WO2019132004A1 - Agent prophylactique ou agent thérapeutique contre la maladie d'alzheimer, méthode de criblage associée, et composition pour prévenir ou traiter la maladie d'alzheimer - Google Patents

Agent prophylactique ou agent thérapeutique contre la maladie d'alzheimer, méthode de criblage associée, et composition pour prévenir ou traiter la maladie d'alzheimer Download PDF

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WO2019132004A1
WO2019132004A1 PCT/JP2018/048471 JP2018048471W WO2019132004A1 WO 2019132004 A1 WO2019132004 A1 WO 2019132004A1 JP 2018048471 W JP2018048471 W JP 2018048471W WO 2019132004 A1 WO2019132004 A1 WO 2019132004A1
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group
disease
carbon atoms
preventing
alzheimer
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PCT/JP2018/048471
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Japanese (ja)
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択実 江良
隆太郎 梶原
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国立大学法人熊本大学
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Priority to JP2019562504A priority Critical patent/JP7445251B2/ja
Publication of WO2019132004A1 publication Critical patent/WO2019132004A1/fr
Priority to JP2024020478A priority patent/JP2024040445A/ja

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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
    • A61K31/395—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
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • 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
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
    • 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

Definitions

  • the present invention relates to an agent for preventing or treating Alzheimer's disease, a method for screening the same, and a composition for preventing or treating Alzheimer's disease.
  • Priority is claimed on Japanese Patent Application No. 2017-254887, filed Dec. 28, 2017, the content of which is incorporated herein by reference.
  • AD Alzheimer's disease
  • a ⁇ amyloid cascade hypothesis
  • a ⁇ is a small protein with a molecular weight of about 4 kD, composed of 38-43 amino acids, and is produced by being cleaved from amyloid precursor protein (APP) by secretase.
  • APP amyloid precursor protein
  • a ⁇ 40 and A ⁇ 42 exist due to the difference in the number of amino acids.
  • a ⁇ 42 is known to have stronger virulence because it has high aggregation.
  • Non-Patent Document 1 describes a method of screening for anti-A ⁇ drugs using neural cells that have expressed forebrain markers differentiated from human iPS cells.
  • the fundamental therapeutic agent for AD has not been found at present, and currently only symptomatic treatment.
  • clinical studies such as secretase inhibitors and anti-A ⁇ immunotherapy have been conducted as fundamental therapeutic agents for AD.
  • the present invention aims to provide an agent for preventing or treating Alzheimer's disease, a method for screening the same, and a composition for preventing or treating Alzheimer's disease based on a novel mechanism of action.
  • GM1 GM1 ganglioside
  • iPS cells GM1 ganglioside
  • An agent for preventing or treating Alzheimer's disease which comprises an agent for preventing or treating GM1 gangliosidosis as an active ingredient.
  • Amodiaquine Amodiaquine
  • Acacetin Acacetin
  • Sulfamerazine Sulphamelazine
  • Ungerine Ungelin
  • Amiodarone Amiodarone
  • Sertindol Sertindol
  • Delcorine Delcholine
  • Perphenazine Perphenazine
  • Althiazide Althiazide
  • Diethylstilbestrol diethylstilbestrol
  • Thiethylperazine thiethylperazine
  • Harmol Harmol
  • Skimmianine skimmianin
  • Succinylsulfathiazole Succinylsulfathiazole
  • Fillalbin filalbin
  • Canavanine Canavanine
  • Harmaline haluline Fluoxetine (fluoxetine)
  • Lovastatin lovastatin
  • Haloperidol Haloperidol
  • Haloperidol Haloperidol
  • R 1 and R 2 each independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an aryl group, an aralkyl group or a cycloalkyl group.
  • X represents a single bond or a divalent linking group.
  • n represents 0, 1 or 2;
  • R 3 represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an aralkyl group, an aryl group or a cycloalkyl group.
  • R 4 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • R 5 represents a hydrogen atom, a hydroxyl group, an alkyl group of 1 to 5 carbon atoms, or an alkoxy group of 1 to 5 carbon atoms.
  • R 6 represents a hydrogen atom, a hydroxyl group, a cyano group, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, an aralkyl group, an aryl group or a cycloalkyl group.
  • a method of screening a preventive or therapeutic agent for Alzheimer's disease characterized by using a screening method of a preventive or therapeutic agent for GM1 gangliosidosis.
  • the method for preventing Alzheimer's disease or the agent for preventing Alzheimer's disease according to [5] which comprises the step of contacting a cultured compound with GM1 gangliosidosis neural stem cells to evaluate the change in accumulated amount of GM1 ganglioside in the neural stem cells.
  • GM1 gangliosidosis neural stem cell is a cell differentiated from a GM1 gangliosidosis patient-derived iPS cell.
  • an Alzheimer's disease preventive or therapeutic agent having a novel mechanism of action can be provided.
  • FIG. 1 It is a figure which compared GM1 accumulation in a healthy subject and a neural stem cell from GM1 patient.
  • A Comparison of ⁇ -gal activity in neural stem cells derived from healthy subjects, GM1 patients and Alzheimer's disease patients.
  • B It is the figure which introduce
  • C shows a comparison of GM1 accumulation in whole neural stem cells from healthy individuals and patients with Alzheimer's disease.
  • D It is a figure which compared GM1 accumulation in a lipid raft fraction of a healthy subject and a neural stem cell from a patient with Alzheimer's disease.
  • A It is the figure which compared the quantity of A (beta) 40 in the healthy subject which overexpressed (beta) -gal protein, and the neural stem cell from Alzheimer's disease.
  • B It is the figure which compared the quantity of A (beta) 42 in the healthy subject which overexpressed (beta) -gal protein, and the neural stem cell from Alzheimer's disease.
  • C It is the figure which compared the value of A (beta) 42 / A (beta) 40 in the healthy subject which overexpressed (beta) -gal protein, and the neural stem cell from Alzheimer's disease.
