hydroxy-13-nonyl) adenine are preferable.
  • Another embodiment of the present invention is a hair restorer comprising, as an active ingredient, one or more compounds having an ATP receptor stimulating action.
  • Examples of the compound having an ATP receptor stimulating action of the present invention include adenosine diphosphate, adenosine triphosphate and derivatives thereof, and among them, adenosine_5, monophosphate, adenosine-15′-trilin Acids and their derivatives are preferred.
  • adenosine diphosphate adenosine triphosphate and derivatives thereof
  • adenosine_5 monophosphate
  • adenosine-15′-trilin Acids and their derivatives are preferred.
  • an ester derivative is preferable.
  • adenosine-15, diphosphate derivative and the adenosine-5, monotriphosphate derivative have the following formula 2:
  • n 2 or 3 1 ⁇ to 11 2 indicates it it hydrogen atom or Ashiru group having 1 to 5 carbon atoms
  • R 3 represents a hydrogen atom or a protecting group. It may be the compound shown by these.
  • adenosine mono- and mono-diphosphate derivatives examples include ⁇ ,? -Methylene adenosine-5, mono-diphosphate, 2-methylthioadenosine_5'-diphosphate, 2,1-benzoyl adenosine-15, mono-diphosphate, and 3-diphosphate.
  • 1-benzoyladenosine-15, dilic acid is preferred.
  • the adenosine 15-monotriphosphate derivatives include: -methyleneadenosine 15-monotriphosphate, 2-methylthioadenosine 15-monotriphosphate, 2,1-benzoyladenosine 15-, 1-monophosphate. Triphosphate, 3,1-benzoyladenosine-15'-triphosphate is preferred.
  • Another aspect of the present invention is a hair restorer containing, as an active ingredient, one or more compounds having an action of releasing a compound having a purine receptor stimulating action from cells.
  • the compound having a purine receptor stimulating action may be adenosine, an adenosine derivative or an adenosine metabolite, and may be ATP, an ATP derivative or AT. It may be a P metabolite.
  • Adenosine derivatives or adenosine metabolites released from cells can be adenosine monophosphate, adenosine diphosphate, or adenosine triphosphate.
  • a compound having a purine receptor stimulating action in particular, a compound having an action of releasing adenosine, adenosine derivative or adenosine metabolite from a cell, is a compound having a stimulating action on ABC transport enzyme existing in the cell. be able to.
  • the compound having a stimulating effect on ABC transporter can be a compound having a stimulating effect on a sulfonylurea receptor.
  • Compounds that have a stimulating effect on the sulfonylprea receptor include meglitinide, nicorandil, levocromakalim, cromakalim, pinacidil, diazoxide, disoviramide, chillisolol, apricam, bimacarim, MgATP, MnATP, CaATP, ZnATP, SrATP , MgADP, MnADP, CaADP, ZnADP, SrADP, MgAMP, MnAMP, CaAMP, ZnAMP, SrAMP, adenyl-5-ylimidodiphosphate, L-lysine, L-arginine. May be.
  • the compound having a stimulating action on the sulfonylprea receptor may be a salt containing a divalent cation selected from the group consisting of calcium, manganese, magnesium, zinc and strontium.
  • the compound having a stimulating effect on the sulfonyldiarea receptor is represented by the following formula 3:
  • the hair restorer of the present invention containing each of the above compounds as an active ingredient is preferably an external preparation, and the content of the active ingredient in the hair restorer of the present invention is 0.01 to 5% of the whole preparation. % By weight.
  • a test substance is added to cells transformed with an ABC transporter gene and a receptor gene for a purine derivative, and the amount of calcium influx into the cells at that time is used as an index. A method for screening a substance having a hair-growth action.
  • the ABC transporter gene may be a sulfonylprea receptor gene.
  • the receptor gene for the purine derivative can be an adenosine receptor gene or an ATP receptor gene.
  • Calcium influx into cells can be measured by fluorescence intensity using a fluorescent calcium indicator.
  • Transformation of the ABC transporter gene or the receptor gene for the purine derivative can be performed by a genetic modification technique using a host vector system.
  • FIG. 1 is an explanatory diagram showing the mechanism of action of the hair growth agent of the present invention and the substance screened by the method of the present invention.
  • FIG. 2 is a graph showing the results of an example of the screening method of the present invention.
  • FIG. 3 is a graph showing the results of the example of the screening method of the present invention. Detailed description of the invention
  • the present inventors have conducted intensive studies on hair-growth components having excellent efficacy, and surprisingly found that stimulating action on purine receptors including adenosine receptors and ATP receptors is closely related to hair-growth effects. It was found to have.
