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WO2018079149A1 - Agent de prévention de la cataracte, agent thérapeutique, et application d'inhibiteur de hat destiné à fabriquer ceux-ci - Google Patents

Agent de prévention de la cataracte, agent thérapeutique, et application d'inhibiteur de hat destiné à fabriquer ceux-ci Download PDF

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Publication number
WO2018079149A1
WO2018079149A1 PCT/JP2017/034204 JP2017034204W WO2018079149A1 WO 2018079149 A1 WO2018079149 A1 WO 2018079149A1 JP 2017034204 W JP2017034204 W JP 2017034204W WO 2018079149 A1 WO2018079149 A1 WO 2018079149A1
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Prior art keywords
cataract
medium
hat
lens
inhibitor
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Japanese (ja)
Inventor
昌也 沖
文人 金田
佳弘 ▲高▼村
誠司 三宅
博之 内田
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University of Fukui NUC
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University of Fukui NUC
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
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    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
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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
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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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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    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—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 sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/603—Salicylic acid; Derivatives thereof having further aromatic rings, e.g. diflunisal
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    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts

Definitions

  • the present invention relates to a preventive agent, a therapeutic agent for cataract, and use of a HAT inhibitor for producing them. More specifically, the present invention relates to a preventive or therapeutic agent for cataract containing a HAT inhibitor as an active ingredient.
  • Cataract is a disease in which a reduction in visual acuity is caused by turbidity of the lens.
  • a lens affected by cataract develops cloudiness in the nucleus, cortex or posterior capsule.
  • Types of cataracts include age-related cataracts and diabetic cataracts.
  • age-related cataract which has the highest number of affected individuals, has an increased prevalence rate with age, and including the initial opacity, the prevalence rate in the 60s in Japan is 66-85%, in the 70s The prevalence rate is 84-97%, reaching 100% for people over 80 years old.
  • diabetic cataract is a disease that has many affected people under 60 years old and can develop even in young people.
  • Non-Patent Document 1 reports glutathione
  • Non-Patent Document 2 reports pirenoxine.
  • the present invention has been made in view of the above-mentioned conventional problems, and an object thereof is to provide a novel cataract preventive agent, therapeutic agent, and use of a HAT inhibitor for producing them.
  • the present inventors have found that a HAT inhibitor can prevent and treat cataract, and have completed the present invention. That is, the present invention has the following configuration.
  • a preventive or therapeutic agent for cataract which contains a HAT inhibitor as an active ingredient.
  • the HAT inhibitor is selected from the group consisting of HAT1, NAA60, GCN5, PCAF, TIP60, MOZ, MORF, HBO1, MOF, P300, CBP, TAF1, TIFIIIC90, SRC1, SCR3, P600, CLOCK and NAT10.
  • the prophylactic or therapeutic agent for cataract according to ⁇ 1> which targets at least one kind of substance.
  • the HAT inhibitor is a compound derived from polyphenol, a compound containing a heterocycle in the structure, a benzoic acid derivative, or an ⁇ - ⁇ unsaturated carbonyl compound, according to ⁇ 1> or ⁇ 2> A preventive or therapeutic agent for cataracts.
  • HAT inhibitors are 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane, CTK7A, Epigenetic Multiple Ligand, MG149, C646, NU9056, CPTH2, 5-chloro-2- (4-Nitrophenyl) -3 (2H) -isothiazolone, butyrolactone 3, EML425, L002, ISOX DUAL, TH1834, SPV106, Windorphen, ketomine, Remodelin, Embelin, Ischemin, CBP30 and KG501
  • the preventive or therapeutic agent for cataract according to ⁇ 1> or ⁇ 2>, which is the above compound, or a derivative or salt of the compound.
  • ⁇ 5> The preventive or therapeutic agent for cataract according to any one of ⁇ 1> to ⁇ 4>, wherein the dosage form is an eye drop.
  • ⁇ 6> The preventive or therapeutic agent for cataract according to any one of ⁇ 1> to ⁇ 5>, wherein the cataract is diabetic cataract.
  • a novel preventive or therapeutic agent for cataract is provided.
  • A It is a model figure showing the example of an action mechanism of the preventive agent or therapeutic agent of a cataract which concerns on one Embodiment of this invention.
  • B It is a model figure showing the example of the other action mechanism of the preventive agent or therapeutic agent of a cataract which concerns on one Embodiment of this invention.
  • C It is a model figure showing the example of the further another action mechanism of the preventive agent or therapeutic agent of a cataract which concerns on one Embodiment of this invention.
  • A A photograph showing the preventive effect of 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane on cataract.
  • B It is a photograph which shows the prevention effect of the cataract by CTK7A.
  • A It is a photograph which shows the prevention effect of the cataract by ISOX DUAL.
  • B It is a photograph which shows the prevention effect of the cataract by a plum baggin.
  • C It is a photograph which shows the prevention effect of the cataract by TH1834.
  • D It is a photograph which shows the prevention effect of the cataract by SPV106.
  • E It is a photograph which shows the prevention effect of the cataract by Windorphen.
  • A It is a photograph which shows the prevention effect of the cataract by Remodelin.
  • B It is a photograph which shows the prevention effect of the cataract by an embelline.
  • C It is a photograph which shows the prevention effect of the cataract by EML425.
  • (D) It is a photograph which shows the prevention effect of the cataract by CBP30.
  • (E) It is a photograph which shows the promotion effect of the cataract by TSA. It is the graph which quantified promotion of lens white turbidity by a HDAC inhibitor, and suppression of lens white turbidity by a HAT inhibitor. It is a photograph which shows the cataract treatment effect by a HAT inhibitor (C646).
  • (A) It is a photograph which shows the cataract treatment effect by the combination of CBP30 and CPTH2.
  • (B) A photograph showing a slice of the lens 4 days after administration of the combination of CBP30 and CPTH2.
  • (A) It is a photograph which shows the cataract treatment effect by CBP30.
  • Cataract refers to any disease that causes opacity in the lens.