  • (D) It is the figure which compared the A (beta) total amount in the healthy subject which overexpressed (beta) -gal protein, and the neural stem cell from Alzheimer's disease.
  • (E) It is the figure which compared the sensitivity with respect to A (beta) 42 in the neural stem cell from a healthy person and the neural stem cell from GM1 gangliosidosis patient, respectively.
  • (A) It is the figure which compared the quantification result of soluble A (beta) 40 in the TBS (Tris Buffered Saline) extraction fraction of the brain of WT mouse, BKO mouse, 5xFAD mouse, and BKO / 5xFAD mouse.
  • TBS Tris Buffered Saline
  • (B) It is the figure which compared the quantification result of soluble A (beta) 42 in the TBS (Tris Buffered Saline) extraction fraction of the brain of WT mouse, BKO mouse, 5 * FAD mouse, and BKO / 5 * FAD mouse.
  • (C) It is the figure which compared the quantification result of insoluble A (beta) 40 in the Guanidin-HCl extraction fraction of the brain of WT mouse, BKO mouse, 5xFAD mouse, and BKO / 5xFAD mouse.
  • (D) It is the figure which compared the quantification result of insoluble A (beta) 42 in the Guanidin-HCl extraction fraction of the brain of WT mouse, BKO mouse, 5xFAD mouse, and BKO / 5xFAD mouse.
  • (E) It is the figure which compared the deposition amount of the amyloid in the brain slice of WT mouse, BKO mouse, 5xFAD mouse, and BKO / 5xFAD mouse. It is the figure which showed the mode of GM1 accumulation at the time of using a GM1 inhibitory compound. It is the figure which showed the mode of GM1 accumulation at the time of using a GM1 inhibitory compound.
  • FIG. 6 is a graph showing the results of comparison of the amount of A ⁇ produced in cells and the A ⁇ 42 / A ⁇ 40 ratio in the case of using a GM1 inhibitory compound. It is the figure which investigated the influence on GM1 accumulation
  • GM1 ganglioside is a kind of glycolipid and is a molecule involved in cell signal transduction and the like.
  • GM1 gangliosidosis is known as a disease in which GM1 is involved.
  • GM1 gangliosidosis is one of lysosomal diseases, which is a congenital metabolic disorder in which GM1 accumulates particularly in the nervous system (brain) due to a deficiency or abnormality of an enzyme involved in the hydrolysis of GM1 ganglioside.
  • GM1 gangliosidosis is classified into infant type, juvenile type and adult type according to onset time and clinical course. Especially in the infant type, developmental delay is seen by 3 to 6 months after birth, and by 1 year after birth most patients develop severe neuropathy such as decerebrate, usually by 3 to 4 years of age To die.
  • the screening method of the preventive or therapeutic agent for Alzheimer's disease of the present invention uses the screening method of the preventive or therapeutic agent for GM1 gangliosidosis.
  • the present invention relates to an agent for preventing or preventing Alzheimer's disease, which comprises the step of bringing a compound to be evaluated into contact with cultured GM1 gangliosidic neural stem cells to evaluate changes in the accumulation amount of GM1 ganglioside in the neural stem cells.
  • a compound library is added to the culture medium of cultured GM1 gangliosidic neural stem cells, and the influence on GM1 ganglioside in the neural stem cells is examined. More specifically, for example, the neural stem cells are seeded in a well plate and cultured in the presence of a compound library for about 1 to 5 days.
  • the GM1 gangliosidosis neural stem cells be cells differentiated from the GM1 gangliosidosis patient-derived iPS cells.
  • Examples of cells derived from GM1 patients include adipocytes, chondrocytes, osteoblasts, blood cells, fibroblasts and the like, with fibroblasts being preferred.
  • the method for reprogramming GM1 patient-derived cells to iPS cells and the method for differentiating iPS cells to neural stem cells follow the standard methods.
  • the compound found by such a step may have a step of evaluating the therapeutic effect of AD, such as evaluating the expression of A ⁇ .
  • evaluating the expression of A ⁇ there is a method of culturing AD patient-derived neural stem cells with a GM1 inhibitory compound and quantifying the ratio of A ⁇ 42 to A ⁇ 40 in the culture medium.
  • the present invention provides a screening method for an agent for preventing or treating Alzheimer's disease, which comprises administering a compound to be evaluated to an animal model for Alzheimer's disease described later.
  • a compound to be evaluated is administered by oral administration or parenteral administration such as intraperitoneal administration to an animal model of Alzheimer's disease described later. Subsequently, amyloid deposits in brain tissue are assessed.
  • the agent for preventing or treating Alzheimer's disease obtained using the screening method of the present invention is preferably a compound capable of exerting the therapeutic effect of AD by suppressing GM1 accumulation directly or indirectly. That is, an AD therapeutic agent containing such an AD therapeutic candidate compound as an active ingredient directly removes accumulated GM1, suppresses the aggregation of GM1, inhibits the synthesis of GM1, and promotes the degradation of GM1 etc. It is preferable that the accumulation of GM1 be suppressed directly or indirectly to exert the therapeutic effect of AD.
  • the present invention includes Amodiaquine (Amodiaquine), Acacetin (Acetetine), Sulfamerazine (Sulphamelazine), Ungerine (Ungelin), Amiodarone (Amiodarone), Sertindol (Sertindol), Delcorine (Delcholine), Perphenazine (Perphenazine) ), Althiazide (altiazide), Diethylstilbestrol (diethylstilbestrol), Thiethylperazine (thiethylperazine), Harmol (harmol), Skimmianine (skimmianin), Succinylsulfathiazole (succinylsulfathiazole), Fillalbin (filalbin), Canavanine (Canabanine armaline) ), Trihexyphenyl (trihexyphenidyl), Fluoxetine
  • the present invention relates to an agent for preventing or treating Alzheimer's disease, which comprises a compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient I will provide a.
  • the agent for preventing or treating Alzheimer's disease can also be provided as an agent for preventing or treating GM1 gangliosidosis.