  • the present invention is based on this finding,
  • a compound having a purine receptor stimulating action a compound which releases a compound having a purine receptor stimulating action after application to a living body, and a compound which enhances the action of a compound having a purine receptor stimulating action
  • B A compound having an action of releasing a compound having a purine receptor stimulating action from cells, for example, a compound having an ABC transport stimulating action, particularly a compound having a sulfonyl urea receptor stimulating action;
  • hair restoration agents containing the above-mentioned compounds of the types A and B (hereinafter, referred to as the direct stimulation type of the purin receptor and the indirect stimulation type of the purine receptor, respectively) will be described in detail.
  • purine receptors are roughly classified into adenosine receptors and ATP receptors. Therefore, first, a hair restorer containing a compound that stimulates the adenosine receptor will be described.
  • Adenosine receptors are currently classified into four sub-groups, Al, A2a, A2b, and A3, based on their pharmacological and structural characteristics.
  • A1 receptor has anticonvulsant effect, neuroprotective effect, behavior suppression effect, sleep effect, etc.
  • A2 (A2a or A2b) receptor has behavior suppression effect, sleep effect, etc.
  • Adenosine receptors are distributed in various organs in the living body and are thought to be involved in the regulation of cell functions and physiological functions.
  • adenosine receptors distributed on the vascular smooth muscle of the heart are known to expand blood vessels and increase coronary blood flow by binding to compounds that stimulate adenosine receptors in blood. ing.
  • stimulation of adenosine receptors present on cells causes phenomena such as an increase in intracellular calcium ion concentration.
  • the present inventors have conducted various studies on the possibility that various phenomena caused by adenosine receptor stimulation may have an important role in regulating other functions of cell tissues.
  • one form of the hair restorer of the present invention is based on adenosine receptor stimulating action. It is a spider.
  • this hair restorer there are compounds having an adenosine receptor stimulating action.
  • One or more compounds that release a compound having adenosine receptor stimulating action after application to a living body, or one or more compounds that enhance the action of adenosine receptor stimulating action or Two or more are mentioned. These compounds may be used alone, or a plurality of types may be used as a mixture.
  • the compound having an adenosine receptor stimulating action is not particularly limited as long as it has an adenosine receptor stimulating action. However, in terms of adenosine receptor binding properties, adenosine, N 6- Cyclohexyl adenosine, N 6-cyclopentyl adenosine, (R) —N 6-phenylisopropyl adenosine,
  • the compound having the structure represented by the above formula 1 is that the compound having the adenosine receptor stimulating action or the compound releasing the compound having the adenosine receptor stimulating action after application to a living body is
  • R t to R 2 are preferably a hydrogen atom or an acyl group having 1 to 5 carbon atoms, respectively, and R 3 is preferably a hydrogen atom or a protecting group.
  • a compound having the adenosine receptor stimulating action enhances the action of the compound, which has the same effect as the compound having the adenosine receptor stimulating action.
  • Examples of the compound that enhances the action of the compound having the adenosine receptor stimulating action, which is combined with the hair restorer of the present invention include a compound having the adenosine receptor stimulating action.
  • Peptide inhibitors and inactivation inhibitors are preferred.
  • the inactivating agent include compounds that inhibit the enzymatic metabolism of a compound having an adenosine receptor stimulating action.
  • an inactivating agent that metabolizes adenosine to inosine that is inactive in a living body. Inhibitors of denosine deaminase may be used.
  • uptake inhibitors examples include diviridamol, dilacep, lidofrazine, hexobendine, carbochromene, chromonaric acid, cinepazide, diazepam, papaverine, 6- (2,1-hydroxynitrobe) in terms of the uptake inhibitory effect.
  • Nyl) thioguanosine and proventophilin are preferable, and as the inactivation inhibitor, 2'-dexoxyformycin, erythro 9-1 (2-hydroxy-13-nonyl) adenine are preferable in terms of their effects. Is preferred.
  • a hair restorer containing a compound of a type that particularly stimulates the ATP receptor will be described.
  • ATP receptors that transmit ligand stimulation into cells, one that utilizes the permeation of ions through the cell membrane and one that mediated by GTP-binding proteins. It is called Y type (each has 7 subtypes).
  • ATP receptors are distributed in various organs in the living body and are thought to be involved in signal transduction and function regulation. For example, it is thought to be responsible for synaptic modulation in the nervous system and blood pressure regulation in the aorta. However, the details and functions of the distribution have not yet been clarified. Since both adenosine and ATP (adenosine triphosphate) have a purine ring, the concept of a purine receptor includes adenosine receptor and ATP (adenosine triphosphate) receptor.
