WO2018203559A1 - Compositions pharmaceutiques pour les maladies à expansion de polyglutamine - Google Patents

Compositions pharmaceutiques pour les maladies à expansion de polyglutamine Download PDF

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WO2018203559A1
WO2018203559A1 PCT/JP2018/017448 JP2018017448W WO2018203559A1 WO 2018203559 A1 WO2018203559 A1 WO 2018203559A1 JP 2018017448 W JP2018017448 W JP 2018017448W WO 2018203559 A1 WO2018203559 A1 WO 2018203559A1
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group
halogen atom
compound
polyglutamine
pharmaceutical composition
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Japanese (ja)
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萩原正敏
奥野友紀子
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国立大学法人京都大学
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/04—Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor
    • 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

Definitions

  • the present disclosure relates to pharmaceutical compositions relating to polyglutamine diseases, their use, and methods for preventing, improving, suppressing progression and / or treating polyglutamine diseases using them.
  • the present disclosure also relates to a method for screening a compound for polyglutamine disease.
  • Huntington's disease In hereditary neurological diseases such as Huntington's disease, which are summarized as polyglutamine diseases, CAG repeats in the causative gene are overextended, and a protein with polyglutamine overextension is generated using this CAG repeat as a template. Accumulate in and form aggregates. This polyglutamine aggregate causes triggering, cell damage, and subsequent neuronal loss. Huntington's disease is the second most common neurological disease after Alzheimer's disease and Parkinson's disease, but the main Huntington's disease drugs currently on the market are symptomatic treatments and drugs that can still be fundamentally treated. I can't say there is.
  • Non-Patent Document 1 discloses a reporter protein for forming a polyglutamine aggregate in which 150 repeats of Huntington gene exon 1 and a fluorescent protein are fused.
  • the present disclosure in one aspect, provides a pharmaceutical composition relating to polyglutamine disease, their use, and a method for preventing, ameliorating, suppressing progression and / or treating polyglutamine disease using them. In another aspect, the present disclosure provides a method for screening a compound relating to polyglutamine disease.
  • the present disclosure provides an intravascular epidermal growth factor receptor (VEGFR) inhibitor compound, a receptor tyrosine kinase (c-Met) inhibitor compound encoded by the c-met gene, and VEGFR and c-Met.
  • VEGFR intravascular epidermal growth factor receptor
  • c-Met receptor tyrosine kinase
  • the present invention relates to a pharmaceutical composition for preventing, ameliorating, suppressing progression and / or treating polyglutamine disease, which contains at least one selected from the group consisting of both inhibitory compounds as an active ingredient.
  • the present disclosure provides a method for screening a candidate substance for an active ingredient of a pharmaceutical composition for prevention, amelioration, progression inhibition, and / or treatment of polyglutamine disease, Culturing an assay cell expressing polyglutamine fused with a reporter protein in contact with a test substance, and measuring a reporter signal (A) in a virtual cell body region of the assay cell; Culturing the assay cell without contacting with the test substance, and measuring a reporter signal (B) in a virtual cell body region of the assay cell; Comparing signal (A) and signal (B); and
  • the present invention relates to a screening method comprising selecting, as a candidate substance, a test substance that reduces signal (A) over signal (B) based on the comparison.
  • FIG. 1 is a schematic diagram of an expression system of a fusion protein of polyglutamine and a reporter protein.
  • FIG. 2 is a schematic diagram of an example of a screening scheme.
  • FIG. 3 shows the expression induction of the assay system used for screening, and the Z ′ factor.
  • FIG. 4 is a graph showing the concentration dependency of compound 4 inhibition of polyglutamine aggregate formation.
  • FIG. 5 is a graph showing the concentration dependence of reporter protein expression level reduction by compound 4.
  • the present disclosure discloses a pharmaceutical composition of a pharmaceutical composition for polyglutamine disease (hereinafter, also referred to as “the pharmaceutical composition according to the present disclosure”).
  • the pharmaceutical composition for polyglutamine disease refers to a pharmaceutical composition for prevention, amelioration, progression inhibition, and / or treatment of polyglutamine disease in one or more embodiments.