  • R 1 and R 2 each independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an aryl group, an aralkyl group or a cycloalkyl group.
  • X represents a single bond or a divalent linking group.
  • n represents 0, 1 or 2;
  • R 3 represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an aralkyl group, an aryl group or a cycloalkyl group.
  • R 4 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • R 5 represents a hydrogen atom, a hydroxyl group, an alkyl group of 1 to 5 carbon atoms, or an alkoxy group of 1 to 5 carbon atoms.
  • R 6 represents a hydrogen atom, a hydroxyl group, a cyano group, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, an aralkyl group, an aryl group or a cycloalkyl group.
  • alkyl group having 1 to 5 carbon atoms as R 1 and R 2 include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group and pentyl group , Isopentyl group, neopentyl group and the like.
  • the aryl group for R 1 and R 2 is preferably one having 6 to 18 carbon atoms, more preferably one having 6 to 10 carbon atoms, and particularly preferably a phenyl group.
  • the aralkyl group in R 1 and R 2 is preferably one in which an alkylene group having 1 to 5 carbon atoms is bonded to the aryl group in R 1 and R 2 .
  • the cycloalkyl group in R 1 and R 2 is preferably a group in which one hydrogen atom has been removed from a monocycloalkane having 3 to 8 carbon atoms, and specific examples include cyclopentane, cyclohexane, cyclooctane and the like. .
  • Alkyl group of 1 to 5 carbon atoms for R 3, an aralkyl group, an aryl group, and the cycloalkyl group include the same as described above in R 1 and R 2.
  • Examples of the alkyl group having 1 to 5 carbon atoms for R 4 include the same ones as described above for R 1 and R 2 .
  • Examples of the alkyl group of 1 to 5 carbon atoms for R 5 include the same as those described above for R 1 and R 2 .
  • Examples of the alkoxy group having 1 to 5 carbon atoms for R 5 include the same ones as the alkyl group having 1 to 5 carbon atoms described above for R 1 and R 2 in the R moiety of —OR.
  • Examples of the alkyl group having 1 to 5 carbon atoms, the aralkyl group, the aryl group and the cycloalkyl group in R 6 include the same as those described above in R 1 and R 2 .
  • Examples of the alkoxy group having 1 to 5 carbon atoms for R 6 include the same ones as described above for R 5 .
  • X is preferably a single bond
  • n is preferably 1
  • R 3 to R 5 are preferably hydrogen atoms.
  • a compound represented by the following general formula (1-1), a pharmaceutically acceptable salt thereof, or a solvate thereof may be contained as an active ingredient ,preferable.
  • R 1 and R 2 each independently represent a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an aryl group, an aralkyl group or a cycloalkyl group.
  • X represents a single bond or a divalent linking group.
  • R 6 represents a hydrogen atom, a hydroxyl group, a cyano group, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, an aralkyl group, an aryl group or a cycloalkyl group.
  • R 6 is preferably a hydroxyl group
  • R 1 and R 2 are preferably an alkyl group having 1 to 5 carbon atoms.
  • the agent for preventing or treating Alzheimer's disease of the present embodiment the compound represented by the following formula (1-1-1), a pharmaceutically acceptable salt thereof, or a solvate thereof is contained as an active ingredient Is particularly preferred.
  • the present invention provides an agent for preventing or treating Alzheimer's disease, which comprises a compound represented by the following general formula (2), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient I will provide a.
  • the agent for preventing or treating Alzheimer's disease can also be provided as an agent for preventing or treating GM1 gangliosidosis.
  • R 10 represents a single bond or a divalent linking group.
  • R 11 represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a hydroxyalkyl group of 1 to 5 carbon atoms, an aralkyl group, an aryl group or a cycloalkyl group.
  • R 12 and R 13 each independently represent a hydrogen atom, a halogen atom, an alkyl group of 1 to 5 carbon atoms, a thioalkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, or 1 to 5 carbon atoms And a hydroxyalkyl group, an aralkyl group, an aryl group or a cycloalkyl group of n 10 and n 11 each independently represent an integer of 0 to 4.
  • R 12 and R 13 When a plurality of R 12 and R 13 exist, they may be the same or different.
  • R 14 represents a hydrogen atom, a halogen atom, an alkyl group of 1 to 5 carbon atoms, a thioalkyl group of 1 to 5 carbon atoms, or an alkoxy group of 1 to 5 carbon atoms.
  • n 12 represents an integer of 0 to 4; When a plurality of R 14 are present, they may be the same or different.
  • Examples of the divalent linking group for R 10 include the same as those described above for X.
  • Alkyl group of 1 to 5 carbon atoms for R 11, an alkoxy group having 1 to 5 carbon atoms, an aralkyl group, an aryl group, and the cycloalkyl group include the same as described above in R 5.
  • Examples of the hydroxyalkyl group having 1 to 5 carbon atoms for R 11 include the same alkyl groups as those described above for R 1 and R 2 .
  • Alkyl group of R 12 and carbon number of 1 to the R 13 5, an alkoxy group having 1 to 5 carbon atoms, hydroxyalkyl group having 1 to 5 carbon atoms, an aralkyl group, an aryl group, and the cycloalkyl group, the R 11 The same as those described above can be mentioned.
  • Examples of the thioalkyl group having 1 to 5 carbon atoms as R 12 and R 13 include the same alkyl groups as those described above for R 1 and R 2 .
  • the alkyl group having 1 to 5 carbon atoms, the thioalkyl group having 1 to 5 carbon atoms, and the alkoxy group having 1 to 5 carbon atoms those similar to those described above for R 12 and R 13 It can be mentioned.
  • n 10 is preferably 1.
  • a compound represented by the following general formula (2-1), a pharmaceutically acceptable salt thereof, or a solvate thereof may be contained as an active ingredient ,preferable.
  • R 10 represents a single bond or a divalent linking group.
  • R 11 represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a hydroxyalkyl group of 1 to 5 carbon atoms, an aralkyl group, an aryl group or a cycloalkyl group.