  • another form of the hair restorer of the present invention is based on a stimulatory action on purine receptors other than adenosine receptors, that is, ATP receptors.
  • the active ingredient of this type of hair restorer includes one or more compounds having an ATP receptor stimulating action. These compounds may be used alone, or a plurality of types may be used as a mixture.
  • the active ingredient of this hair restorer is not particularly limited as long as it has an ATP receptor stimulating action, and examples thereof include adenosine diphosphate, adenosine triphosphate and derivatives thereof.
  • the bonding position of the phosphate moiety is preferably a 5′-position carbon.
  • adenosine monophosphate 5 5 - diphosphate, adenosine monophosphate 5, single-triphosphate and derivatives thereof are preferred.
  • an ester derivative is preferred as the derivative of adenosine-5'-diphosphate or the derivative of adenosine-5'-triphosphate.
  • an oxygen atom bonded to the carbon at the 2 or 3 position of the adenosine moiety forms an ester together with an acyl group containing 1 to 10, preferably 1 to 5 carbon atoms. Is preferred.
  • the derivative of adenosine mono 5'-diphosphate and the derivative of adenosine_5'-triphosphate may be specifically a compound represented by the above formula 2, in which case, R t to R 2 it hydrogen atom or Ashiru group having a carbon number. 1 to 5, R 3 is also hydrogen atoms is preferably set to a suitable protecting group.
  • the adenosine-5′-diphosphate derivatives are: ⁇ -methyleneadenosine-15′-diphosphate ester derivatives, 2-methylthioadenosine-15, monophosphate phosphate derivatives, Preferably, it is a monobenzoyladenosine-15, monophosphate derivative or a 3, -benzoyladenosine-15, -diphosphate ester derivative.
  • the adenosine 15-monotriphosphate derivatives include: methylene adenosine 15-monophosphate, 2-methylthioadenosine 15-monotriphosphate, 2,1-monophosphate. Benzoyladenosine 1-5, 1 tolly Acid, or 3, -benzoyladenosine-15, monotriphosphate.
  • ABC transporter is a generic name for similar proteins that have the effect of causing intracellular release of ATP to the outside of the cell.As proteins, a part of the so-called ABC protein super family, ATP It is also called binding cassette, ATP binding protein, ABC binding transposon or ABC protein, MDR (P-glycoprotein, multidrug resistance protein), MRP (encompass-related protein), CFTR (cyctic fibrosis transmembrane conduct) ance regulator) and SU (sulfonyldiarea receptor) have been shown to play important roles in the expression and regulation of various cell functions.
  • MDR P-glycoprotein, multidrug resistance protein
  • MRP encompass-related protein
  • CFTR cyctic fibrosis transmembrane conduct
  • SU sulfonyldiarea receptor
  • the ABC transporter present in the cell membrane of the knee controls the opening and closing of the adjacent ATP-dependent force channel to regulate the release of force ions and the subsequent influx of calcium ions. It controls the secretion of insulin inside the cell vesicles to the outside of the cell.
  • the ABC transporter in the myocardium is located in the mitochondria, regulates the function of ATP-sensitive potassium channels also present in the mitochondria, and has a preconditioning effect during ischemia-reperfusion (cardioprotective effect). It has been clarified to be involved in the expression of.
  • the ABC transporter has become known to be present in various tissues of the living body, including the myocardium and vascular smooth muscle, and has a role as a transporter, that is, a cell. It has been speculated that the action of causing extracellular release of ATP in cells is also involved in various regulatory actions. It has also been clarified that the ABC transporter present in the // ⁇ cells, vascular smooth muscle and cardiac muscle of the brain is a sulfonylprea receptor.
  • the present inventors have reported that APC transfusions and ATP receptors or a PP 0
  • the denosine receptor was expressed. Conventionally, these receptors, that is, compounds having an action of releasing compounds having a purinergic receptor stimulating action from cells, particularly compounds which exert their action by stimulating ABC transvoi all over the cell, have been conventionally used. It has been found that it shows excellent efficacy not found in the hair growth component.
  • the compound having a purine receptor stimulating action includes a compound having an ATP receptor and / or adenosine receptor stimulating action. Specifically, ATP, an ATP inducer or an ATP metabolite, and / or adenosine And adenosine derivatives or adenosine metabolites.
  • ABC transporters such as sulfonyl-peryl receptors can be used.