  • the opacity that occurs in the lens due to cataract includes, for example, cortical turbidity, nuclear turbidity, posterior subcapsular turbidity, cortical spoke turbidity, anterior capsular turbidity, fibrous folds, water space, transilluminated spot-like turbidity around the nucleus, blisters, There are types such as point cloudiness and coronal cloudiness.
  • the term “cataract” in this specification is intended to refer to diseases that collectively refer to disease types such as diabetic cataract, congenital cataract, traumatic cataract, atopic cataract, radiation cataract, and steroid cataract. To do.
  • diabetes cataract refers to opacity of the lens that occurs in a patient suffering from a disease that is characterized by a continuously rising glucose concentration in blood or plasma.
  • the disease is hyperglycemia or diabetes.
  • the diabetes is type 1 diabetes or type 2 diabetes.
  • turbidity it is known in large-scale epidemiological studies that turbidity often occurs in the cortex or posterior capsule of the lens. However, the location where turbidity occurs is not limited thereto.
  • the cataract preventive or therapeutic agent according to an embodiment of the present invention is preferably used for the purpose of preventing or treating diabetic cataract.
  • the “prophylactic agent” intends an agent that provides a preventive effect.
  • the preventive effect is intended to be the effect exemplified below, but is not limited thereto.
  • the one or more symptoms related to the disease may be systemic or local.
  • therapeutic agent intends an agent that provides a therapeutic effect.
  • the therapeutic effect is intended to be the effect exemplified below, but is not limited thereto.
  • the one or more symptoms related to the disease may be systemic or local.
  • HAT inhibitor One embodiment of the present invention contains a HAT inhibitor as an active ingredient.
  • a HAT inhibitor intends the substance which inhibits the function of histone acetylase (Histone Acetyl Transferase: HAT).
  • HAT replaces the amino group of a specific lysine residue contained in histone with an acetyl group. As a result, the chromatin structure formed by DNA and histone is partially loosened, and the gene in the vicinity of the site where histone is acetylated is easily expressed.
  • a HAT inhibitor causes a result of suppressing the expression of a specific gene by inhibiting the above-described process. Therefore, the preventive or therapeutic agent for cataract according to one embodiment of the present invention acts on epigenetic gene expression control.
  • HAT whose function is inhibited by a specific HAT inhibitor is referred to as a “target” of the HAT inhibitor.
  • a HAT inhibitor may “directly” inhibit HAT function, such as by binding to a target HAT.
  • the HAT inhibitor may inhibit the function of HAT "indirectly” by capturing a substance necessary for the function of HAT (in this case, the substance necessary for the function of HAT is also Like the above HAT, it is called “target of HAT inhibitor”). That is, the target of the HAT inhibitor may be HAT or not HAT.
  • the HAT targeted by the HAT inhibitor may be one or more subtypes of HAT among the HAT groups listed in the table below. In one embodiment, the HAT targeted by the HAT inhibitor may be a HAT group belonging to one or more families among the HAT groups described in Table 1 below.
  • the substance targeted by the HAT inhibitor may be NAT10 or BRD4.
  • the target of the HAT inhibitor is selected from substances described herein that can be a target of a HAT inhibitor, and substances recognized by those skilled in the art as a target of a HAT inhibitor. More than types. That is, the target of the HAT inhibitor may be only one type or two or more types. In addition, the HAT inhibitor may target both a substance that is HAT and a substance other than HAT. Furthermore, the target of the HAT inhibitor may be a complex containing the substances described above.
  • the HAT inhibitor is curcumin.
  • the above IUPAC name of curcumin is (1E, 6E) -1,7-bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione, CAS number is 458-37-7, structural formula Is the following formula 1.
  • the curcumin targets the P300 / CBP family HAT.
  • the HAT inhibitor is 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane (also known as HAT inhibitor II).
  • the IUPAC name of 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane is 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexan, CAS number is 932749- 62-7, the structural formula is the following formula 2.
  • the 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane targets the P300 / CBP family HAT.
  • the HAT inhibitor is CTK7A (also known as HAT inhibitor VII).
  • CTK7A also known as HAT inhibitor VII.
  • the IUPAC name of the above CTK7A is Sodium-4- (3,5-bis (4-hydroxy-3-methoxystyryl) -1H-pyrazol-1-yl) benzoate, CAS number is 1,297262-16-8, and the structural formula is 3.
  • the CTK7A targets P300 and PCAF.
  • the HAT inhibitor is Epigenetic Multiple.
  • Ligand The IUPAC name of Epigenetic Multiple Ligand is 3,5-bis (3,5-Dibromo-4-hydroxybenzylidene) -tetrahydro-2H-pyran-4-one, CAS number is 1020399-52-3, and the structural formula is It is.
  • the Epigenetic Multiple Ligand targets P300.
  • the HAT inhibitor is garcinol.
  • the IUPAC name of the above garcinol is 3-[(3,4-Dihydroxyphenyl) -hydroxymethylidene] -6,6-dimethyl-5,7-bis (3-methylbut-2-enyl) -1- (5-methyl-2- prop-1-en-2-ylhex-4-enyl) bicyclo [3.3.1] nonane-2,4,9-trione, CAS number is 78824-30-3, structural formula is the following formula 5.
  • the garcinol targets P300 and PCAF.
  • the HAT inhibitor is anacardic acid.
  • the IUPAC name of the anacardic acid is 2-hydroxy-6-[(8Z, 11Z) -pentadeca-8,11,14-trienyl] benzoic acid, the CAS number is 11034-77-8, and the structural formula is .
  • the anacardic acid targets P300 and PCAF.
  • the HAT inhibitor is MG149.
  • the IUPAC name of MG149 is 2- (4-heptylphenethyl) -6-hydroxybenzoic acid, the CAS number is 1243583-85-8, and the structural formula is Formula 7.
  • the MG149 targets TIP60 and MOZ.
  • the HAT inhibitor is C646.
  • the IUPAC name of C646 is 4- [4-[[5- (4,5-Dimethyl-2-nitrophenyl) -2-furanyl] methylene] -4,5-dihydro-3-methyl-5-oxo-1H- pyrazol-1-yl] benzoic acid, CAS No. 328968-36-1 and structural formula is Formula 8 below.
  • the C646 targets the P300 / CBP family HAT.