  • R 12 represents a hydrogen atom, a halogen atom, an alkyl group of 1 to 5 carbon atoms, a thioalkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a hydroxyalkyl group of 1 to 5 carbon atoms, an aralkyl group, It represents an aryl group or a cycloalkyl group.
  • an alkylene group is preferable as R 10 .
  • the alkylene group for R 10 a group in which one hydrogen atom has been removed from a linear or branched alkyl group having 1 to 5 carbon atoms is preferable.
  • Examples of the alkyl group having 1 to 5 carbon atoms include the same as those described above for R 1 and R 2 .
  • the agent for preventing or treating Alzheimer's disease of the present embodiment contains a compound represented by the following general formula (2-1-1), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient Is more preferred.
  • R 11 represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a hydroxyalkyl group of 1 to 5 carbon atoms, an aralkyl group, It represents an aryl group or a cycloalkyl group.
  • R 12 represents a hydrogen atom, a halogen atom, an alkyl group of 1 to 5 carbon atoms, a thioalkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a hydroxyalkyl group of 1 to 5 carbon atoms, an aralkyl group, It represents an aryl group or a cycloalkyl group.
  • R 11 an alkyl group of 1 to 5 carbon atoms or a hydroxyalkyl group of 1 to 5 carbon atoms is preferable.
  • R 12 a halogen atom or a thioalkyl group having 1 to 5 carbon atoms is preferable.
  • the present invention provides an agent for preventing or treating Alzheimer's disease, which comprises a compound represented by the following general formula (3), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient I will provide a.
  • the agent for preventing or treating Alzheimer's disease can also be provided as an agent for preventing or treating GM1 gangliosidosis.
  • R 20 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, a thioalkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, 1 to 5 carbon atoms And a hydroxyalkyl group, an aralkyl group, an aryl group or a cycloalkyl group of R 21 and R 24 each independently represent a single bond or a divalent linking group.
  • R 22 and R 23 each independently represent a hydrogen atom, a halogen atom, an alkyl group of 1 to 5 carbon atoms, a haloalkyl group of 1 to 5 carbon atoms, a thioalkyl group of 1 to 5 carbon atoms, or 1 to 5 carbon atoms And an alkoxy group of 1 to 5 carbon atoms and a hydroxyalkyl group having 1 to 5 carbon atoms.
  • R 20 is a halogen atom, an alkyl group of 1 to 5 carbon atoms, a thioalkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a hydroxyalkyl group of 1 to 5 carbon atoms, an aralkyl group, an aryl group, And as the cycloalkyl group, the same as described above for R 12 can be mentioned.
  • Examples of the divalent linking group for R 21 and R 24 include the same as those described above for X.
  • a halogen atom, an alkyl group of 1 to 5 carbon atoms, a thioalkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, and a hydroxyalkyl group of 1 to 5 carbon atoms include The same as described above for R 12 can be mentioned.
  • the haloalkyl group having 1 to 5 carbon atoms as R 22 and R 23 include a fluoroalkyl group, an alkyl chloride group and an alkyl bromide group, and at least one of the alkyl groups described above in R 1 and R 2 What has a hydrogen atom replaced by a halogen atom is mentioned.
  • R 20 an alkyl group having 1 to 5 carbon atoms or an aralkyl group is preferable.
  • the aralkyl group for R 20 one in which an alkylene group of 1 to 5 carbon atoms is bonded to a phenyl group is preferable.
  • R 21 and R 24 a single bond or —O— is preferable.
  • R 22 and R 23 a hydrogen atom or a trifluoromethyl group is preferable.
  • a compound represented by the following formula (3-1) or (3-2), a pharmaceutically acceptable salt thereof, or a solvate thereof as an agent for preventing or treating Alzheimer's disease of the present embodiment is an active ingredient It is particularly preferable to contain it as
  • the present invention provides an agent for preventing or treating Alzheimer's disease, which comprises a compound represented by the following general formula (4), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient I will provide a.
  • the agent for preventing or treating Alzheimer's disease can also be provided as an agent for preventing or treating GM1 gangliosidosis.
  • each of R 30 and R 31 independently represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group of 1 to 5 carbon atoms, a thioalkyl group of 1 to 5 carbon atoms, or 1 to 5 carbon atoms]
  • 5 represents an alkoxy group, a hydroxyalkyl group having 1 to 5 carbon atoms, or an aralkyl group.
  • the solid and dotted double line portions represent single bonds or double bonds.
  • R 30 and R 31 each represent a halogen atom, an alkyl group of 1 to 5 carbon atoms, a thioalkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a hydroxyalkyl group of 1 to 5 carbon atoms, and an aralkyl group And the same as those described above for R 12 can be mentioned.
  • R 30 and R 31 an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, and a hydroxyl group are preferable.
  • a compound represented by the following formula (4-1) or (4-2), a pharmaceutically acceptable salt thereof, or a solvate thereof as an agent for preventing or treating Alzheimer's disease of the present embodiment is an active ingredient. It is particularly preferable to contain it as
  • the present invention provides an agent for preventing or treating Alzheimer's disease, which comprises a compound represented by the following general formula (5), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient: I will provide a.
  • the agent for preventing or treating Alzheimer's disease can also be provided as an agent for preventing or treating GM1 gangliosidosis.
  • R 40 represents a single bond or a divalent linking group.
  • R 41 to R 43 each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group having 1 to 5 carbon atoms, a thioalkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, It represents a hydroxyalkyl group of -5 or an aralkyl group.
  • Examples of the divalent linking group for R 40 include the same as those described above for X.
  • a halogen atom for R 41 to R 43 an alkyl group having 1 to 5 carbon atoms, a thioalkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, and an aralkyl group are the same as described above for R 12 .
  • an alkylene group is preferable.
  • the alkylene group for R 40 a group in which one hydrogen atom has been removed from a linear or branched alkyl group having 1 to 5 carbon atoms is preferable.
  • Examples of the linear or branched alkyl group having 1 to 5 carbon atoms include the same as those described above for R 1 and R 2 .