  • ATP adenosine trilinate
  • adenosine generated by the degradation of ATP acts on the adenosine receptor, and the intracellular force It is thought to be responsible for the mechanism that causes the hair growth rate and the hair growth rate and hair cycle.
  • stimulation of mitochondrial sulfonylurea receptors may act on mitochondrial ATP-sensitive helium channels, which may release ATP, adenosine, their derivatives or metabolites from cells. .
  • still another form of the hair restorer of the present invention is based on the action of releasing a compound having a purine receptor stimulating action from cells.
  • the active ingredient of the hair restorer include one or more compounds having an action of releasing ATP, adenosine, a derivative or metabolite thereof from cells. These compounds may be used alone, or a plurality of types may be used as a mixture.
  • a specific example of the action of releasing a compound having a purine receptor stimulating action, such as adenosine and a derivative or metabolite thereof, from a cell is, for example, stimulating the ABC transporter present in the cell.
  • adenosine and its derivatives or metabolites include adenosine, adenosine monophosphate, adenosine diphosphate and adenosine. And triphosphate.
  • a compound having a stimulating action on ABC transport a compound having a stimulating action on any of MDR, MRP, CFTR, and sulfonyl-rea receptor can be used.
  • Compounds having a stimulatory action on the receptor are mentioned.
  • Examples of the compound having a stimulating action on the sulfonylprea receptor include, for example, meglitinide, nicorandil, levocromakalim, cromakalim, pinacidil, diazoxide, disoviramide, tilisolol, apricam, bimacarim, MgATP, MnATP, CaATP, ZnATP, SrATP, MgADP, MnADP, CaADP, ZnADP, SrADP, MgAMP, MnAMP, Ca AMP, ZnAMP, SrAMP, adenyl-5-ylimidodiphosphate, L-lysine, L-arginine, calcium, manganese, magnesium, zinc or stront A salt containing a divalent cation of Pum, and the following formula
  • R is a 14-30 carbon group which may be branched and contains 0-3 double bonds].
  • a long-chain acylchoenzyme A represented by 0 A Noretoyl_CoA, Oleyl-CoA, Myristoyl-CoA, Ben-Yu-Decanyl-CoA, Stearyl-CoA.
  • potassium channel openers eg, Takahashi et al., “K channel openers”, Pharmaceutical Journal, vol.34, Sl, P.70-74 (1998), and Endo et al. , “Potassium channel openers”, Pharmaceutical Journal, vol. 35, Sl, P. 112-119 (1999)
  • the sulfonylprea receptor functions as a regulator of ATP-sensitive potassium channels, and it is already known that potassium channel openers bind to sulfonylurea receptors (eg, Bray et al., Jounal of Bailogical Chemistry, vol.267, p.11689 (1992)).
  • the sulfonylurea receptor is involved in the release of ATP from inside the cell to outside the cell (Awqati et al., Science vol. 269, 805 (1995)).
  • the above substances known as potassium channel openers, are thought to bind to and stimulate the sulfonylprea receptor.
  • the action of stimulating sulfonylurea by binding of these substances to the sulfonylurea receptor is caused by the purine receptor such as ATP, adenosine, a derivative or metabolite thereof.
  • the hair restorer of the present invention is preferably an external preparation, and can be used by applying an appropriate amount to the scalp or skin once or several times a day.
  • the amount of each active ingredient contained in the hair restorer of the present invention is preferably 0.01 to 5% by weight, more preferably 0.1 to 5% by weight, and particularly preferably 0.1 to 5% by weight of the whole preparation. Is 1 to 5% by weight. If the amount is less than 0.01% by weight, the hair-growth effect is not sufficient, and if it exceeds 5% by weight, the dissolution stability of the active ingredient in the preparation often decreases. It is not preferable because adverse effects on quality such as crystal precipitation are sometimes observed.
  • the hair restorer of the present invention can be used as a dosage form usually used as an external preparation, for example, a lotion, an emulsion, a cream, a tonic, an ointment, a gel, an aerosol, and the like.
  • the dosage form is not limited to these.
  • the amount is set as described above with respect to the stock solution.
  • the hair restorer of the present invention includes, as necessary, water, lower alcohols (such as methanol, ethanol, denatured ethanol, and isopropyl alcohol), solubilizers, surfactants, emulsion stabilizers, gelling agents, Adhesives and other base ingredients that are commonly used to obtain the desired dosage form can be incorporated.