  • the HAT inhibitor is NU9056.
  • the IUPAC name of NU9056 is 5- (1,2-Thiazol-5-yldisulfanyl) -1,2-thiazole, the CAS number is 14450644-28-6, and the structural formula is Formula 9 below.
  • the NU9056 targets TIP60.
  • the HAT inhibitor is CPTH2.
  • the IUPAC name of CPTH2 is 2- [4- (4-chlorophenyl) -2-thiazolyl] hydrazone-cyclopentanone, monohydrochloride, CAS number is 357649-93-5, and structural formula is the following formula 10.
  • the CPTH2 targets GCN5.
  • the HAT inhibitor is 5-chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone.
  • the IUPAC name of 5-chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone is 5-Chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone and CAS number is 748777-47- 1.
  • the structural formula is the following formula 11.
  • the 5-chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone targets P300 and PCAF.
  • the HAT inhibitor is butyrolactone 3 (also known as MB-3).
  • the butyrolactone 3 has an IUPAC name of 3-Methylene-4-hydroxycarbonyl-5- (1-propyl) -tetrahydrofuran-2-one, a CAS number of 7786649-18-6, and a structural formula of the following formula 12.
  • the butyrolactone 3 targets GCN5.
  • the HAT inhibitor is gallic acid.
  • the IUPAC name of the gallic acid is 3,4,5-trihydroxybenzoic acid, the CAS number is 149-91-7, and the structural formula is Formula 13.
  • the gallic acid is a non-specific HAT inhibitor.
  • the HAT inhibitor is ( ⁇ )-epigallocatechin gallate.
  • the IUPAC name of the above ( ⁇ )-epigallocatechin gallate is [(2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-yl] 3,4,5- trihydroxybenzoate, CAS number is 989-51-5, and structural formula is the following formula 14.
  • the ( ⁇ )-epigallocatechin gallate is a non-specific HAT inhibitor.
  • the HAT inhibitor is EML425.
  • the IUPAC name of the EML425 is 5-[(4-Hydroxy-2,6-dimethylphenyl) methylene] -1,3-bis (phenylmethyl) -2,4,6 (1H, 3H, 5H) -pyrimidinetrione, CAS number is 1675821-32-5, the structural formula is the following formula 15.
  • the EML425 targets the P300 / CBP family HAT.
  • the HAT inhibitor is L002.
  • the IUPAC name of L002 is 4- [O-[(4-Methoxyphenyl) sulfonyl] oxime] -2,6-dimethyl-2,5-cyclohexadiene-1,4-dione, CAS number is 321695-57-2, structure
  • the formula is the following formula 16.
  • the above L002 targets P300.
  • the HAT inhibitor is ISOX DUAL.
  • ISOX above The IUPAC name of DUAL is [3- [4- [2- [5- (Dimethyl-1,2-oxazol-4-yl) -1- [2- (morpholin-4-yl) ethyl] -1H-1, 3-benzodiazol-2-yl] ethyl] phenoxy] propyl] dimethylamine, CAS number is not registered, and the structural formula is the following formula 17.
  • the ISOX DUAL targets the bromodomain of CBP and BRD4.
  • the HAT inhibitor is plumbagin.
  • the IUPAC name of plumbagin is 5-Hydroxy-2-methyl-1,4-naphthalened-ione, CAS number is 481-42-5, and the structural formula is Formula 18.
  • the plum bagin targets P300.
  • the HAT inhibitor is TH1834.
  • the IUPAC name of TH1834 is 2- (5- (4-((phenethyl (4- (4- (pyrrolidin-1-ylmethyl) phenoxy) butyl) amino) methyl) phenyl) -2H-tetrazol-2-yl) acetic
  • the acid dihydrochloride and CAS number are not registered, and the structural formula is the following formula 19.
  • the TH1834 targets TIP60.
  • the HAT inhibitor is SPV106.
  • the IUPAC name of the SPV 106 is 2-Pentadecylidene-Propanedioic acid 1,3-diethyl ester, the CAS number is 1036939-38-4, and the structural formula is Formula 20 below.
  • the SPV 106 targets the P300 / CBP family HAT.
  • the SPV 106 is also a PCAF activator.
  • the HAT inhibitor is Windorphen.
  • the IUPAC name of Windorphen is (E) & (Z) -3-Chloro-2,3-bis (4-methoxyphenyl) acrylaldehyde, the CAS number is 19881-70-0, and the structural formula is Formula 21 below. Windorphen is a non-specific HAT inhibitor.
  • the HAT inhibitor is ketomin.
  • the IUPAC name of ketomin is 2,3S, 5aR, 6,10bS, 11-hexahydro-3- (hydroxymethyl) -10b-[(1S, 4S) -3-[[4- (hydroxymethyl) -5,7-dimethyl -6,8-dioxo-2,3-dithia-5,7-diazabicyclo [2.2.2] oct-1-yl] methyl] -1H-indol-1-yl] -2-methyl-3,11aS-epidithio -11aH-pyrazino [1 ′, 2 ′: 1,5] pyrrolo [2,3-b] indole-1,4-dione, CAS number is 1403-36-7, and structural formula is the following formula 22.
  • the ketomin targets the TAZ1 domain of the H1F1 ⁇ / P300 complex.
  • the HAT inhibitor is Remodelin.
  • the IUPAC name of Remodelin is 4- [2- (2-cyclopentylidenehydrazinyl) -1,3-thiazol-4-yl] benzonitrile; hydrobromide, CAS number is 1622921-15-6, and the structural formula is Formula 23 below.
  • the above Remodelin targets NAT10.
  • the HAT inhibitor is envelin.
  • the IUPAC name of the above embellin is 2,5-Dihydroxy-3-undecyl-1,4-benzoquinone, the CAS number is 550-24-3, and the structural formula is Formula 24 below.
  • the envelin targets PCAF.
  • the HAT inhibitor is Ischemin.
  • the IUPAC name of the above Ischemin is 5-[(1E) -2- (2-Amino-4-hydroxy-5-methylphenyl) diazenyl] -2,4-dimethylbenzenesulfonic acid sodium salt, CAS number is 1357059-00-7, structure
  • the formula is the following formula 25.