  • R 41 to R 43 a hydrogen atom or a halogen atom is preferable.
  • a compound represented by the following formula (5-1) or (5-2), a pharmaceutically acceptable salt thereof, or a solvate thereof as an agent for preventing or treating Alzheimer's disease of the present embodiment is an active ingredient. It is particularly preferable to contain it as
  • the above-mentioned compound may be used in the form of a free form or in the form of a pharmaceutically acceptable salt. Also, they may be used in the form of a free form solvate, or may be used in the form of a salt solvate.
  • the salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and, for example, hydrochloride, sulfate, hydrobromide, hydroiodide, phosphate, nitrate, benzoate, methanesulfone Acid, 2-Hydroxyethane Sulfonate, p-Toluene Sulfonate, Acetate, Propanoate, Oxalate, Malonate, Succinate, Glutarate, Adipate, Tartrate, Maleic Acid Salts, fumarates, malates, mandelates and the like can be mentioned.
  • the solvate is not particularly limited as long as it is a pharmaceutically acceptable solvate, and includes, for example, hydrate, organic solvate and the like.
  • the present invention provides a composition for the prophylaxis or treatment of Alzheimer's disease, which comprises the above-mentioned prophylactic or therapeutic agent for Alzheimer's disease, and a pharmaceutically acceptable carrier.
  • the composition for preventing or treating Alzheimer's disease can also be provided as a composition for preventing or treating GM1 gangliosidosis.
  • composition for preventing or treating Alzheimer's disease of the present embodiment may be, for example, orally in the form of a tablet, a coated tablet, a pill, a powder, a granule, a capsule, a solution, a suspension, an emulsion, etc.
  • the pharmaceutically acceptable carrier those generally used for the preparation of pharmaceutical compositions can be used without particular limitation. More specifically, for example, binders such as gelatin, corn starch, tragacanth gum and gum arabic; excipients such as starch and crystalline cellulose; swelling agents such as alginic acid; solvents for injection such as water, ethanol and glycerin;
  • the pressure-sensitive adhesive include rubber-based pressure-sensitive adhesives and silicone-based pressure-sensitive adhesives.
  • the pharmaceutically acceptable carrier can be used alone or in combination of two or more.
  • the composition for preventing or treating Alzheimer's disease of the present embodiment may further contain an additive.
  • additives such as calcium stearate and magnesium stearate; sweeteners such as sucrose, lactose, saccharin and maltitol; flavoring agents such as peppermint and red mono oil; stabilizers such as benzyl alcohol and phenol; phosphoric acid Salts, buffers such as sodium acetate; solubilizers such as benzyl benzoate and benzyl alcohol; antioxidants; preservatives and the like.
  • the additives may be used alone or in combination of two or more.
  • the administration method of the preventive or therapeutic agent for Alzheimer's disease or the composition for preventing or treating Alzheimer's disease is not particularly limited, and may be appropriately determined according to the condition, weight, age, sex and the like of the patient. For example, tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions and the like are orally administered.
  • the injections are intravenously administered alone or mixed with ordinary fluid replacements such as glucose and amino acids, and further, if necessary, intraarterially, intramuscularly, intradermal, subcutaneous or intraperitoneally. Suppositories are administered rectally.
  • the external skin preparation is applied, affixed or sprayed to the affected area.
  • the dose of the prophylactic or therapeutic agent for Alzheimer's disease, or the composition for the prophylaxis or treatment of Alzheimer's disease varies depending on the patient's condition, body weight, age, sex, etc. and can not be determined generally, but in the case of oral administration
  • 1 ⁇ g to 10 g per day for example, 0.01 to 2000 mg of the active ingredient per day may be administered.
  • 0.1 ⁇ g to 1 g per day for example, 0.001 to 200 mg of the active ingredient per day may be administered.
  • suppositories for example, 1 ⁇ g to 10 g per day, for example, 0.01 to 2000 mg of the active ingredient per day may be administered.
  • a skin external preparation for example, 1 ⁇ g to 10 g of active ingredient per day, for example, 0.01 to 2000 mg per day may be administered.
  • the present invention provides for the prevention or treatment of Alzheimer's disease, Amodiaquine (Amodiaquine), Acacetin (Acacetin), Sulfamerazine (Sulfamelazine), Ungerine (Ungelin), Amiodarone (Amiodarone), Sertindol (Sertindole) , Delcorine (Dercoline), Perphenazine (Perphenazine), Althiazole (Althiazide), Diethylstilbestrol (Diethylstilbestrol), Thiethylperazine (Thiethylperazine), Harmol (Halmol), Skimmianine (Skimmianin), Succinylsulfathiazole (Succinyl Sulfathiazole), ), Canavanine (Canavanine), Harmaline (Halmarin), Trihexyphenidyl (Trihexyphenidyl), Flu
  • the present invention includes Amodiaquine (Amodiaquine), Acacetin (Acacetin), Sulfamerazine (Sulphamelazine), Ungerine (Ungelin), Amiodarone (Amiodarone), Sertindol (Sertindol), Delcorine (Delcholine), Perphenazine (Perphenazine) ), Althiazide (altiazide), Diethylstilbestrol (diethylstilbestrol), Thiethylperazine (thiethylperazine), Harmol (harmol), Skimmianine (skimmianin), Succinylsulfathiazole (succinylsulfathiazole), Fillalbin (filalbin), Canavanine (Canabanine armaline) ), Trihexyphenyl (trihexyphenidyl), Fluoxetine (fluoxetine), Lovastatin (lovastatin), Halope
  • the present invention relates to Amodiaquine (Amodiaquine), Acacetin (acacetin), Sulfamerazine (sulfamelazine), Ungerine for producing a preventive or therapeutic agent for Alzheimer's disease, or a composition for preventing or treating Alzheimer's disease.
  • Amodiaquine Amodiaquine
  • Acacetin acacetin
  • Sulfamerazine sulfamelazine
  • Ungerine for producing a preventive or therapeutic agent for Alzheimer's disease, or a composition for preventing or treating Alzheimer's disease.
