WO2017209027A1 - Agent induisant l'autophagie - Google Patents

Agent induisant l'autophagie Download PDF

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WO2017209027A1
WO2017209027A1 PCT/JP2017/019848 JP2017019848W WO2017209027A1 WO 2017209027 A1 WO2017209027 A1 WO 2017209027A1 JP 2017019848 W JP2017019848 W JP 2017019848W WO 2017209027 A1 WO2017209027 A1 WO 2017209027A1
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autophagy
cloperastine
enalapril
norethisterone
azidothymidine
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PCT/JP2017/019848
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English (en)
Japanese (ja)
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昇 水島
剛志 貝塚
祐太郎 濱
雄一郎 豊田
水島　徹
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国立大学法人東京大学
株式会社Ｌｔｔバイオファーマ
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Publication of WO2017209027A1 publication Critical patent/WO2017209027A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K31/495—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
    • 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
    • A61K31/495—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 or sparfloxacin
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an autophagy-inducing agent and a neurodegenerative disease therapeutic agent.
  • Autophagy is one of the mechanisms for degrading intracellular proteins that cells have and is also called autophagy.
  • autophagy a part of the cytoplasm is first surrounded by an isolation membrane to form an autophagosome, and then the outer membrane of the autophagosome is fused with the lysosomal membrane to become an autolysosome and the contents are degraded.
  • Autophagy is a large-scale system capable of degrading not only proteins but also organelles such as mitochondria, and is well preserved from yeast to higher animals and plants. Autophagy has been considered to be a non-selective degradation system in principle, since the region of about 1 ⁇ m is randomly wrapped in autophagy, but recently, some substrates may be selectively incorporated. I understand.
  • Non-patent Document 1 Autophagy occurs at a certain level on a daily basis and is important as a quality control mechanism for intracellular components. Mice deficient in autophagy exhibit neurodegeneration with reflex abnormalities, motor dysfunction, etc. (Non-patent Document 1). Autophagy-related gene mutations have also been found in human Parkinson's disease and neurodegenerative diseases (SENDA) with iron deposition (Non-patent Documents 2 and 3). Based on these facts, animal experiments have attempted to treat diseases characterized by abnormal protein accumulation by enhancing intracellular purification by autophagy (Non-Patent Documents 4 to 9).
  • an object of the present invention is to provide a new autophagy inducer.
  • the present inventor has screened components already used as pharmaceuticals in order to search for new autophagy-inducing agents, and since 12 specific components have a strong autophagy-inducing action, neurodegeneration has occurred.
  • the present invention was completed by finding it useful as a disease therapeutic agent.
  • the present invention provides the following [1] to [8].
  • Neurodegenerative diseases comprising as an active ingredient an ingredient selected from adefovir pivoxil, azidothymidine, benproperin, cloperastine, enalapril, homochlorcyclidine, lomerizine, methyltestosterone, norethisterone, oxaprozin, pullrifloxacin, tipipedin and salts thereof Therapeutic agent.
  • the active ingredients of the autophagy-inducing agent and neurodegenerative disease therapeutic agent of the present invention are components already used as pharmaceuticals, safety has been confirmed and they have a strong autophagy-inducing action, and amyloid ⁇ It is effective in the treatment of neurodegenerative diseases caused by peptide aggregates represented by
  • the active ingredients of the autophagy-inducing agent and neurodegenerative disease therapeutic agent of the present invention are adefovir pivoxil, azidothymidine, benproperin, cloperastine, enalapril, homochlorcyclidine, lomerizine, methyltestosterone, norethisterone, oxaprozin, pullrifloxacin, tipipedin and It is a component selected from these salts.
  • Adefovir pivoxil is a reverse transcription inhibitor used for the treatment of chronic hepatitis B.
  • Azidothymidine is a kind of nucleic acid reverse transcriptase inhibitor and is a component used as a therapeutic agent for HIV.
  • Benproperin is an antitussive agent that acts on the cough center. Examples of the salt of benproperin include phosphate. Cloperastine acts directly on the cough center and is used as an antitussive. Examples of the salt of cloperastine include hydrochloride.
  • Enalapril is known as an angiotensin converting enzyme inhibitor and is used as a therapeutic agent for hypertension.
  • the salt of enalapril includes maleate.
  • Homochlorcyclidine is a histamine H 1 receptor blocker and is used to treat pruritus, urticaria, allergic rhinitis and the like associated with skin diseases.
  • Examples of the salt of homochlorocyclidine include hydrochloride.
  • Lomeridine is a calcium antagonist and is used as a migraine treatment.
  • Examples of the salt of romeridine include hydrochloride.
  • Methyltestosterone is a male hormone drug (androgen) and is used for male infertility due to male gonad dysfunction and spermatogenic dysfunction.
  • Norethisterone also known as norethindrone, is a luteinizing hormone drug used for the treatment of amenorrhea, menstrual cycle abnormalities and the like.