  • the Ischemin targets the bromodomain of the P300 / CBP family HAT.
  • the HAT inhibitor is CBP30.
  • the IUPAC name of the CBP30 is 8- (3-chloro-4-methoxy-phenethyl) -4- (3,5-dimethyl-isoxazol-4-yl) -9- (2- (morpholin-4-yl) -propyl ) -7,9-diaza-bicyclo [4.3.0] nona-1 (6), 2,4,7-tetraene, CAS number is 1613695-14-9, structural formula is the following formula 26.
  • the CBP30 targets the bromodomain of the P300 / CBP family HAT.
  • the HAT inhibitor is KG501 (also known as naphthol AS-E phosphate).
  • KG501 also known as naphthol AS-E phosphate.
  • the IUPAC name of the above KG501 is 3-[(4-chlorophenyl) carbamoyl] -2-naphthyl dihydrogen phosphate; N- (4-Chlorophenyl) -3- (phosphonooxy) naphthalene-2-carboxamide, CAS number is 18228-17-6
  • the structural formula is the following formula 27.
  • the KG501 targets the KIX domain of the P300 / CBP family HAT.
  • 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane, CTK7A, garcinol, anacardic acid, MG149, gallic acid, ( ⁇ )-epigallocatechin gallate, plumbagin And embellin is a compound derived from polyphenol.
  • CTK7A anacardic acid
  • MG149 gallic acid
  • C646 gallic acid
  • ( ⁇ )-epigallocatechin gallate and plumbagin are benzoic acid derivatives.
  • CTK7A, C646, CPTH2, ISOX DUAL, TH1834, and Remodelin contain a heterocycle in the structure.
  • 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane, butyrolactone 3, SPV106, and Windorphen are ⁇ - ⁇ unsaturated carbonyl compounds.
  • the HAT inhibitor may be a derivative or salt of the substances described above.
  • a derivative or salt of the above-mentioned substance as a HAT inhibitor, (1) the preventive or therapeutic effect of cataract is increased, (2) the safety of the substance to the human body is increased, and (3) the preparation is easy to handle. Effects such as obtaining physical properties can be imparted.
  • “derivative” means a group of compounds produced by substituting a part of the compound in the molecule with another functional group or another atom for a specific compound.
  • Examples of the other functional groups include alkyl groups, alkoxy groups, alkylthio groups, aryl groups, aryloxy groups, arylthio groups, arylalkyl groups, arylalkoxy groups, arylalkylthio groups, arylalkenyl groups, arylalkynyl groups, allyls.
  • Examples of the other atoms include a carbon atom, a hydrogen atom, an oxygen atom, a nitrogen atom, a sulfur atom, a phosphorus atom, and a halogen atom.
  • salt is not limited as long as it is a salt that is physiologically acceptable to be administered to a subject as a pharmaceutical product.
  • salts include alkali metal salts (potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), ammonium salts, organic base salts (trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamines).
  • N N, N'-dibenzylethylenediamine salt
  • organic acid salt acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate
  • inorganic acid salts hydroochloride, hydrobromide, sulfate, phosphate, etc.
  • HAT inhibitors Derivatives or salts of the substances described above as examples of HAT inhibitors can be produced by known methods.
  • the prophylactic or therapeutic agent for cataract is administered to a subject.
  • the subject is a human.
  • the subject is a non-human animal. Examples of the non-human animals include mammals other than humans (cow, pig, sheep, goat, horse, dog, cat, rabbit, mouse, rat, etc.).
  • the prophylactic or therapeutic agent for cataract can be administered to a subject by any route of administration.
  • the administration route include oral administration, parenteral administration, transdermal administration, transmucosal administration, and intravenous administration.
  • the dosage form of the prophylactic or therapeutic agent for cataract may be an internal medicine, an external medicine, an injection, a suppository, an inhalant, an eye drop and the like.
  • parenteral administration is preferred, ophthalmic administration, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, subtenon administration is more preferred, and ophthalmic administration is even more preferred.
  • eye drops or injections are preferable, and eye drops are more preferable.
  • the reasons why ophthalmic solutions are preferable are that the route until the active ingredient is delivered to the lens is short, that other organs are difficult to irritate, that there is little invasion, and that the effect on the whole body is small (the punctum after instillation) The effects on the whole body can be further suppressed by compression), administration is simple, repeated administration is possible, and patients can be self-administered. For this reason, it can be expected that the effect of preventing or treating cataract is made quicker or increased.
  • the preventive or therapeutic agent for cataract contains a HAT inhibitor as an active ingredient.
  • active ingredient intends a substance that can provide a prophylactic or therapeutic effect against one or more symptoms.
  • the preventive or therapeutic agent for cataract may contain only one type of HAT inhibitor, or may contain a combination of two or more types of HAT inhibitors. By combining two or more HAT inhibitors, a synergistic effect that cannot be predicted from the effects of the individual HAT inhibitors can be obtained.
  • HAT inhibitors examples include (1) a combination of CBP30 and CPTH2, and (2) a combination of C646 and CPTH2.
  • the concentration of the HAT inhibitor contained in the preventive or therapeutic agent for cataract varies depending on the type of the HAT inhibitor, the administration route and the dosage form selected.
  • the lower limit of the concentration of the HAT inhibitor is 0.001 ⁇ M or more, 0.002 ⁇ M or more, 0.005 ⁇ M or more, 0.01 ⁇ M or more, 0.02 ⁇ M or more, 0.05 ⁇ M or more, 0.1 ⁇ M or more, 0.
  • the upper limit of the concentration of the HAT inhibitor is 0.01 ⁇ M or less, 0.02 ⁇ M or less, 0.05 ⁇ M or less, 0.1 ⁇ M or less, 0.2 ⁇ M or less, 0.5 ⁇ M or less, 1 ⁇ M or less, 2 ⁇ M or less, 3 ⁇ M 4 ⁇ M or less, 5 ⁇ M or less, 6 ⁇ M or less, 7 ⁇ M or less, 8 ⁇ M or less, 9 ⁇ M or less, 10 ⁇ M or less, 20 ⁇ M or less, 30 ⁇ M or less, 40 ⁇ M or less, 50 ⁇ M or less, 60 ⁇ M or less, 70 ⁇ M or less, 80 ⁇ M or less, 90 ⁇ M or less, 100 ⁇ M or less, 200 ⁇ M or less, 300 ⁇ M or less, 400 ⁇ M or less, 500 ⁇ M or less, 1000 ⁇ M or less, 2000 ⁇ M or less, or 5000 ⁇ M or less.