  • the animal model for Alzheimer's disease used in the evaluation of the present invention is a ⁇ -gal protein of which ⁇ -Galactosidase (hereinafter also referred to as ⁇ -gal) gene expression is suppressed or lost or which is encoded by the ⁇ -gal gene. It is a non-human mammal whose function has been suppressed or lost and a mutation has been introduced into the expression control region of the ⁇ -gal gene or the ⁇ -gal gene.
  • ⁇ -gal ⁇ -Galactosidase
  • the ⁇ -gal protein is an enzyme present in lysosomes that plays a role in the hydrolysis of various biomolecules.
  • GM1 ganglioside is a substrate for ⁇ -gal protein and is abundant in the brain. Therefore, suppression or loss of ⁇ -gal leads to accumulation of GM1 ganglioside.
  • the loss of the function of the ⁇ -gal protein refers to the state in which the function originally possessed by the ⁇ -gal protein is completely lost.
  • the fact that the function of ⁇ -gal protein is suppressed refers to a state in which the function originally possessed by ⁇ -gal protein is partially lost.
  • the degree of suppression of the function of the ⁇ -gal protein is determined by comparing the model animal and the wild-type animal of the animal model with the control. It should be such an extent that a condition (difference from control) appears in a model animal in comparison with the animal.
  • An indicator of a condition recognized as Alzheimer's disease includes deposition of amyloid proteins (A ⁇ 40 and 42) in the brain.
  • Suppression or loss of function of ⁇ -gal protein can also be caused by suppression or loss of expression of ⁇ -gal gene.
  • Loss of expression of the ⁇ -gal gene means loss of the ⁇ -gal gene product in a model animal.
  • the suppression of the expression of the ⁇ -gal gene means that the amount of the ⁇ -gal gene product is suppressed as compared to a control animal such as a wild-type animal of a model animal. .
  • the degree of suppression is compared to Alzheimer's disease as shown above in comparison with a control animal such as a wild-type animal of a model animal. It is sufficient if it is in such an extent that a recognized state appears.
  • a nucleic acid sequence that causes expression of RNAi-inducing nucleic acid, antisense nucleic acid, aptamer or ribozyme for ⁇ -gal gene is introduced into a model animal and generated by gene knockdown etc. Can.
  • the model animal used for the evaluation of the present invention preferably has a mutation introduced into the expression control region of the ⁇ -gal gene or ⁇ -gal gene.
  • the introduced mutation may be one that suppresses or loses the expression of the ⁇ -gal gene or suppresses or loses the function of the ⁇ -gal protein encoded by the ⁇ -gal gene.
  • the above-mentioned ⁇ -gal gene is not only an exon which is a region encoding ⁇ -gal protein, but also suppresses or loses the expression of ⁇ -gal gene or functions of ⁇ -gal protein encoded by the above-mentioned ⁇ -gal gene Introns are also included if they can be suppressed or lost.
  • the expression regulatory region of the ⁇ -gal gene is a region that regulates the expression of the ⁇ -gal gene, and is, for example, a promoter, a silencer, an enhancer, or a response element.
  • Loss of function of the ⁇ -gal protein can be produced, for example, by introducing a mutation into the ⁇ -gal gene and disrupting the ⁇ -gal gene.
  • the suppression or loss of the expression ability of the ⁇ -gal gene can be produced, for example, by introducing a mutation into the expression regulatory region of the ⁇ -gal gene.
  • the method for introducing a mutation into the expression control region of the ⁇ -gal gene or ⁇ -gal gene can be carried out by genetic modification which is a known genetic engineering technique.
  • the mutation can be generated by deletion or substitution of part or all of the expression control region of the ⁇ -gal gene or ⁇ -gal gene, insertion of any sequence, and the like.
  • the deletion is preferably a deletion of one or more exons.
  • Introduction of these mutations includes, for example, treatment with mutagenic substances (Mutagen), gene targeting by ultraviolet irradiation, homologous recombination technology etc., gene knockout, conditional knock out by gene knockdown, Cre-loxP system etc. It can be done using the method.
  • ⁇ -gal gene mutation examples include mutations in human ⁇ -gal protein such as E186A, P10L, R201C, C127Y, W161G, Q255H, R351X, S532G, R148S and the like.
  • the animal model for Alzheimer's disease used in the evaluation of the present invention further includes deletion of exon 9 of human prisenilin 1 (PS1), M146L mutation, L285V mutation, N141I mutation of human PS2, KM670 / of human amyloid precursor protein (APP) It is preferable to have at least one mutation selected from the group consisting of 671 NL Swedish type mutation, I716V Florida type mutation, and V717 I London type mutation, M146L mutation of human prisenilin 1 (PS1), and L285V mutation, and human amyloid precursor It is more preferable to have five types of mutations, KM670 / 671 NL Swedish type mutation, I716V Florida type mutation, and V717I London type mutation of body protein (APP).
  • the non-human mammal is preferably, but not limited to, an animal classified into rodents.
  • Non-human mammals include mice, rats, guinea pigs, hamsters, rabbits, goats, pigs, dogs and cats.
  • the model animal according to the evaluation of the present invention can be used for elucidating the mechanism of Alzheimer's disease, searching for a substance useful for the treatment or the like, and developing a treatment method or the like.
  • Fibroblasts were established from skin biopsies explants of GM1 gangliosidosis patients and healthy persons under informed consent according to a protocol approved by the ethics committee. Skin samples from patients and healthy individuals were minced and cultured in DMEM medium supplemented with 10% fetal bovine serum (FBS). After confirming that fibroblasts appeared, fibroblasts were expanded to introduce a reprogramming gene.
  • FBS fetal bovine serum
  • iPS cells were established from established human-derived fibroblasts. Specifically, 1 day before infection, 5 ⁇ 10 5 human fibroblasts are seeded per well in a 6-well plate, and then Oct3 / 4 gene, Sox2 gene, K1f4 gene, and c-Myc gene. The cells were infected with a Sendai virus (SeV) vector containing MOI (multiplicity of infection) 3.