  • lower alcohols such as methanol, ethanol, denatured ethanol, and isopropyl alcohol
  • solubilizers such as methanol, ethanol, denatured ethanol, and isopropyl alcohol
  • surfactants such as sodium ethanol, sodium ethanol, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfit
  • vasodilators such as minoxidil and carpronium chloride, spironolactone, fluuramide, and cyprote mouth Androgen inhibitors such as acetate and oxendrone, steroid inhibitors such as finasteride and ebilisteride, anti-inflammatory agents such as glycyrrhetinic acid and azulene, hydrocortisone acetate, dexamethasone acetate, etc.
  • vasodilators such as minoxidil and carpronium chloride, spironolactone, fluuramide, and cyprote mouth Androgen inhibitors such as acetate and oxendrone
  • steroid inhibitors such as finasteride and ebilisteride
  • anti-inflammatory agents such as glycyrrhetinic acid and azulene, hydrocortisone acetate, dexamethasone acetate, etc.
  • Corticosteroids keratolytics such as urea, salicylic acid, propylene Recall, 1, 3-butylene glyco Ichiru, macrogol, glycerin, dipropylene glyco Alcohols such as alcohol, ethanol, and isopropanol; glyceryl monopenic acid; fatty acid glycerin esters such as decanoate; antihistamines such as isopendyl hydrochloride; diphene hydrochloride; hydramine; chlorhexidine gluconate; isopropyl butylphenol; quaternary ammonium salts; Fungicides such as hinokitiol and bilocton olamine, moisturizers such as sodium hyaluronate, glycerin, and chondroitin sulfate, yew, buttony, kanzo, otogiriso, shrimp, beetle, potato mugwort, comfrey, ashiyuba, saffron
  • the hair growth agent of the present invention may contain both the above-mentioned A and B type compounds, if necessary, although it depends on the application target or the required degree of the hair growth effect.
  • the method for screening a hair growth substance of the present invention will be described.
  • the dermal papilla cells express the ABC transporter and the ATP receptor or adenosine receptor, which are considered to be closely related to each other and exhibit a hair-growth effect. It is.
  • stimulation of the ATP receptor or adenosine receptor through the stimulatory effect on ABC transporter increases hair growth with an increase in intracellular calcium concentration. It is thought that it shows the effect.
  • Hair papilla cells have a very low proliferative capacity, require a large amount of hair tissue to secure the number of cells required for screening, and require a great deal of labor and cost. Therefore, it has been desired to develop a simple method for finding a substance that acts on an ATP receptor or an adenosine receptor through the ABC transport system to find an effective substance.
  • the present inventors have conducted intensive studies and found that the ABC transporter gene and the ATP receptor gene or adenosine receptor gene were transformed into a transgenic cell by a genetic recombination technique using an appropriate host vector method, and calcium was transferred to this cell.
  • the present invention was completed by establishing a method for screening hair growth substances by measuring influx.
  • the method for screening a hair-growth substance of the present invention uses a cell in which a receptor gene for the ABC transport protein and a purine derivative is expressed by a host vector method, and detects calcium influx into the cell. It is characterized as an index.
  • the ABC transporter is a generic name for similar proteins that have the effect of causing the release of intracellular ATP outside the cell, and as a protein, constitutes the so-called ABC protein superfamily. Some are also referred to as ATP binding cassettes, ATP binding proteins, ABC binding transports or ABC proteins.
  • the ABCC transport examples include MDR (P-sugar protein multidrug resistance protein), MRP (thigh-related protem), CFT (cyctic fibrosis transmembrane conductance regulator), S UR (sulfonylurea receptor) Body) and the like.
  • the ATP binding transporter gene used in the present invention is particularly preferably a sulfonylprea receptor gene (hereinafter also referred to as SUR gene).
  • the sulfonyl receptor gene is known from SUR gene sequence information already known, for example, the Hamus Yuichi SUR gene sequence described in Y. Tokuyama et al., Biochemical and Biophysical Research Communications, ⁇ 20, p.532-538 (1996). It can be obtained by a well-known PCR method or a hybridization method from a cDNA library using a suitable probe prepared from the sequence based on the information.
  • the rat SUR cDNA sequence is also known (GenBank Accession No. L40624).
  • the hamster SUR gene transfer is described in Aguilar-Bryan et al., Science, vol. 268, p. 423 (1995). I have.
  • rat and mouse SUR The amino acid sequence of rat and mouse SUR is described in Inagaki et al., "Sulfonylurea Receptor” (Biochemistry Vol. 69, No. 9, p. 1067, 1997).
  • receptor gene for the adenosine derivative include a purine receptor gene and an adenosine receptor gene.
  • the human cDNA gene sequence is already known (GenBank Accession No. X68485).
  • the sulfonyl receptor gene it can be obtained by a well-known PCR method or a hybridization method from a cDNA library.