  • the concentration of the HAT inhibitor is 0.001 to 0.01 ⁇ M, 0.002 to 0.02 ⁇ M, 0.005 to 0.05 ⁇ M, 0.01 to 0.1 ⁇ M, 0.02 to 0.2 ⁇ M.
  • the preventive or therapeutic agent for cataract according to one embodiment of the present invention may contain components other than the HAT inhibitor.
  • Ingredients other than the HAT inhibitor may be active ingredients or not active ingredients.
  • the active ingredient may be an active ingredient for symptoms related to cataract (symptoms of cataracts, complications of cataracts, etc.), or an active ingredient for symptoms not related to cataracts It may be.
  • the types of components that are not active components include buffers, pH adjusters, tonicity agents, preservatives, antioxidants, high molecular weight polymers, excipients, carriers, and dilutions. Agents, solvents, solubilizers, stabilizers, fillers, binders, surfactants, stabilizers and the like.
  • Examples of the buffer include phosphoric acid or phosphate, boric acid or borate, citric acid or citrate, acetic acid or acetate, carbonic acid or carbonate, tartaric acid or tartrate, ⁇ -aminocaproic acid, trometamol Etc.
  • Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate.
  • Examples of the borate include borax, sodium borate, and potassium borate.
  • Examples of the citrate include sodium citrate, disodium citrate, and trisodium citrate.
  • Examples of the acetate include sodium acetate and potassium acetate.
  • Examples of the carbonate include sodium carbonate and sodium hydrogen carbonate.
  • Examples of the tartrate salt include sodium tartrate and potassium tartrate.
  • pH adjusting agents examples include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide and the like.
  • tonicity agent examples include ionic tonicity agents (sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc.) and nonionic tonicity agents (glycerin, propylene glycol, sorbitol, mannitol, etc.). Can be mentioned.
  • preservatives examples include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol and the like.
  • antioxidants examples include ascorbic acid, tocophenol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.
  • high molecular weight polymer examples include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate Carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, atelocollagen and the like.
  • telocollagen as a high molecular weight polymer because the absorption rate of the HAT inhibitor is increased.
  • the prophylactic or therapeutic agent for cataract according to one embodiment of the present invention may contain an active ingredient and / or a pharmaceutical additive known to those skilled in the art, other than those exemplified above.
  • the prophylactic or therapeutic agent for cataract according to one embodiment of the present invention can be formulated by a known technique using ingredients other than the HAT inhibitor and the HAT inhibitors exemplified above as raw materials.
  • the dose is not limited as long as a desired effect is obtained.
  • the administration interval is not limited as long as a desired effect is obtained.
  • the administration interval is usually once every 1 hour to 6 months, preferably once per hour, once every 2 hours, once every 3 hours, once every 6 hours, once every 12 hours, Once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, three weeks 1 time, 1 time in 1 month, 1 time in 2 months, 1 time in 3 months, 1 time in 4 months, 1 time in 5 months, 1 time in 6 months, more preferably At least once a day, at least once every two days, at least once every three days, at least once every four days, at least once every five days, at least once every six days, at least once a week is there.
  • the cataract preventive or therapeutic agent according to one embodiment of the present invention may be prescribed in combination with a drug for preventing or treating cataract and / or other diseases.
  • FIG. 1 (a) shows the mechanism of action of a prophylactic or therapeutic agent for cataract according to one embodiment of the present invention.
  • This mechanism of action is a model in which the expression of PLK3 located upstream of the apoptosis-related gene P53 is suppressed by a HAT inhibitor.
  • FIG. 1 (b) shows the mechanism of action of a prophylactic or therapeutic agent for cataract according to another embodiment of the present invention.
  • This mechanism of action is a model in which ALDH1A1 expression is promoted by HAT inhibitors.
  • FIG. 1 (c) shows the mechanism of action of a prophylactic or therapeutic agent for cataract according to still another embodiment of the present invention.
  • This mechanism of action is a model in which GJA1 expression is promoted by HAT inhibitors.
  • HAT inhibitor When no HAT inhibitor is administered, the function of activating GJA1 in HAT is suppressed, and the cell-cell adhesion of lens epithelial cells is reduced. As a result, moisture is taken into the crystalline lens and turbidity occurs as the osmotic pressure increases.
  • the expression of GJA1 is promoted by promoting the function of HAT (for example, the substance described in [2-1]) by the HAT inhibitor, As a result, cataract is prevented or treated.
  • HDAC histone deacetylase
  • An example of a HAT inhibitor having such a mechanism of action is anacardic acid.
  • HAT inhibitors prevent or treat cataracts by intervening in epigenetic control mechanisms of gene expression. Therefore, all the preventive or therapeutic agents for cataracts containing a substance having a function as a HAT inhibitor as an active ingredient are included in the scope of the present invention.
  • One embodiment of the present invention is a method for preventing or treating cataract using a prophylactic or therapeutic agent for cataract containing an HAT inhibitor as an active ingredient.
  • Example 1 Using a diabetic cataract model using a galactose-added medium, the following cataract preventive effects of HAT inhibitors were investigated.
  • Example 1-1 The lens was extracted from the left and right eyeballs of 6-week-old SD rats (Sankyo Lab Service Co., Ltd.).
  • the lens extracted from the right eye was cultured in a medium obtained by adding 30 mM galactose to M199 medium (manufactured by SIGMA), and used as a model for developing diabetic cataract.
  • the lens extracted from the left eye was obtained by adding 30 mM galactose and 40 ⁇ M 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane (abcam) to the M199 medium. Incubated in An incubator was used for the culture, and the temperature was maintained at 37 ° C.
  • 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane is a HAT inhibitor that targets HAT of the P300 / CBP family.