  • SeV Sendai virus
  • NSCs neural stem cells
  • the induced NSCs were deprived of the medium, the cells were detached using StemPro Accutase Cell Dissociation Reagent (Thermo Fisher Scientific), the cells were suspended in Neural Expansion Medium (Thermo Fisher Scientific), and then 100 mm cell culture coated with Geltrex was performed. Sowing to petri dishes. The cells at this time point were designated as P0 NSCs (NSCs with zero passage number), and thereafter, NSCs were appropriately increased in this medium and used for experiments.
  • Example 3 The amount of GM1 ganglioside in the brains of Alzheimer's patients is reported to be greater than the amount of GM1 gangliosides in the brains of healthy individuals.
  • the inventors examined the metabolic state of GM1 ganglioside in neural stem cells derived from Alzheimer's disease. First, when ⁇ -gal activity of patient-derived neural stem cells was examined, it was found that ⁇ -gal activity of Alzheimer's disease-derived neural stem cells was decreased as compared to that of healthy individuals. See confirmed ( Figure 2A). ). In FIG.
  • 201B7 and 409B2 indicate neural stem cells derived from healthy persons
  • A138 and A154 indicate neural stem cells derived from GM1 gangliosidosis patients
  • A232 # 3-1 and A232 # 2-2 indicate Alzheimer's disease.
  • 1 shows neural stem cells derived from.
  • Sol means the insoluble fraction
  • Sup means the soluble fraction. It is shown that there is no difference in ⁇ -gal activity in the insoluble fraction / availability fraction in this experimental example.
  • the inventors examined the effect of overexpression of APP on ⁇ -gal activity.
  • a control vector or an APP overexpression vector was introduced into neural stem cells from healthy individuals, and ⁇ -gal activity was measured. It was confirmed that ⁇ -gal activity was reduced in neural stem cells into which the APP overexpression vector was transferred, as compared to neural stem cells into which the control vector was transferred (see FIG. 2B).
  • FIG. 2C is a graph showing the amount of GM1 ganglioside in the whole cell
  • FIG. 2D is a graph showing the amount of GM1 ganglioside in the lipid raft fraction. It has been confirmed that the amount of GM1 ganglioside in neural stem cells derived from Alzheimer's disease is greater than the amount in neural stem cells derived from healthy individuals. In particular, the difference in the lipid raft fraction was large. There is also a finding that ⁇ -gal is involved in the degradation of GM1 ganglioside. From these facts, in neural stem cells derived from Alzheimer's disease, ⁇ -gal activity is reduced, whereby GM1 ganglioside is accumulated. It was suggested that.
  • Example 4 To confirm whether GM1 ganglioside reduction affected A ⁇ metabolism, ⁇ -gal protein was overexpressed in neural stem cells (see FIG. 3A-D).
  • Control indicates a neural stem cell into which a control vector has been introduced
  • GLB1 OE indicates a neural stem cell into which a ⁇ -gal protein overexpression vector has been introduced.
  • FIG. 3B it was confirmed that the amount of A ⁇ 42 decreased due to the overexpression of ⁇ -gal protein in neural stem cells derived from Alzheimer's disease.
  • 201B7 NSC represents neural stem cells derived from healthy subjects
  • A138 NSC represents neural stem cells derived from GM1 gangliosidosis patients
  • 201 B7 + GM1 represents neural stem cells derived from healthy subjects treated with GM1 ganglioside.
  • neural stem cells derived from GM1 gangliosidosis patients are more sensitive to A ⁇ 42 than neural stem cells derived from healthy individuals. Furthermore, it was confirmed that the sensitivity to A ⁇ 42 in neural stem cells derived from GM1 ganglioside-treated healthy individuals shows a tendency similar to that of GM1 gangliosidosis-derived neural stem cells. From these facts, it was suggested that GM1 ganglioside affects the production of A ⁇ in neural stem cells.
  • FIGS. 4A and 4B show the results of quantification of soluble A ⁇ in TBS (Tris Buffered Saline) extract fractions, and FIGS.
  • Example 6 ⁇ Evaluation of compounds by drug screening using imaging cytometer> A screening agent for Alzheimer's disease was conducted as follows. After coating a 96-well plate with Geltrex, neural stem cells derived from healthy individuals and iPS cells from GM1 gangliosidosis patients suspended in Neural Expansion Medium were seeded at a density of 5 ⁇ 10 4 / well. Thereafter, compounds of the known drug library were added to each well to a final concentration of 5 ⁇ M, and culture was performed for 72 hours.
  • FIG. 5 and FIG. 5 staining images of neural stem cells after drug treatment with several compounds hit as GM1 inhibitory compounds are shown in FIG. 5 and FIG.
  • the hit compounds it is confirmed that the fluorescence of CTB is lower and the accumulation of GM1 is suppressed, as compared with the case where no drug is added (FIG. 5 b, lower, FIG. 6 e, lower). (FIG. 5 c and d, FIG. 6 f to g, each lower).
  • Example 7 ⁇ Effect on hit (extracellular) A ⁇ of a hit drug that reduces GM1 accumulation> Neural stem cells derived from Alzheimer's disease patient-derived iPS cells are seeded at a density of 2 ⁇ 10 6 / well in Geltrex-coated 6-well plates, hit drug is added to a final concentration of 5 ⁇ M, and culture is performed for 72 hours did. After 72 hours, the cell supernatant was collected, and the supernatant obtained by centrifugation at 400 g for 10 minutes was used as a sample for analysis.
  • a ⁇ 42 / A ⁇ 40 in the medium of neural stem cells derived from Alzheimer's disease patients and A ⁇ 42 / A ⁇ 40 in the cells showed high values as compared to healthy persons (lower row in FIGS. 7 and 8). It was confirmed that the treatment with the GM1 inhibitory compound reduced the total A ⁇ and A ⁇ 42 / A ⁇ 40 ratio in the medium and cells of neural stem cells derived from Alzheimer's disease patients (FIG. 7 c, FIG. 8 f).
