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WO2011121645A1 - Inhibiteur de formation de fibrilles amyloïdes - Google Patents

Inhibiteur de formation de fibrilles amyloïdes Download PDF

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Publication number
WO2011121645A1
WO2011121645A1 PCT/JP2010/002309 JP2010002309W WO2011121645A1 WO 2011121645 A1 WO2011121645 A1 WO 2011121645A1 JP 2010002309 W JP2010002309 W JP 2010002309W WO 2011121645 A1 WO2011121645 A1 WO 2011121645A1
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Prior art keywords
fibril formation
amyloid fibril
amyloid
group
cyd
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Japanese (ja)
Inventor
安東由喜雄
有馬英俊
城野博史
植田光晴
本山敬一
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Kumamoto University NUC
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Kumamoto University NUC
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Priority to PCT/JP2010/002309 priority Critical patent/WO2011121645A1/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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof

Definitions

  • the present invention relates to an amyloid fibril formation inhibitor comprising a cyclodextrin derivative or a salt thereof as an active ingredient, and a medicament for the prevention and / or treatment of amyloidosis comprising the amyloid fibril formation inhibitor.
  • Amyloidosis refers to a group of diseases in which a protein having a ⁇ -sheet structure is polymerized to form insoluble fibrils called amyloid, which are deposited in the living body and cause tissue damage.
  • Virchow a German pathologist, has discovered that tissue samples of amyloidosis are stained purple with iodine. From this result, Virchow considered that the substance deposited in the tissue was a polysaccharide, named it “starch-like substance”, that is, “amyloid”, and proposed that the pathological condition caused by amyloid deposition was called amyloidosis .
  • amyloid is a protein that forms a fiber by polymerizing like nylon, and that amyloid contains serum amyloid P component, glycosaminoglycan and the like.
  • amyloid is defined as “an accumulation of unbranched fibrils with a width of 8-15 nm that causes a birefringence that shines orange with congo red staining and is strongly green when observed under a polarizing microscope”.
  • Amyloidosis includes various diseases such as familial amyloid polyneuropathy (FAP), Alzheimer's disease, Creutzfeldt-Jakob disease (mad cow disease), Huntington's disease and other inherited diseases.
  • FAP familial amyloid polyneuropathy
  • Alzheimer's disease Creutzfeldt-Jakob disease (mad cow disease)
  • Huntington's disease and other inherited diseases.
  • FAP is amyloidosis that causes amyloid deposition in systemic organs such as peripheral nerves, autonomic nerves, kidneys, skin, mucous membranes, and infiltrates in an autosomal dominant manner. Case has been confirmed. Since the first report of Portuguese FAP cases in 1952, similar cases have been reported from around the world.
  • Amyloid fibrils that cause FAP are mainly composed of mutated serum protein transthyretin (TTR).
  • TTR mutated serum protein transthyretin
  • Normal TTR has a three-dimensional structure containing many ⁇ -sheet structures, and is produced in the liver, choroid plexus, retina, pancreatic ⁇ cells, etc., and more than 90% of them are said to be produced in the liver. Yes. Normal TTR forms a tetramer and plays a role as a transporter of vitamin A via thyroxine (T4), retinol binding protein (RBP) and the like. More than 100 types of mutants of normal TTR have been reported so far, and it has been clarified that the structural stability is low and the structural change from tetramer to monomer is likely to occur.
  • T4 thyroxine
  • RBP retinol binding protein
  • type I FAP that is common in Japan is type I FAP with Val30Met type mutant TTR as a causal protein.
  • the major characteristics of type I FAP are polyneuritis and autonomic neuropathy (alternative diarrhea and constipation, orthostatic hypotension, urination injury, etc.) with perceptual impairment that rises symmetrically from the lower limb end. Both are caused by nerve damage caused by amyloid. Later, amyloid deposits in the heart, kidney, and gastrointestinal tract become prominent, causing dysfunction of these organs. Generally, it is a disease with a poor prognosis that develops in the late 20s to 30s, becomes unwalkable in 10 years, and dies from infection, heart failure, kidney failure, etc. in 10 to 20 years. Is also one of the designated intractable diseases.
  • a mutant TTR protein capable of causing type I FAP has lower structural stability than normal TTR protein, and ⁇ -sheet structures in the molecule associate with each other to form insoluble amyloid fibrils and deposit in tissues. Therefore, it is considered that type I FAP can be prevented and / or treated by inhibiting amyloid fibril formation by the mutant TTR protein.