  • the human cDNA gene sequence is also known for the ATP receptor gene (GenBank Accession No. X83688).
  • the receptor gene for the ABC transporter gene or purine derivative a part of the gene sequence inside or at the end within a range that functions as a receptor for ABC transporter or purine derivative in transformed cells after transformation. But also includes those that have been inserted, replaced, or deleted.
  • the host used in the present invention is not particularly limited as long as the introduced gene is efficiently expressed and cultivation is easy.
  • Various strains of Escherichia coli which is a genus Escherichia and Bacillus spp.
  • Various strains of Bacillus subtilis various strains of Saccharomyces cerevisiae as yeast, C0S-7 cells, CHO cells, PC12 cells, NIH3T3 cells, NRK cells, CV-1 cells as animal cells, CO S-1 cells and the like are preferred.
  • the vector is not particularly limited as long as it is easy to prepare and can be efficiently introduced.
  • Plasmids derived from Escherichia coli eg, pBR322, pUC118, etc.
  • Plasmids derived from Bacillus subtilis eg, pUB110, pC194, etc.
  • yeast derived plasmids eg, pSH19, etc.
  • Animal viruses such as vaccinia virus are preferred.
  • an appropriate expression promoter is connected upstream of the gene to express the gene.
  • the mouth motor to be used may be selected according to the host.
  • the T7 promoter, the lac promoter, the trp promoter, the aPL promoter, and the SP0 promoter are used when the host is Bacillus.
  • the host is yeast, the PHO promoter, GAP promoter, ADH promoter, etc., and when the host is an animal cell, SV40-derived promoter, retrovirus promoter, etc. , It can use it.
  • Transformation means introducing DNA into an organism such that the DNA becomes replicable as an extrachromosomal element or by chromosomal integration.
  • Methods for transforming host cells using the above-described recombinant vector include transformation methods generally used for each host cell, for example, calcium treatment using calcium chloride, transfection by calcium phosphate method, electoporation, or Lipophexion and the like can be applied (Sambrook et al., Molecular Biology: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, New York 1989, etc.).
  • the transformed cells thus obtained are cultured in an appropriate selection medium and used for screening.
  • the culture for this screening is preferably performed by culturing the cells on a cover glass.
  • the transformed cells are suspended in a medium at a cell concentration of 3 ⁇ 10 7 / mL, an appropriate amount is placed on a cover glass, and cultured at about 37 ° C. for about 24 to 48 hours.
  • test substance solution is added to the cultured cells, and the amount of calcium flowing into the cells is measured.
  • a well-known fluorescent calcium indicator which is a calcium chelating agent and whose fluorescent property changes depending on the amount of calcium binding, such as fura-2, fura-2-AM, indo-1, quin2, fluo-3, rhod-2, etc.
  • fura-2-AM (l- (2--(5, -carboxoxazoyl-2, -yl ) -6-Aminobenzofuran-5-oxy) -2- (2, -amino-5, -methylphenoxy) -ethane- ⁇ , ⁇ , ⁇ ,, ⁇ , -tetraacetic acid ⁇
  • fura-2-AM l- (2--(5, -carboxoxazoyl-2, -yl ) -6-Aminobenzofuran-5-oxy
  • N-acetoxymethyl ester and Wako Pure Chemical Tokyo
  • the hair restorer of the present invention exerts a hair restorer effect by, for example, releasing ATP, ATP derivative, adenosine, adenosine derivative and the like from cells and stimulating ATP receptor and / or adenosine receptor. It is based on a novel mechanism of action and has a remarkable hair-growth effect.
  • a particularly high hair restorer can be obtained when an adenosine 15-monophosphate derivative or an adenosine 15-monophosphate derivative is used as the compound. The effect can be obtained.
  • a novel action of exerting a hair-growth effect by a purine receptor stimulating action through a stimulating action on ABC transport that is, an ATP receptor and / or adenosine receptor stimulating action. It is possible to easily screen a hair-growth substance having a mechanism. Examples Next, the present invention will be described in more detail with reference to Formulation Examples and Test Examples (Examples and Comparative Examples). Hair restorer
  • an external aerosol was prepared according to the usual method for producing an aerosol.
  • the hair growth test of the hair growth agents of Examples 1 to 15 was performed using C 3H / HeNCr J This was performed using mice.
  • the test method consisted of 10 mice per group, divided into Examples 1 to 15, Comparative Examples 1 and 2, and 17 groups of no-administration group, and the back of the mouse was shaved with a palycan and a power razor. Each sample was applied once, 100 L per 8 cm 2 of shaved back.