  • the lens cultured in the medium supplemented with 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane is The turbidity of the cortex was kept low compared to the lens cultured in a medium not added with -bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane.
  • Example 1-2 The lens was extracted from the left eye, and the experiment was carried out in the same manner as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 100 ⁇ M CTK7A (EMD Millipore). It was. CTK7A is a HAT inhibitor that targets P300 and PCAF. The results are shown in FIG.
  • the lens cultured in the medium supplemented with CTK7A suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with CTK7A. It was done.
  • Example 1-3 The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 2 ⁇ M garcinol (manufactured by Selleckchem) were added to the M199 medium. .
  • Garcinol is a HAT inhibitor that targets P300 and PCAF. The results are shown in FIG.
  • the lens cultured in the medium added with garcinol suppresses the turbidity of the cortex to be lower than the lens cultured in the medium not added with garcinol. It was done.
  • Example 1-4 The lens was extracted from the left eye, and the experiment was carried out in the same manner as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 20 ⁇ M anacardic acid (abcam). It was. Anacardic acid is a HAT inhibitor that targets P300 and PCAF. The results are shown in FIG.
  • the lens cultured in the medium to which the anacardic acid was added was more turbid in the cortex than the lens cultured in the medium to which the anacardic acid was not added. It was kept low.
  • Example 1-5 The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 50 ⁇ M MG149 (manufactured by Selleckchem) were added to the M199 medium. . MG149 is a HAT inhibitor that targets TIP60 and MOZ. The results are shown in FIG.
  • the lens cultured in the medium supplemented with MG149 has a slightly lower turbidity in the cortex than the lens cultured in the medium not added with MG149. It was suppressed.
  • Example 1-6 The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 40 ⁇ M C646 (manufactured by SIGMA) were added to the M199 medium. .
  • C646 is a HAT inhibitor that targets P300 / CBP family HAT. The results are shown in FIG.
  • the lens cultured in the medium supplemented with C646 has a lower turbidity in the cortex than the lens cultured in the medium not supplemented with C646. It was done.
  • Example 1-7 The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 40 ⁇ M CPTH2 (manufactured by Cayman) to the M199 medium. .
  • CPTH2 is a HAT inhibitor that targets GCN5. The results are shown in FIG.
  • the lens cultured in the medium added with CPTH2 suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with CPTH2. It was done.
  • Example 1-8 The experiment was performed in the same manner as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 500 ⁇ M butyrolactone 3 (abcam) to the M199 medium. It was. Butyrolactone 3 is a HAT inhibitor that targets GCN5. The results are shown in FIG.
  • the lens cultured in the medium added with butyrolactone 3 has more turbidity in the cortex than the lens cultured in the medium not added with butyrolactone 3. It was kept low.
  • Example 1-9 The lens extracted from the left eye was subjected to the same procedure as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 100 ⁇ M gallic acid (manufactured by SIGMA). It was. In addition, gallic acid is a non-specific HAT inhibitor. The results are shown in FIG.
  • the lens cultured in the medium added with gallic acid is more turbid in the cortex than the lens cultured in the medium not added with gallic acid. It was a little lower.
  • Example 1-10 Example 1 except that the lens removed from the left eye was cultured in the above M199 medium supplemented with 30 mM galactose and 50 ⁇ M ( ⁇ )-epigallocatechin gallate (Wako Pure Chemical Industries, Ltd.). Experiments were performed in the same procedure as for -1. Note that ( ⁇ )-epigallocatechin gallate is a non-specific HAT inhibitor. The results are shown in FIG.
  • the lens cultured in the medium supplemented with the ( ⁇ )-epigallocatechin gallate was added to the medium without the addition of the ( ⁇ )-epigallocatechin gallate.
  • the turbidity of the cortex was somewhat lower.
  • Example 1-11 The experiment was performed in the same manner as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 20 ⁇ M ISOX DUAL (manufactured by SIGMA) were added to the M199 medium. It was. ISOX DUAL is a HAT inhibitor that targets the bromodomain of CBP and BRD4. The results are shown in FIG.
  • the lens cultured in the medium supplemented with the above ISOX DUAL is more turbid in the cortex than the lens cultured in the medium not added with the above ISOX DUAL. It was kept low.
  • Example 1-12 The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 2 ⁇ M plumbagin (manufactured by SIGMA) were added to the M199 medium. .
  • Plumbagin is a HAT inhibitor that targets P300. The results are shown in FIG.
  • the lens cultured in the medium to which the plumbagin was added had less turbidity in the cortex compared to the lens cultured in the medium to which the plumbagin was not added. It was done.
  • Example 1-13 The lens was extracted from the left eye, and the experiment was performed in the same manner as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 100 ⁇ M TH1834 (manufactured by axon medchem). It was. TH1834 is a HAT inhibitor that targets TIP60. The results are shown in FIG.
  • the lens cultured in the medium added with TH1834 suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with TH1834. It was done.
  • Example 1-14 The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 100 ⁇ M SPV106 (manufactured by SIGMA) were added to the M199 medium. . SPV106 is a HAT inhibitor that targets the P300 / CBP family HAT. The results are shown in FIG.
  • the lens cultured in the medium to which the SPV 106 is added suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium to which the SPV 106 is not added. It was done.
  • Example 1-15 An experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 40 ⁇ M Windorphen (manufactured by SIGMA) to the M199 medium. . Windorphen is a non-specific HAT inhibitor. The results are shown in FIG.
  • the lens cultured in the medium added with Windorphen suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with Windorphen. It was done.
  • Example 1-16 The experiment was performed in the same manner as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 40 ⁇ M Remodelin (manufactured by Cayman) to the M199 medium. . Remodelin is a HAT inhibitor that targets NAT10. The results are shown in FIG.
  • the lens cultured in the medium added with Windorphen suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with Windorphen. It was done.
  • Example 1-17 The experiment was performed in the same manner as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 40 ⁇ M Embelin (abcam) to the M199 medium.
  • Embelin is a HAT inhibitor that targets PCAF. The results are shown in FIG.
  • the lens cultured in the medium supplemented with the above-described embellin suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with the above-described embellin. It was done.