  • mouse brain was embedded with OCT compound, and a section was prepared with a thickness of 5 ⁇ m. The section was fixed with 4% paraformaldehyde and then 1 % Blocked with BSA solution and fluorescently stained with Alexa Fluor 488-CTB, Hoechst 33342.
  • mouse brain was fractionated and purified based on the extraction method of Svennerholm and Fredman, and used as a sample. , These samples Agilent 64 Analysis was carried out with 60 Triple Quadrupole LC / MS to quantify GM1 in the brain The results of the fluorescent staining are shown in FIG.
  • FIG. 9a In negative subjects, little CTB fluorescence was seen (Fig. 9a, upper row). On the other hand, in the positive subjects, the fluorescence of CTB was strong, and the accumulation of GM1 was confirmed (Fig. 9b, upper row). On the other hand, it was confirmed that the fluorescence of CTB was strongly suppressed and the accumulation of GM1 was suppressed in any of the treatments with the GM1 inhibitory compound (FIG. 9 c, d, each upper row). The quantitative result of GM1 is shown in FIG.
  • 11C and 11C show the results of determination of insoluble A ⁇ in Guanidin-HCl extract fractions. It was confirmed that A ⁇ 40 and 42 decreased in the Amodiaquine administration group and Thiethylperanzine administration group, as compared with the PBS administration group.
  • FIG. 11E Similar to the results of FIGS. 11A to D, it was confirmed that A ⁇ 40 and 42 decrease in the Amodiaquine administration group and the Thiethylperanzine administration group.
  • Example 10 ⁇ Influence on autophagy by addition of GM1 inhibitory compound> The synthesis and degradation process of ganglioside is shown in FIG. Each ganglioside of GM1, GM2 and GM3 is produced by the sequential addition of monosaccharides and N-acetylneuraminic acid. Furthermore, the degradation of gangliosides is carried out by the stepwise action of glycosidases in lysosomes. (1) to (7) in FIG. 12 show enzymes acting in each reaction. FIG. 13 shows that expression of NEU1 and ⁇ -GLU is increased by treatment with candidate compounds.
  • Neural stem cells obtained by differentiating from normal (201B7) and disease-derived (A138 # 1-3) iPS cells are seeded in the wells, Amodiaquine or Thiethylperanzine is added to 5 ⁇ M, respectively, and culture is performed for 72 hours. The After culture, RNA was isolated, and the expression amount of each enzyme gene was analyzed. In FIG. 13,-indicates an additive-free sample, amo indicates an Amodiaquine-loaded sample, and thie indicates a Thiethylperanzine-loaded sample. The present results suggest that the action of the GM1 inhibitory compound promotes degradation of ganglioside in lysosome and activates autophagy.
  • an Alzheimer's disease preventive or therapeutic agent having a novel mechanism of action can be provided.

Abstract

L'invention concerne un agent prophylactique ou un agent thérapeutique contre la maladie d'Alzheimer caractérisés en ce qu'ils contiennent comme principe actif un agent prophylactique ou un agent thérapeutique contre la gangliosidose à GM1. L'invention concerne également une méthode de criblage d'agents prophylactiques ou d'agents thérapeutiques contre la maladie d'Alzheimer, caractérisée en ce qu'elle implique l'utilisation d'un agent prophylactique ou d'un agent thérapeutique contre la gangliosidose à GM1.
PCT/JP2018/048471 2017-12-28 2018-12-28 Agent prophylactique ou agent thérapeutique contre la maladie d'alzheimer, méthode de criblage associée, et composition pour prévenir ou traiter la maladie d'alzheimer WO2019132004A1 (fr)

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JP2024020478A JP2024040445A (ja) 2017-12-28 2024-02-14 アルツハイマー病予防剤又は治療剤、アルツハイマー病予防用又は治療用組成物、及び方法

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Citations (3)

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US4806537A (en) * 1987-04-16 1989-02-21 City Of Hope Use of amodiaquin and related compounds in treatment of nervous system degeneration
JP2002542194A (ja) * 1999-04-20 2002-12-10 オックスフォード グリコサイエンシズ（ユーケー）リミテッド 治療におけるグルコシルセラミド合成阻害剤と糖脂質分解酵素の組み合わせ
JP2013508371A (ja) * 2009-10-19 2013-03-07 アミカス セラピューティックス インコーポレイテッド 薬理シャペロンを用いてガングリオシドの活性を増大させて、アルツハイマー病を治療するための方法

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US20090270453A1 (en) 2007-12-17 2009-10-29 H. Lundbeck A/S Anti-manic effective doses of sertindole
US10588921B2 (en) 2013-12-05 2020-03-17 National University Corporation Kumamoto University Drug for the treatment of cholesterol accumulation disorders
EP3012321B1 (fr) 2014-09-05 2019-04-03 Korea Research Institute of Bioscience and Biotechnology Modèle cellulaire humain de gangliosidose à gm1 et utilisation de ce dernier
JP7333608B2 (ja) 2017-12-28 2023-08-25 国立大学法人 熊本大学 Ｇｍ１ガングリオシドーシス予防剤又は治療剤、及びｇｍ１ガングリオシドーシス予防用又は治療用組成物

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Publication number Priority date Publication date Assignee Title
US4806537A (en) * 1987-04-16 1989-02-21 City Of Hope Use of amodiaquin and related compounds in treatment of nervous system degeneration
JP2002542194A (ja) * 1999-04-20 2002-12-10 オックスフォード グリコサイエンシズ（ユーケー）リミテッド 治療におけるグルコシルセラミド合成阻害剤と糖脂質分解酵素の組み合わせ
JP2013508371A (ja) * 2009-10-19 2013-03-07 アミカス セラピューティックス インコーポレイテッド 薬理シャペロンを用いてガングリオシドの活性を増大させて、アルツハイマー病を治療するための方法

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