  • the hair restorers of Examples 1 to 15 and Comparative Examples 1 and 2 were prepared by stirring the components shown in Tables 1 and 2 until the whole was uniform as in Formulation Example 1.
  • Tables 3 and 4 show the hair regenerating area (after 15 days) with respect to the applied area of the hair-growing agents of Examples 1 to 15 and the hair-growing agents of Comparative Examples 1 and 2, and the non-administered group.
  • the hair restorer of the present invention has a high effect on hair regeneration.
  • Tritriphosphoric acid 10 0
  • Medium-chain fatty acid triglyceride 200 0
  • Isopropyl myristate 1 0
  • Formulation Example 7 (External gel): A cream for external use was prepared from the above ingredients according to the usual method for producing an emulsifier.
  • the hair growth tests of the hair restorers of Examples 16 to 22 were carried out using # 311 /; The test method consisted of 10 mice per group, divided into 9 groups: the hair restorer-administered group of Examples 16 to 22, the hair restorer-administered group of Comparative Example 3, and the non-administered group. Shaved on the back, shaved samples once a day 100 L was applied every 8 square cm.
  • the hair restorers of Examples 16 to 22 and Comparative Example 3 were prepared by stirring each component shown in Table 5 until the whole was uniform, as in Formulation Example 5.
  • Table 6 shows the hair regenerating area (after 15) with respect to the application area of the administration groups of the hair restorers of Examples 16 to 22 and the hair restorer of Comparative Example 3 and the non-administration group.
  • Example 16 Component name Example 16 Example 1 ⁇ Example 18 Example 19 Example 20 Example 21 Example 22 Comparative example 3
  • the hair restorer of the present invention has a high effect on hair regeneration.
  • their derivatives are more effective than adenosine-5'-diphosphate (Example 21) or adenosine-5, -triphosphate (Example 22). It became clear that it had a high hair growth effect.
  • a cream for external use was prepared according to the method of emulsifier, Formulation Example 1 1 (gel for external use)
  • an aerosol for external use was prepared according to the method for producing an aerosol, Example 23 (a lotion for external use) (Components) Compounding amount (W / V5 Nicorandil 1.0 propylene glycol 20.0 ethanol 50.0 Purified water 100 ml in total
  • Example 24 nicorandil in Example 23 was replaced with pinacidil (Example 24), cromakalim (Example 25), MnATP (Example 26), megrotinide (Example 27), and L-arginine (Example 28). ) was prepared in the same manner as in Example 23 except that the lotion was used instead. Comparative Example 4
  • Example 7 As shown in Table 7, an external lotion was prepared in the same manner as in Example 23 except that nicorandil in Example 23 was omitted.
  • Example 2 Component name Example 2 3 Example 2 4 Example 2 5 Example 2 6 Example 2 7 Example 2 8 Comparative example 4 Compound 23 1 g
  • the test method consisted of 10 mice per group, divided into 8 groups: a sample administration group and a non-administration group, and the back of the mouse was shaved with a clipper and a force razor, and each sample was shaved once. 100 L per 8 cm 2 of the back was applied.
  • Table 8 shows the hair regeneration area (after 15 days) with respect to the application area of the sample administration group of Examples 23-28, the sample administration group of Comparative Example 4, and the non-administration group. Table 8
  • COS-1 cells (3 ⁇ 10 5 cells / 35 mm diameter petri dish) were cultured in Dulbecco's modified MEM medium containing 10% fetal bovine serum at 37 ° C. in a 5% CO 2 atmosphere.
  • human adenosine receptor cDNA GenBank Accession No. X68485, reference: A. Kollias-Baker et al., The Journal of Pharmacology and Experimental Th erapeutics, 281 (2), 761-768 (1997)
  • rat sulfonyldiarea receptor cDNA GenBank Accession No.
  • L40624 References: Y ⁇ Tokuyama et al., Biochemical and Biophysical Research Communications, 220, 532- 538 (1996)) into pcDNA3.1 vector-1 (Invitrogen, California, USA) and pcDNA3.1 / Hygro vector-1 (Invitrogen, California, USA) according to standard methods.
  • 3.1 hAD and pc DNA 3.1 / Hygro raS UR were obtained.
  • pcDNA3.lhAD is obtained by inserting the HindIII / Xbal fragment (1.4 kb) of human adenosine receptor cDNA into the EcoRI / Notl site of pcDNA3.1 vector. .