  • polyglutamine disease is an overextension of a CAG repeat in a causative gene, generation of a protein having polyglutamine overextension using the CAG repeat as a template, or a nerve cell of this protein It refers to a disease caused by at least one of accumulation in the body and aggregate formation.
  • Polyglutamine disease includes, in one or more embodiments, Huntington's disease, hereditary spinocerebellar degeneration, or bulbar spinal muscular atrophy.
  • an inhibitor of intravascular epidermal growth factor receptor (VEGFR), an inhibitor of c-Met, or both VEGFR and c-Met
  • VEGFR intravascular epidermal growth factor receptor
  • a substance having inhibitory activity against VEGFR2 a substance having inhibitory activity against both VEGFR and c-Met, or a substance having inhibitory activity against both VEGFR2 and c-Met
  • a substance that suppresses the formation of polyglutamine aggregates a plurality of known VEGER inhibitors and substances having inhibitory activity against both VEGFR and c-Met were selected by the screening method according to the present disclosure described later.
  • VEGFR inhibitor that is an active ingredient includes a VEGFR inhibitor having a structure represented by the following formula (I).
  • W, Z and R 1 in the following formula (I) are arbitrary groups.
  • R 1 is a hydrogen atom, a halogen atom, a C 1-4 alkyl group, or a C 1-4 alkyl group substituted with a halogen atom
  • W is
  • R 2 and R 3 are each independently a hydrogen atom, a halogen atom, a C 1-4 alkyl group, or a C 1-4 alkyl group substituted with a halogen atom
  • X 1 is a C 1-4 alkylene group, C 1-4 alkylene group substituted with a halogen atom or an imino group
  • X 2 and Y are each independently, C 1-4 alkylene group, C 1-4 alkylene group substituted with a halogen atom, or an imino group, or, X 2 and Y together with the atom marked with a form an aromatic ring or a heteroaromatic ring, said ring being unsubstitute
  • Examples thereof include a compound or a pharmaceutically acceptable salt thereof having one or more substituents which are oxy groups.
  • a bond with a wavy line indicates a bond portion with the compound or group represented by the formula (I), (II) or (III).
  • the VEGFR inhibitor in the present disclosure is a control in which the substance is not added to the activity of VEGFR when the substance is added in a known VEGFR inhibition assay system in at least one of in vitro and in vivo. Compared to, for example, it refers to a compound that can be inhibited to 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, or 10% or less. In the assay system, the amount of substance added is 0.01-10 ⁇ M in one or more embodiments.
  • the c-Met inhibitory substance in the present disclosure refers to the activity of c-Met when the substance is added in a known c-Met inhibition assay system in at least one of in vitro and in vivo. Compared with the control to which the substance is not added, it refers to a compound that can be inhibited to, for example, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, or 10% or less. In the assay system, the amount of substance added is 0.01-10 ⁇ M in one or more embodiments.
  • the inhibitor of both VEGFR and C-Met refers to the activity of VEGFR in the known VEGFR inhibition assay system in at least one of in vitro and in vivo in the one or a plurality of embodiments when the substance is added. Compared with a control to which the substance is not added, for example, it can be inhibited to 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, or 10% or less, and at least one of in vitro and in vivo
  • the activity of c-Met when the substance is added is, for example, 60% or less, 50% or less, 40% or less, 30% or less compared to a control without the substance. , 20% or less, or a compound that can be inhibited to 10% or less.
  • the amount of substance added is 0.01-10 ⁇ M in one or more embodiments.
  • the alkyl group or alkylene group includes a linear, branched, or cyclic alkyl group or alkylene group.
  • the “C 1-4 alkyl group” is a linear, branched or cyclic alkyl group having 1 to 4 carbon atoms in one or a plurality of embodiments.
  • the linear or branched alkyl group having 1 to 4 carbon atoms includes a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and a sec-butyl group. And tert-butyl group.
  • Examples of the cyclic alkyl group having 3 to 4 carbon atoms include a cyclopropyl group and a cyclobutyl group in one or more embodiments.
  • Heterocycle in one or more embodiments, contains 1-2 heteroatoms in the atoms constituting the ring, may contain double bonds in the ring, and is non-aromatic. Or an aromatic ring. “Heteroaromatic ring” means an aromatic heterocycle. “Hetero atom” means, in one or more embodiments, a sulfur atom, an oxygen atom or a nitrogen atom.