  • Non-patent Document 1 As a method of suppressing amyloid fibril formation, a method of inhibiting the dissociation of the tetrameric TTR molecule has been tried, but clinical therapeutic effect has not been recognized (Yoshiki Sekijima et.al., "Long- term effects of diflunisal on familial amyloid polyneuropathy, "2008, VIIth International symposium on Familial Amyloid Polyneuropathy). Furthermore, no highly safe substance that suppresses amyloid fibril formation that can be applied to the prevention and / or treatment of amyloidosis has been reported so far (Non-patent Document 1).
  • a first object of the present invention is to provide a highly safe amyloid fibril formation inhibitor containing a substance that suppresses amyloid fibril formation of TTR protein as an active ingredient. Furthermore, a second object of the present invention is to provide a medicament for the prevention and / or treatment of amyloidosis, particularly a medicament for the prevention and / or treatment of familial amyloidosis polyneuropathy (FAP), comprising the inhibitor. Furthermore, the present invention provides a medicament for preventing the onset of sensory impairment and autonomic neuropathy caused by amyloidosis, and a medicament for treatment that enables prevention of progression of the perceptual disorder and autonomic neuropathy. There is.
  • an amyloid fibril formation inhibitor comprising as an active ingredient a cyclodextrin derivative modified with at least one selected from the group consisting of an optionally substituted sugar, a peptide, and polyethylene glycol, or a salt thereof.
  • the cyclodextrin derivative is a ⁇ -cyclodextrin derivative.
  • the cyclodextrin derivative is represented by the following formula 1.
  • R is a carboxyl group, a methoxycarbonyl group, a hydroxymethyl group, a hydroxyethyl group, a methyl group, an ethyl group, a formyl group, or an acetyl group
  • R is a carboxyl group, a methoxycarbonyl group, a hydroxymethyl group, a hydroxyethyl group, a methyl group, an ethyl group, a formyl group, or an acetyl group
  • a medicament for the prevention and / or treatment of amyloidosis comprising the amyloid fibril formation inhibitor of the present invention.
  • a cyclodextrin modified with at least one selected from the group consisting of an optionally substituted sugar, a peptide, and polyethylene glycol for the production of an amyloid fibril formation inhibitor Use of a derivative or salt thereof is provided. According to still another aspect of the present invention, at least one selected from the group consisting of an optionally substituted sugar, peptide, and polyethylene glycol for the manufacture of a medicament for the prevention and / or treatment of amyloidosis. There is provided the use of a cyclodextrin derivative or salt thereof modified with
  • a cyclodextrin derivative modified with at least one selected from the group consisting of an optionally substituted sugar, a peptide, and polyethylene glycol or a salt thereof is administered to a patient.
  • a method of inhibiting amyloid fibril formation is provided.
  • a cyclodextrin derivative modified with at least one selected from the group consisting of an optionally substituted sugar, a peptide, and polyethylene glycol or a salt thereof is administered to a patient. Methods for preventing and / or treating amyloidosis are provided.
  • the amyloid fibril formation inhibitor of the present invention can significantly suppress amyloid fibril formation. Therefore, the medicament containing the amyloid fibril formation inhibitor of the present invention is useful as a medicament for the prevention and / or treatment of amyloidosis, and particularly familial amyloidosis polyneuropathy (FAP), which has only a symptomatic treatment or a liver transplantation treatment method. Can be used as a highly effective medicine. Furthermore, the pharmaceutical of the present invention is effective for the highly safe cyclodextrin derivative in which the amyloid fibril formation inhibitor of the present invention is widely used as a pharmaceutical excipient for the purpose of solubilizing and stabilizing fat-soluble drugs and the like.
  • FAP familial amyloidosis polyneuropathy
  • the medicament of the present invention is a medicament that can be put to practical use at an early stage in the prevention and / or treatment of amyloidosis because of its effectiveness and safety.
  • FIG. 1 shows the results of inhibition of amyloid fibril formation by 10 mM, 20 mM and 30 mM GUG- ⁇ -CyD.
  • FIG. 2 shows the results of suppression of amyloid fibril formation by 1 mM, 10 mM and 100 mM G 2 - ⁇ -CyD.
  • FIG. 3 shows the results of comparison of suppression of amyloid fibril formation in the presence or absence of HP- ⁇ -CyD, GUG- ⁇ -CyD, and G 2 - ⁇ -CyD.
  • FIG. 4 shows the results of suppression of amyloid fibril formation in the presence or absence of SBE- ⁇ -CyD and GUG- ⁇ -CyD.