  • Oxaprozin is one of non-steroidal anti-inflammatory drugs and is used as an anti-inflammatory analgesic.
  • Plurifloxacin is used as a quinolone synthetic antibacterial agent.
  • Tipepidine is used as an antitussive expectorant, and its salt includes hibenzate.
  • the component used as an active ingredient of the autophagy-inducing agent of the present invention has already been used as a therapeutic agent for various diseases, but it has no autophagy-inducing action and is effective for neurodegenerative diseases. unknown.
  • the above components have an excellent autophagy-inducing action, and are therefore useful as therapeutic agents for neurodegenerative diseases based on protein abnormalities such as amyloid.
  • Neurodegenerative diseases and their proteins include Alzheimer's disease (amyloid ⁇ , tau protein), Parkinson's disease ( ⁇ synuclein), diabetes (amylin), systemic amyloid-cis (transthyretin), Huntington's disease (huntingtin), etc. Can be mentioned.
  • the autophagy-inducing agent of the present invention can treat neurodegenerative diseases by reducing abnormal proteins in these neurodegenerative diseases by autophagy-inducing action.
  • Examples of the administration form of the autophagy-inducing agent and neurodegenerative disease therapeutic agent of the present invention include injections, oral agents (tablets, granules, powders, capsules), ointments, creams, patches, suppositories and the like. It is done. Of these, oral preparations are particularly preferred.
  • These pharmaceutical compositions can be formulated with a pharmaceutically acceptable carrier. Examples of such carriers include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, carboxymethylcellulose calcium.
  • Salt magnesium stearate, talc, acetylcellulose, saccharose, titanium oxide, benzoic acid, p-hydroxybenzoate, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, egg yolk, surfactant, sucrose, simple syrup, citric acid, distillation Water, ethanol, glycerin, propylene glycol, macrogol, sodium phosphate-sodium hydrogen, sodium dihydrogen phosphate, sodium phosphate, grape , Sodium chloride, phenol, thimerosal, p-hydroxybenzoic acid esters, and sodium hydrogen sulfite.
  • the content of the active ingredient of the present invention in the pharmaceutical composition preparation of the present invention varies greatly depending on the form of the preparation and is not particularly limited, but is usually 0.01% with respect to the total amount of the composition. To 100% by mass, preferably 1 to 100% by mass.
  • the dosage of the autophagy-inducing agent and therapeutic agent for neurodegenerative diseases of the present invention varies depending on the symptoms, age, and administration method of the patient to be administered, but the amount of the active ingredient is 1-1000 mg per day for an adult. Is preferred.
  • the dose can be divided into 1 to 4 times a day, preferably 2 to 4 times a day.
  • GFP-LC3-RFP-LC3 ⁇ G expressed by this cell is from the head (amino terminus) to green fluorescent protein (GFP), microtube-associated protein light chain 3 (LC3), red fluorescent protein (RFP), carboxy-terminal glycine of LC3 Deficient body (LC3 ⁇ G) is linked.
  • GFP-LC3-RFP-LC3 ⁇ G is cleaved and separated into GFP-LC3 and RFP-LC3 ⁇ G immediately after being synthesized in the cell.
  • GFP-LC3 is degraded by autophagy, but RFP-LC3 ⁇ G remains in the cell without being degraded.
  • the GFP / RFP ratio decreases.
  • 30,000 of these cells were seeded in 96-well plates, and the following day, the medium was replaced with a medium containing only the drug or solvent (3 wells were used for each drug). After 24 hours, the cells in each well were fixed with a 4% paraformaldehyde solution for 10 minutes.
  • the GFP / RFP ratio was calculated by measuring the amount of fluorescence of GFP and RFP in each well with a microplate reader (EnSpire, PerkinElmer Japan). The ratio of the control (cells treated with the solvent) to the GFP / RFP ratio is shown in Table 1.
  • Example 2 Visualization of autophagosome formation
  • HeLa cells stably expressing GFP-LC3-RFP-LC3 ⁇ G were used. Since GFP-LC3 produced by these cells binds to autophagosomes, they are observed as bright spots with a fluorescence microscope. The cells were treated with each drug for 2 hours and 24 hours, fixed with a 4% paraformaldehyde solution for 10 minutes, and then observed with a fluorescence microscope (IX81, OLYMPUS) (FIGS. 1 to 3). The number of observed bright spots of GFP-LC3 was evaluated in five levels:-, ⁇ , +, ++, and ++ (Table 2).
  • GFP-Q81 is obtained by adding a sequence (PolyQ) in which 81 glutamines are linked to green fluorescent protein (GFP).
  • PolyQ is known to self-interact in cells to form aggregates.
  • PolyQ aggregates are known to be associated with the pathology of multiple human neurodegenerative diseases and have been reported to be selective substrates for autophagy.
  • the cells were seeded on a cover glass, and at the same time, the induction of aggregates was started by adding DOX. After 72 hours, the medium was replaced with a medium containing a solvent (DMSO) or an autophagy inducer (10 ⁇ M).
  • DMSO solvent
  • an autophagy inducer 10 ⁇ M
  • each cell was fixed with a 4% paraformaldehyde solution for 10 minutes, stained with nuclei, and then observed with a fluorescence microscope.
  • the total number of cells in the image was quantified from the nuclear staining image, and the number of aggregate-positive cells from the GFP image, and the ratio of aggregate-positive cells to the total number of cells was calculated. The results are shown in FIGS. 4 and 5 and Table 3.