  • the “pharmaceutically acceptable salt” includes a pharmacologically and / or pharmaceutically acceptable salt, for example, an inorganic acid salt, an organic acid salt, an inorganic basic salt, an organic basic salt, an acidic amino acid salt. Or a basic amino acid salt etc. are mentioned.
  • Preferable examples of the inorganic acid salt include hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like, and preferable examples of the organic acid salt include, for example, acetate, succinate, Examples thereof include fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, and p-toluenesulfonate.
  • Preferred examples of the inorganic base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt.
  • Preferable examples of the organic base salt include diethylamine salt, diethanolamine salt, meglumine salt, N, N′-dibenzylethylenediamine salt and the like.
  • Preferred examples of the acidic amino acid salt include aspartate and glutamate.
  • Preferable examples of the basic amino acid salt include arginine salt, lysine salt, ornithine salt and the like.
  • the “salt of a compound” may include a hydrate that can be formed by absorbing moisture when the compound is left in the air. Further, in the present disclosure, the “salt of a compound” may include a solvate that can be formed by absorbing a certain kind of other solvent.
  • R 1 in the above formula (I) includes, in one or more embodiments, a halogen atom, or a C 1-4 alkyl group substituted with a halogen atom, and in one or more embodiments, fluorine atom Or a trifluoromethyl group.
  • W in the above formula (I) is one or more embodiments, Is mentioned.
  • R 2 and R 3 each independently represents a hydrogen atom or a halogen atom.
  • X 1 is an imino group in one or a plurality of embodiments
  • X 2 and Y are each independently an imino group or a group in one or a plurality of embodiments.
  • W in the above formula (I) has an inhibitory activity against c-Met in addition to the inhibitory activity against VEGFR.
  • R 2 , R 3 , X 2 and Y are the same as above.
  • Z in the above formula (I) is, in one or more embodiments, Is mentioned.
  • R 4 and R 5 in one or more embodiments, are each independently a halogen atom or an amino group, or R 4 and R 5 , together with atoms marked with b and c, Is mentioned.
  • R 6 and R 7 are each independently a methyl group, or Is mentioned.
  • the formula (I) is the following formula (III) in one or more embodiments.
  • W is R 1 -R 3 , R 6 and R 7 , X 1 , X 2 and Y are the same as in formula (I). ]
  • the formula (I) is represented by the following formula (IV) in one or more embodiments. [In formula (IV), R 1 -R 5 , X 2 and Y are the same as in formula (I)]
  • VEGFR inhibitor which is an active ingredient
  • the following compound 1-5 may be mentioned.
  • One or more embodiments of a substance having both VEGFR and c-Met inhibitory activity include the following compound 2-4.
  • the active ingredient of the pharmaceutical composition according to the present disclosure may include the following compound 6-11.
  • the above-mentioned compound that is an active ingredient of the pharmaceutical composition according to the present disclosure is, in one or a plurality of embodiments, a mixture or a single isomer. It has been released.
  • cis-trans isomers may be mentioned.
  • prodrug includes those that are easily hydrolyzed in vivo and regenerate the above compound.
  • carboxyl group is an alkoxycarbonyl group.
  • a compound that becomes an alkylthiocarbonyl group, or a compound that becomes an alkylaminocarbonyl group is an alkoxycarbonyl group.
  • a compound having an amino group a compound in which the amino group is substituted with an alkanoyl group to become an alkanoylamino group, a compound in which the amino group is substituted with an alkoxycarbonyl group to become an alkoxycarbonylamino group, an acyloxymethylamino group, Or a compound that has become hydroxylamine.
  • a compound having a hydroxyl group a compound in which the hydroxyl group is substituted with the acyl group to become an acyloxy group, a compound that has become a phosphate ester, or a compound that has become an acyloxymethyloxy group can be given.
  • alkyl moiety of the group used for forming a prodrug examples include an alkyl group described later, and the alkyl group may be substituted (for example, with an alkoxy group having 1 to 6 carbon atoms).
  • the alkyl group may be substituted (for example, with an alkoxy group having 1 to 6 carbon atoms).
  • lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, methoxymethoxycarbonyl, ethoxymethoxy, etc.
  • Examples include lower (eg, having 1 to 6 carbon atoms) alkoxycarbonyl substituted with an alkoxy group such as carbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, and pivaloyloxymethoxycarbonyl.
  • the pharmaceutical composition of the present disclosure contains the inhibitor as an active ingredient, and further includes a pharmaceutically acceptable carrier, preservative, diluent, excipient, or other pharmaceutical agent. May contain acceptable components.
  • the “pharmaceutical composition” may be a dosage form suitable for an administration form by applying a well-known formulation technique in one or a plurality of embodiments.
  • the dosage form include, but are not limited to, oral administration in a dosage form such as a tablet, capsule, granule, powder, pill, troche, syrup, and liquid.
  • parenteral administration in dosage forms such as injections, solutions, aerosols, suppositories, patches, patches, lotions, liniments, ointments, eye drops and the like can be mentioned.
  • These preparations can be produced by known methods using additives such as, but not limited to, excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.
  • excipient examples include, but are not limited to, starch such as starch, potato starch, and corn starch, lactose, crystalline cellulose, calcium hydrogen phosphate, and the like.
  • coating agent examples include, but are not limited to, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, paraffin, and the like.
  • binder include, but are not limited to, polyvinyl pyrrolidone, macrogol and the same compound as the excipient.
  • disintegrant examples include, but are not limited to, compounds similar to the excipients and chemically modified starch and celluloses such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone.
  • stabilizer examples include, but are not limited to, paraoxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenol, cresol Mention may be made of such phenols; thimerosal; dehydroacetic acid; and sorbic acid.
  • flavoring agent examples include, but are not limited to, sweeteners, acidulants, and fragrances that are commonly used.
  • the solvent is not limited to these, but ethanol, phenol, chlorocresol, purified water, distilled water and the like can be used, and a surfactant or an emulsifier can also be used as necessary.
  • a surfactant or an emulsifier include, but are not limited to, polysorbate 80, polyoxyl 40 stearate, lauromacrogol, and the like.
  • the method of using the pharmaceutical composition according to the present disclosure may vary depending on symptoms, age, administration method, and the like.
  • the method of use is not limited to these, but intermittently or continuously, orally, transdermally, submucosally, subcutaneously, so that the in vivo concentration of the compound as the active ingredient is between 100 nM and 1 mM.
  • Administration can be intramuscular, intravascular, intracerebral, or intraperitoneal.
  • the lower limit is 0.01 mg (preferably converted into the compound represented by the above general formula (I) per day for a subject (adult if human)) 0.1 mg), and as an upper limit, 2000 mg (preferably 500 mg, more preferably 100 mg) can be divided into one or several doses and administered according to symptoms.
  • the lower limit is 0.001 mg (preferably 0.01 mg) and the upper limit is 500 mg (preferably 50 mg) per day for a subject (adult if human). Is divided into one or several times and administered according to symptoms.
  • the present disclosure is a method for preventing, ameliorating, suppressing progression and / or treating polyglutamine disease, the method comprising administering a pharmaceutical composition according to the present disclosure to a subject.
  • administration of the pharmaceutical composition according to the present disclosure can be based on the above-described method of using the pharmaceutical composition. Examples of the subject include humans and non-human animals.
  • the present disclosure relates to the use of the above-described compound or a pharmaceutically acceptable salt thereof as an active ingredient for prevention, amelioration, progression inhibition, and / or treatment of polyglutamine disease.
  • the present compound or the pharmaceutical thereof is an active ingredient for producing a pharmaceutical composition for prevention, amelioration, progression inhibition, and / or treatment of polyglutamine disease. It relates to the use of top acceptable salts.
  • the present disclosure relates to a method for screening a substance that affects the formation of a polyglutamine aggregate.
  • the screening method of this aspect is: Culturing an assay cell expressing polyglutamine fused with a reporter protein in contact with a test substance, and measuring a reporter signal (A) in a virtual cell body region of the assay cell; Culturing the assay cell without contacting with the test substance, and measuring a reporter signal (B) in a virtual cell body region of the assay cell; Comparing signal (A) and signal (B); and Selecting a test substance that reduces the signal (A) over the signal (B) as a candidate substance based on the comparison.