  • pc DN A3.1 / Hygro raS UR is the nucleotide number of the rat sulfonylrea receptor cDNA at Hindlll / Xbal site of pcDNA3.1 / Hygro vector. DNA fragment was inserted. The thus obtained pCDNA3.1 hAD (1 ⁇ g) and pcDNA3.1 / Hygro raS UR (ljg) were lipofected into the previously cultured C0S-1 cells.
  • the cells were further cultured.
  • the cells were washed with phosphate buffered saline and treated with 0.05% trypsin and 0.53 mM EDTA solution.
  • Highly expressing cell lines were obtained using neomycin and hygromycin resistance as indices.
  • cells were cultured on a cover glass and provided.
  • the fluorescence intensity method using FURA-2 was used for measuring the intracellular force lucidum concentration. That is, 5 g / m1: fura—2 am loaded for 30 min, washed with iodine solution, then fluorescence at 340 nm and 380 nm as indicators of intracellular calcium concentration The intensity ratio was determined. Test example
  • nicorandil which is known as a sulfonylprea receptor stimulant.
  • nicorandil 25 and 100 M increases the intracellular calcium concentration. This effect is due to the pretreatment of the adenosine receptor inhibitor 8-sulfophenyltheophylline. Was confirmed to be suppressed.
  • Test example 2
  • the effects of nicorandil and adenosine were not observed in the calcium-free medium. From this, it is clear that the increase in intracellular calcium concentration is due to the influx of extracellular calcium.
  • the transformed cells obtained by the present invention have good proliferation ability and can be easily used for screening of hair growth agents.

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Abstract

Cette invention concerne de nouveaux agents dotés d'un excellent pouvoir de stimulation de la croissance capillaire qui agissent selon des mécanismes différents de ceux des stimulants de croissance classique, ainsi qu'une méthode de recherche systématique de ces agents. Les agents de stimulation de la croissance capillaire susmentionnés renferment des ingrédients actifs qui stimulent des récepteurs de la purine (récepteur de l'adénosine, récepteur ATP, etc.), accentuent cet effet et libèrent des composés qui stimulent des récepteurs de l'adénosine (adénosine, dérivés de l'adénosine, métabolites de l'adénosine, etc.) des cellules. La méthode de recherche systématique susmentionnée consiste à ajouter une substance d'essai à des cellules transformées au moyen d'un gène transporteur ABC et un gène récepteur de dérivé de la purine et d'utiliser l'entrée d'ions calcium en ce point comme indicateur.
PCT/JP2000/000694 1999-02-10 2000-02-09 Agent de stimulation de la croissance capillaire et recherche systematique de substances ayant cet effet Ceased WO2000047172A1 (fr)

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FR2838641A1 (fr) * 2002-04-23 2003-10-24 Oreal Composition cosmetique, procede de traitement cosmetique et preparation d'une composition pour favoriser la pousse et/ou empecher ou retarder la chute des cheveux
WO2003090699A1 (fr) * 2002-04-23 2003-11-06 L'oreal Composition cosmetique pour favoriser la pousse et/ou empecher ou retarder la chute des cheveux
WO2005044205A1 (fr) * 2003-11-11 2005-05-19 Shiseido Company, Ltd. Procede et composition destines a epaissir les cheveux
CN113827608A (zh) * 2021-09-18 2021-12-24 福州博德新材料科技有限公司 一种含有嘌呤核苷的高效型米诺地尔生发酊剂及其制备方法

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JP3228797B2 (ja) 1992-10-29 2001-11-12 ワイケイケイ株式会社 テープ状物の端部自動切断・溶着整形機

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2838641A1 (fr) * 2002-04-23 2003-10-24 Oreal Composition cosmetique, procede de traitement cosmetique et preparation d'une composition pour favoriser la pousse et/ou empecher ou retarder la chute des cheveux
WO2003090699A1 (fr) * 2002-04-23 2003-11-06 L'oreal Composition cosmetique pour favoriser la pousse et/ou empecher ou retarder la chute des cheveux
EP1358868A3 (fr) * 2002-04-23 2003-11-19 L'oreal Composition cosmétique pour favoriser la pousse et/ou empecher ou retarder la chute des cheveux
WO2005044205A1 (fr) * 2003-11-11 2005-05-19 Shiseido Company, Ltd. Procede et composition destines a epaissir les cheveux
JPWO2005044205A1 (ja) * 2003-11-11 2007-05-17 株式会社資生堂 毛髪の太毛化の方法及び組成物
CN113827608A (zh) * 2021-09-18 2021-12-24 福州博德新材料科技有限公司 一种含有嘌呤核苷的高效型米诺地尔生发酊剂及其制备方法

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