  • Example 1-18 The lens extracted from the left eye was subjected to the same procedure as in Example 1-1 except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 200 ⁇ M EML425 (manufactured by axon medchem). It was. EML425 is a HAT inhibitor that targets P300 / CBP family HAT. The results are shown in FIG.
  • the lens cultured in the medium to which the EML425 is added suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium to which the EML425 is not added. It was done.
  • Example 1-19 An experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 5 ⁇ M CBP30 (manufactured by Cayman) to the M199 medium.
  • CBP30 is a HAT inhibitor that targets the bromodomain of the P300 / CBP family HAT. The results are shown in FIG.
  • the lens cultured in the medium added with CBP30 suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with CBP30. It was done.
  • Example 1-1 The same procedure as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 0.8 ⁇ M TSA (manufactured by Wako Pure Chemical Industries, Ltd.) were added to the M199 medium. The experiment was conducted. TSA is a histone deacetylase (HDAC) inhibitor. The results are shown in FIG.
  • HDAC histone deacetylase
  • the lens cultured in the medium to which TSA was added increased the turbidity of the cortex compared with the lens cultured in the medium to which TSA was not added. It was.
  • Example 2 The concentration of the HAT inhibitor (C646) or HDAC inhibitor (TSA) added to the medium was changed, and the turbidity generated in the lens was quantified.
  • the lens extracted from the left eye was cultured in the same manner as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 40 ⁇ M C646 (manufactured by SIGMA).
  • a photomicrograph of the later lens was obtained.
  • the above-mentioned micrograph was converted into a gray scale image using Adobe photoshop (registered trademark) cs6.
  • Example 3 The lens was extracted from the left and right eyeballs of 6-week-old SD rats (Sankyo Lab Service Co., Ltd.). The lens extracted from both the left and right eyes was cultured in a medium in which 30 mM galactose was added to M199 medium (manufactured by SIGMA) for 2 days, and used as a model for developing diabetic cataract. Thereafter, the lens of the left eye was transferred to a medium supplemented with 30 mM galactose and 40 ⁇ M C646. On the other hand, the lens of the right eye did not change the medium.
  • the lens transferred to the medium added with C646 and cultured has a lower turbidity of the cortex than the lens that has been cultured in the medium not added with C646. It was.
  • Example 4 Microarrays were used to investigate gene expression and to estimate the mechanism by which HAT inhibitors prevent or treat cataracts.
  • M199 medium (manufactured by SIGMA), medium obtained by adding 30 mM galactose to M199 medium, medium obtained by adding 30 mM galactose and 40 ⁇ M HAT inhibitor (C646) to M199 medium, and 30 mM galactose to M99 medium And a medium supplemented with 0.8 ⁇ M HDAC inhibitor (TSA).
  • TSA 0.8 ⁇ M HDAC inhibitor
  • RNA extraction methods are described in the TRIZOL (registered trademark) instruction manual.
  • the sample prepared by the above procedure was used as a sample for microarray analysis.
  • the expression of the gene in each lens was examined.
  • the obtained data was analyzed using Excel (registered trademark).
  • genes that showed different expression levels were selected between the lens cultured in the HAT inhibitor-added medium and the lens cultured in the HDAC inhibitor-added medium.
  • the expression level of a gene in a lens cultured in a medium containing only galactose was set to 1, and a gene corresponding to the following condition (i) or (ii) was selected.
  • the expression level in M199 medium (control) and in a medium to which galactose and HAT inhibitors are added is 1.5 or more, and the expression level in a medium to which galactose and HDAC inhibitors are added is 0.5 or less.
  • the expression level in the M199 medium (control) and the medium to which galactose and HAT inhibitors are added is 0.5 or less, and the expression level in the medium to which galactose and HDAC inhibitors are added is 1.5 or more.
  • Table 2 shows the genes corresponding to the above conditions and the expression levels of the genes.
  • FIG. 1 (a) shows an example of the mechanism of action for preventing or treating cataract by a HAT inhibitor, which is estimated from the behavior of PLK3 among the genes listed in Table 2.
  • FIG. 1B shows an example of the action mechanism of the effect of preventing or treating cataract by a HAT inhibitor, which is estimated from the behavior of ALDH1A1.
  • FIG. 1 (c) shows an example of the action mechanism of the effect of preventing or treating cataract by a HAT inhibitor, which is estimated from the behavior of GJA1 (Cx43).
  • Example 5 The therapeutic effect of cataract by the combination of HAT inhibitors was examined.
  • Example 5-1 A medium was prepared by adding 30 mM galactose and DMSO (prepared to a final concentration of 0.8%) to M199 medium (manufactured by SIGMA).
  • M199 medium manufactured by SIGMA
  • a lens extracted from both left and right eyes of a 6-week-old SD rat was cultured at 37 ° C. under 5% CO 2 for 4 days to develop diabetic cataract.
  • the lens of the left eye was transferred to a medium supplemented with (1) 30 mM galactose and (2) CBP30 and CPTH2 (both dissolved in DMSO).
  • the final concentration of CPB30 in the medium was 10 ⁇ M
  • the final concentration of CPTH2 was 80 ⁇ M
  • the final concentration of DMSO was 0.8%.
  • the lens of the right eye is prepared again by adding a medium obtained by adding 30 mM galactose and DMSO (prepared so that the final concentration becomes 0.8%) to M199 medium (manufactured by SIGMA). Moved to.
  • the lens was immersed in an FG (Formalin-Glutaraldehyde) solution (Formalin: manufactured by Muto Chemical Co., Ltd., Glutaraldehyde: manufactured by Wako Pure Chemical Industries, Ltd.) at 4 ° C. for 3 days, and then immersed in a 10% formalin solution.
  • FG Formin-Glutaraldehyde
  • the new histochemical laboratory was commissioned to prepare stained sections.
  • FIG. 1 A micrograph was taken in which the section was magnified 100 times with IX70 (Olympas). The result is shown in FIG. In the figure, the left side is the whole image of the above section, and the right side is an enlarged image near the equator.
  • Experiment 1-1 The lens of the left eye was cultured in a medium supplemented with 30 mM galactose and CBP30 (prepared to a final concentration of 10 ⁇ M).