  • the assay cell in the screening method according to the present disclosure has a gene capable of expressing polyglutamine fused with a reporter protein.
  • the assay cell can be prepared by introducing a gene expression vector constructed and adapted to express a polyglutamine mRNA fused with a reporter protein into the cell.
  • the cell used for the production of the assay cell that is, the cell into which the vector is introduced is not particularly limited, and in one or more embodiments, is a mammalian cell.
  • the mammalian cell is a human, bovine, cat, monkey, dog, hamster, mink, mouse, pig, rabbit, rat cell.
  • the type of cell is not particularly limited, and in one or a plurality of embodiments, a nerve cell or a cultured cell thereof can be mentioned.
  • the vector may be a type that performs transient expression or a type that performs stable expression.
  • the promoter of the gene expression vector a promoter known in the art or developed in the future that can induce protein expression in the assay cell can be used.
  • the reporter protein include a photoprotein in one or a plurality of embodiments, and examples include a fluorescent protein.
  • a gene capable of expressing polyglutamine fused with a reporter protein those described in the Examples can be used.
  • the virtual cell body region refers to a predetermined region including the periphery of the cell nucleus.
  • the reporter signal in this region By measuring the reporter signal in this region by image analysis, polyglutamine aggregates can be detected with high sensitivity.
  • calculating the average luminance in the polyglutamine protein existing region from the total luminance of the signal in the polyglutamine protein existing region of the virtual cell body region and the area of the existing region Is mentioned.
  • the virtual cell body region can be set, for example, as a region including a region in which the peripheral region of the nucleus is expanded with a certain number of pixels.
  • cell nuclei in mammalian cell images are defined as a region stained by the DNA stain DAPI. Only one cell nucleus exists in a cell, and the cell body is regarded as a space surrounding it.
  • each cell nucleus region is defined in the captured image of the DAPI-stained region, and the region having a certain number of pixels is defined as the cytoplasm attached to the cell nucleus.
  • a reporter fluorescent region having a certain luminance or higher existing in the identified cytoplasmic region is defined as a polyglutamine protein existing region belonging to the nucleus / cell. The total luminance in the existing region and the area of the identified existing region are calculated, and the average luminance in the polyglutamine protein existing region is calculated.
  • the aggregate is defined as a region having a high reporter-derived fluorescence value on the image
  • the polyglutamine protein existing region identified in the above method is identified relatively narrowly as compared with the case where it is not formed. Therefore, when aggregates are significantly formed in the virtual cell body region, the difference between the average luminance in the polyglutamine protein-existing region and the presence or absence of aggregate formation is larger than the total difference, and the measurement is derived from the size of the aggregate. Variations in results are offset, thus increasing measurement accuracy.
  • the present disclosure may relate to one or more of the following embodiments;
  • [1] Containing as an active ingredient at least one selected from the group consisting of an intravascular epidermal growth factor receptor (VEGFR) inhibitor compound, a c-Met inhibitor compound, and both VEGFR and c-Met inhibitor compounds
  • the inhibitory compound is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 is a hydrogen atom, a halogen atom, a C 1-4 alkyl group, or a C 1-4 alkyl group substituted with a halogen atom
  • W is
  • R 2 and R 3 are each independently a hydrogen atom, a halogen atom, a C 1-4 alkyl group, or a C 1-4 alkyl group substituted with a halogen atom
  • X 1 is a C 1-4 alkylene group, C 1-4 alkylene group substituted with a halogen atom or an imino group
  • X 2 and Y are each independently, C 1-4 alkylene group, C 1-4 alkylene group substituted with a halogen atom, or an imino group, or, X 2 and Y together with the atom marked with a form an aromatic ring or a heteroaromatic ring, said ring being unsubstituted or hydrogen atom, halogen atom, C 1-4 alkyl A C 1-4 alky
  • W is R 1 -R 3 , X 1 , X 2 and Y are the same as in formula (I), R 6 and R 7 is a hydrogen atom, a halogen atom, C 1-4 alkyl groups, C 1-4 alkyl group substituted by a halogen atom or an aliphatic ring or heterocyclic ring.