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Abstract

La présente invention concerne un nouvel agent induisant l'autophagie L'agent induisant l'autophagie comprend, en tant qu'ingrédient actif, un ingrédient choisi parmi l'adéfovir dipivoxil, l'azidothymidine, la clopérastine, l'énalapril, l'homochlorcyclizine, la lomerizine, la méthyltestostérone, la noréthistérone, l'oxaprozine, la prulifloxacine, la tipépidine et des sels de ceux-ci.
PCT/JP2017/019848 2016-05-30 2017-05-29 Agent induisant l'autophagie WO2017209027A1 (fr)

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JP2016-107609 2016-05-30
JP2016107609A JP2017214302A (ja) 2016-05-30 2016-05-30 オートファジー誘導剤

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114057822A (zh) * 2021-11-22 2022-02-18 浙江大学 一种甾酮类化合物的提取方法和医药用途

Citations (2)

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JP2002512789A (ja) * 1998-04-28 2002-05-08 マイトコー 変化したミトコンドリア機能に関連する疾患の細胞および動物モデル
JP2013506686A (ja) * 2009-09-30 2013-02-28 プレジデント アンド フェロウズ オブ ハーバード カレッジ オートファジー阻害遺伝子産物の変調によりオートファジーを変調する方法

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JP2002512789A (ja) * 1998-04-28 2002-05-08 マイトコー 変化したミトコンドリア機能に関連する疾患の細胞および動物モデル
JP2013506686A (ja) * 2009-09-30 2013-02-28 プレジデント アンド フェロウズ オブ ハーバード カレッジ オートファジー阻害遺伝子産物の変調によりオートファジーを変調する方法

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BERTRAND, LUC ET AL.: "Dysregulation of Endoplasmic Reticulum Stress and Autophagic Responses by the Antiretroviral Drug Efavirenz", MOLECULAR PHARMACOLOGY, vol. 88, no. 2, 2015, pages 304 - 315, XP055443524 *
KAIZUKA, TAKESHI ET AL.: "An Autophagic Flux Probe that Peleases an Internal Control", MOLECULAR CELL, vol. 64, no. 4, November 2016 (2016-11-01), pages 835 - 849, XP029812406 *
MITSUHIRO KITAGAWA ET AL.: "Chemical Biology for the Study of Autophagy", KAGAKU KOGYO, vol. 65, no. 4, 2014, pages 22 - 27 *
PURNELL, PHILLIP R. ET AL.: "Efavirenz Induces Neuronal Autophagy and Mitochondrial Alterations", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 351, no. 2, 2014, pages 250 - 258, XP055443531 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114057822A (zh) * 2021-11-22 2022-02-18 浙江大学 一种甾酮类化合物的提取方法和医药用途
CN114057822B (zh) * 2021-11-22 2022-11-08 浙江大学 一种甾酮类化合物的提取方法和医药用途

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