  • Experiment 1-2 The lens of the left eye was cultured in a medium supplemented with 30 mM galactose and CPTH2 (prepared to a final concentration of 80 ⁇ M).
  • the lens transferred and cultured in the medium to which the combination of CBP30 and CPTH2 was added had only one of CBP30 or CPTH2 added.
  • the turbidity of the cortex was suppressed to be lower than that of the lens that had been transferred to the cultured medium and cultured.
  • Example 5-2 A medium was prepared by adding 30 mM galactose and DMSO (prepared to a final concentration of 0.8%) to M199 medium (manufactured by SIGMA).
  • M199 medium manufactured by SIGMA
  • a lens extracted from the left and right eyes of a 6-week-old SD rat was cultured at 37 ° C. under 5% CO 2 for 3 days to develop diabetic cataract.
  • the lens of the left eye was transferred to a medium supplemented with (1) 30 mM galactose and (2) C646 and CPTH2 (both dissolved in DMSO).
  • the final concentration of C646 in the medium was 40 ⁇ M
  • the final concentration of CPTH2 was 80 ⁇ M
  • the final concentration of DMSO was 0.8%.
  • the lens of the right eye is prepared again by adding a medium obtained by adding 30 mM galactose and DMSO (prepared so that the final concentration becomes 0.8%) to M199 medium (manufactured by SIGMA). Moved to.
  • Experiment 2-1 The lens of the left eye was cultured in a medium supplemented with 30 mM galactose and C646 (prepared to a final concentration of 40 ⁇ M).
  • Experiment 2-2 The lens of the left eye was cultured in a medium supplemented with 30 mM galactose and CPTH2 (adjusted to a final concentration of 80 ⁇ M).
  • the lens transferred to the medium supplemented with the combination of C646 and CPTH2 was cultured in the cortex compared with the lens that had been cultured in the medium without the combination of C646 and CPTH2.
  • the turbidity of was kept low.
  • FIG. 10 when FIG. 10 is compared with (a) and (b) of FIG. 11, the lens cultured after being transferred to the medium to which the combination of C646 and CPTH2 was added was transferred to the medium to which only one of C646 or CPTH2 was added.
  • the turbidity of the cortex was lower than that of the cultured lens.
  • Example 6 Under in vivo conditions, the effect of HAT inhibitors to prevent cataracts was examined.
  • the lens was extracted from both the left and right eyes, and a micrograph magnified to 10 with SZX12 (Olympas) was taken. The result is shown in FIG.
  • the injection into the anterior chamber was performed only once.
  • food containing 25% galactose was continuously fed.
  • Example 7 A medium was prepared by adding 30 mM galactose and DMSO (prepared to a final concentration of 0.8%) to M199 medium (manufactured by SIGMA). In the above medium, a lens extracted from the left and right eyes of a 6-week-old SD rat (Sankyo Lab Service Co., Ltd.) was cultured at 37 ° C. under 5% CO 2 for 3 days to develop diabetic cataract. Model.
  • the lens of the left eye was transferred to a medium supplemented with 30 mM galactose and TH1834 (dissolved in DMSO).
  • the final concentration of TH1834 in the medium was 50 ⁇ M, and the final concentration of DMSO was 0.8%.
  • the lens of the right eye is prepared again by adding a medium obtained by adding 30 mM galactose and DMSO (prepared so that the final concentration becomes 0.8%) to M199 medium (manufactured by SIGMA). Moved to.
  • the lens cultured after being transferred to the medium supplemented with TH1834 had a lower turbidity in the cortex compared to the lens continuously cultured in the medium not supplemented with TH1834. . This suggests that TH1834 has a therapeutic effect on cataracts with only one agent.
  • the present invention can be used as an agent for preventing or treating cataract.

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Abstract

L'invention fournit un nouvel agent de prévention de la cataracte, un agent thérapeutique et une application d'inhibiteur de HAT destiné à fabriquer ceux-ci. L'agent de prévention de la cataracte ou l'agent thérapeutique de l'invention comprennent un inhibiteur de HAT en tant que principe actif.
PCT/JP2017/034204 2016-10-24 2017-09-22 Agent de prévention de la cataracte, agent thérapeutique, et application d'inhibiteur de hat destiné à fabriquer ceux-ci Ceased WO2018079149A1 (fr)

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CN110051841A (zh) * 2019-05-28 2019-07-26 北京大学 Nat10抑制剂在制备用于抑制hif表达的药物中的应用

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CN112274507A (zh) * 2020-09-23 2021-01-29 中山大学附属第一医院 NAT10的小分子抑制剂remodelin在制备口腔鳞癌治疗药物中的应用
CN114306583B (zh) * 2022-01-20 2023-11-07 承德医学院附属医院 Kat5在制备治疗哺乳动物过敏性疾病药物中的用途

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WO2012022468A2 (fr) * 2010-08-16 2012-02-23 Santhera Pharmaceuticals (Schweiz) Ag Dérivés de benzoquinone utilisés en tant que modulateurs de la fonction mitochondriale
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JPH11343234A (ja) * 1998-05-28 1999-12-14 Kyowa Hakko Kogyo Co Ltd テトラヒドロクルクミン誘導体を含有する組成物
WO2009044294A2 (fr) * 2007-06-15 2009-04-09 Université De Geneve Moyens et procédés permettant le traitement de la cataracte et de la presbytie
WO2016123054A2 (fr) * 2015-01-26 2016-08-04 The University Of North Carolina At Chapel Hill Combinaisons de médicaments à base de kinase et leurs procédés d'utilisation

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WO2012022468A2 (fr) * 2010-08-16 2012-02-23 Santhera Pharmaceuticals (Schweiz) Ag Dérivés de benzoquinone utilisés en tant que modulateurs de la fonction mitochondriale
WO2016123044A1 (fr) * 2015-01-27 2016-08-04 Mayo Foundation For Medical Education And Research Méthodes et matériel pour traiter l'endométriose

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CN110051841A (zh) * 2019-05-28 2019-07-26 北京大学 Nat10抑制剂在制备用于抑制hif表达的药物中的应用

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