  • R 6 and R 7 is a hydrogen atom, a halogen atom, C 1-4 alkyl groups, C 1-4 alkyl group substituted by a halogen atom or an aliphatic ring or heterocyclic ring.
  • a pharmaceutical composition for preventing, ameliorating, inhibiting progression and / or treating polyglutamine disease comprising as an active ingredient at least one selected from the group consisting of the following compounds 1-11.
  • a method of prevention, improvement, progression suppression, and / or treatment of polyglutamine disease comprising administering to a subject the pharmaceutical composition according to any one of [1] to [6] Method.
  • Intravascular epidermal growth factor receptor (VEGFR) inhibitory compound Intravascular epidermal growth factor receptor (VEGFR) inhibitory compound, c-Met inhibitory compound for producing a pharmaceutical composition for prevention, improvement, progression inhibition, and / or treatment of polyglutamine disease, And at least one use selected from the group consisting of both VEGFR and c-Met inhibitor compounds.
  • VEGFR vascular epidermal growth factor receptor
  • a screening method for a candidate substance of an active ingredient of a pharmaceutical composition for prevention, improvement, progression inhibition, and / or treatment of polyglutamine disease Culturing an assay cell expressing polyglutamine fused with a reporter protein in contact with a test substance, and measuring a reporter signal (A) in a virtual cell body region of the assay cell; Culturing the assay cell without contacting with the test substance, and measuring a reporter signal (B) in a virtual cell body region of the assay cell; Comparing signal (A) and signal (B); and A screening method comprising selecting, as a candidate substance, a test substance that reduces the signal (A) over the signal (B) based on the comparison.
  • Experimental Example 1 Screening for a substance that affects the formation of polyglutamine aggregates
  • a reporter as shown in FIG. 1 was fused to a host neuron (Neuro2a cell).
  • Cells into which a polyglutamine expression system was introduced (hereinafter referred to as “polyQ cells”) were used (Matsumoto et al. Molecular Cell, 2011; 44: 279-289). Screening was performed using polyQ cells according to the scheme shown in FIG.
  • the concentration at which the relative average luminance fluorescence of polyglutamine per visual field was 50% of that of DMSO control was measured as IC50.
  • the virtual cell body region was acquired as a 20x objective lens equipped with a cell image analyzer ArrayScan VTi, and each cell nucleus region was defined in the captured image of the DAPI stained region, and was defined as a region having a width of 15 pixels. .
  • compound 1-5 was a compound known as a VEGFR inhibitor.
  • Compound 2-4 was a compound known as a VEGFR2 inhibitor and a c-MET inhibitor.
  • Compound 8 was a known compound as a MAPK / ERK-kinase (MEK) inhibitor.
  • Experimental Example 2 Inhibition of polyglutamine aggregate formation by Compound 4 4 mM in a culture solution of polyQ cells cultured for 1 day after seeding (high glucose DMEM medium, 10% FBS, 100 u / mL penicillin, 100 ⁇ g / ml streptomycin) dbcAMP and 10 ⁇ g / ml Dox were added to induce expression of the 24h reporter. Thereafter, the medium was replaced with a culture solution (high glucose DMEM medium, 10% FBS, 100 u / mL penicillin, 100 ⁇ g / ml streptomycin) excluding 10 ⁇ g / ml Dox, and then compound 4 (10 nM-10 ⁇ M) was added and cultured for 2 days. After fixing with 4% PFA and nuclear staining with DAPI, the emission luminance of the aggregates in the virtual cell body region was measured with a cell image analyzer. The result is shown in FIG.
  • Compound 4 inhibited the formation of polyglutamine aggregates in an induced concentration-dependent manner after reporter expression.
  • the addition of compound 4 shows an inhibitory effect on aggregates even when added after the transient expression of the reporter, and the action point of this drug is the false action due to the suppression of the tet-on promoter used during reporter construction. It was also shown not to be positive.
  • Experimental Example 3 Relationship between Compound 4 and Reporter Protein Mass 4 mM in a culture solution (high glucose DMEM medium, 10% FBS, 100 u / mL penicillin, 100 ⁇ g / ml streptomycin) cultured for 1 day after seeding. dbcAMP and 10 ⁇ g / ml Dox were added to induce expression of the 24h reporter. Thereafter, the medium was replaced with a culture solution (high glucose DMEM medium, 10% FBS, 100 u / mL penicillin, 100 ⁇ g / ml streptomycin) excluding 10 ⁇ g / ml Dox, and then compound 4 (10 nM-10 ⁇ M) was added and cultured for 2 days. .
  • Compound 4 decreased the expression level of the reporter protein and the RNA level in a concentration-dependent manner. Together with the results in FIG. 4, it is suggested that the present compound promotes the degradation of reporter protein or RNA.

Abstract

La présente invention concerne : des compositions pharmaceutiques pour les maladies à expansion de polyglutamine et leurs utilisations ; des procédés de prévention, d'atténuation, de suppression de la progression et/ou de traitement des maladies à expansion de polyglutamine utilisant de telles compositions pharmaceutiques ; et un procédé de criblage d'un composé pour les maladies à expansion de polyglutamine. Un mode de réalisation de la présente invention concerne une composition pharmaceutique destinée à la prévention, l'atténuation, la suppression de la progression, et/ou le traitement des maladies à expansion de polyglutamine, et qui contient, comme principe actif, au moins un constituant sélectionné dans le groupe constitué du récepteur du facteur de croissance endothéliale vasculaire (VEGFR) des composés inhibiteurs, des composés d'inhibition du récepteur de la tyrosine kinase (c-Met) codé par le gène c-Met, et des composés d'inhibition à la fois du VEGFR et de c-Met. Un autre mode de réalisation de la présente invention concerne un procédé de criblage d'une substance qui possède un effet sur la formation d'un agrégat de polyglutamine, le procédé comprenant une étape de mesure, comme indicateur d'agrégats de polyglutamine formés dans une solution de culture dans laquelle les cellules ayant été introduites à l'intérieur d'un système d'expression qui exprime la polyglutamine fusionnée à une protéine rapporteur ont été cultivées, d'un signal de la protéine rapporteur se trouvant dans une région somatique putative comprenant un noyau cellulaire.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113891711A (zh) * 2019-03-11 2022-01-04 复旦大学 用于治疗神经退行性疾病的化合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003531570A (ja) * 1999-07-27 2003-10-28 アブジェニックス インク． 神経障害に関連したポリペプチド蓄積を阻害する方法および組成物
US20100298280A1 (en) * 2007-06-13 2010-11-25 Petra Kioschis-Schneider Compounds for the Modulation of Huntingtin Aggregation, Methods and Means for Identifying Such Compounds
WO2013061279A1 (fr) * 2011-10-25 2013-05-02 University Of Macau Utilisations d'indole-cétones ou d'indolidones comme médicaments neuroprotecteurs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003531570A (ja) * 1999-07-27 2003-10-28 アブジェニックス インク． 神経障害に関連したポリペプチド蓄積を阻害する方法および組成物
US20100298280A1 (en) * 2007-06-13 2010-11-25 Petra Kioschis-Schneider Compounds for the Modulation of Huntingtin Aggregation, Methods and Means for Identifying Such Compounds
WO2013061279A1 (fr) * 2011-10-25 2013-05-02 University Of Macau Utilisations d'indole-cétones ou d'indolidones comme médicaments neuroprotecteurs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AKINLEYE, A. ET AL.: "MEK and the inhibitors: from bench to bedside", J HEMATOL ONCOL, vol. 6, no. 27, 2013, XP021147527 *
SONG, E. K. ET AL.: "Potent anti tumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model", INT J CANCER, vol. 136, no. 8, 2015, pages 1967 - 1975, XP055562341 *
STRAND, A. D. ET AL.: "Expression profiling of Huntington's disease models suggests that brain- derived neurotrophic factor depletion plays a major role in striatal degeneration", J NEUROSCI, vol. 27, no. 43, 2007, pages 11758 - 11768, XP009122871 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113891711A (zh) * 2019-03-11 2022-01-04 复旦大学 用于治疗神经退行性疾病的化合物
EP3954368A4 (fr) * 2019-03-11 2023-04-26 Fudan University Composé pour le traitement de troubles neurodégénératifs

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