  • FIG. 5 shows the results of suppression of amyloid fibril formation in the presence or absence of GUG- ⁇ -CyD and ⁇ -CyD.
  • FIG. 6 shows an outline of a synthetic route for dimethylacetyl- ⁇ -cyclodextrin.
  • FIG. 7 shows the sustained effect of GUG- ⁇ -CyD in inhibiting amyloid fibril formation.
  • FIG. 8 shows the effect of GUG- ⁇ -CyD on TTR amyloid deposition.
  • cyclodextrin derivative which is an active ingredient of the amyloid fibril formation inhibitor of the present invention, part or all of the glucose skeleton constituting the cyclodextrin is modified.
  • Cyclodextrin is a cyclic oligosaccharide in which several molecules of D-glucose are bonded by ⁇ (1 ⁇ 4) glucoside bonds, and has a characteristic that a hydrophobic molecule can be included in the pores in the molecule. Cyclodextrins are widely used in the pharmaceutical field such as solubilization and stabilization of fat-soluble drugs and reduction of local irritation from the viewpoint of the properties and safety (Kaneto Uekama, (2004), YAKUGAKU ZASSHI, 124, ( 12), pp.909-935). Furthermore, cyclodextrin exhibits actions such as control of cholesterol and phospholipids and protein stabilization, and has various functions as well as a use as a mere pharmaceutical additive.
  • the cyclodextrin constituting the cyclodextrin derivative is not particularly limited as long as it can include molecules.
  • ⁇ -cyclodextrin having 6 glucose skeletons ⁇ -cyclodextrin having 7 glucose skeletons, and the like.
  • Cyclodextrin and ⁇ -cyclodextrin having 8 glucose skeletons are preferable.
  • ⁇ -cyclodextrin is readily available, has a proven track record as a pharmaceutical excipient, and has a wide range of inclusion targets. Is more preferable.
  • the cyclodextrin derivative is not particularly limited as long as it can suppress amyloid fibril formation of TTR protein.
  • cyclodextrin modified with one or more selected from the group consisting of sugar, peptide, and polyethylene glycol A derivative is preferable, and a cyclodextrin derivative modified with a sugar is more preferable.
  • the number of modifying groups in the cyclodextrin derivative is preferably 1 to 5, more preferably 1 to 3, more preferably 1 or 2, and still more preferably 1.
  • sugars used for modification of cyclodextrin derivatives include monosaccharides such as glucose, mannose, galactose, fructose, ribose, xylose, and arabinose; maltose, trehalose, cozybiose, nigerose, isomaltose, sophorose, laminaribio , Cellobiose, gentiobiose, lactose, sucrose, palatinose, melibiose, lutinose, primebellose, tulanose and other disaccharides; Not only trisaccharides such as umbelliferose, lactosucrose, and raffinose, but also xylooligosaccharides with higher polymerization degree, galactose Gore sugar, maltooligosaccharides, and oligosaccharides such as isomaltooligosaccharides are preferred.
  • monosaccharides such as glucose, mannose, galactose,
  • Peptides that modify cyclodextrin preferably have, for example, 1 to 10 amino acids, more preferably 2 to 8 amino acids, and even more preferably 2 to 6 amino acids.
  • the kind of amino acid which comprises a peptide can be set suitably, the thing containing many amino acids which have a hydrophobic side chain is preferable.
  • the polyethylene glycol that modifies cyclodextrin preferably has a molecular weight of 200 to 50,000, more preferably a molecular weight of 1,000 to 50,000, and still more preferably a molecular weight of 10,000 to 30,000.
  • part or all of the hydroxyl group may be substituted with a carboxyl group, a methoxycarbonyl group, a hydroxymethyl group, a hydroxyethyl group, a methyl group, an ethyl group, a formyl group, an acetyl group, etc. .
  • a carboxyl group a methoxycarbonyl group, a hydroxymethyl group, a hydroxyethyl group, a methyl group, an ethyl group, a formyl group, an acetyl group, etc.
  • 6-O- ⁇ -maltose and 6-O- ⁇ - (4-O- ⁇ -D-gluconyl) -D-glucose are most preferably used.
  • a preferred embodiment of the cyclodextrin derivative is represented by the following formula 1 [Wherein, R is a carboxyl group, a methoxycarbonyl group, a hydroxymethyl group, a hydroxyethyl group, a methyl group, an ethyl group, a formyl group, or an acetyl group] It is a compound of this.
  • the obtained reaction product is dried over anhydrous magnesium sulfate, and then separated and / or purified by silica gel chromatography (Kieselgel 60; 0.063 to 0.2 mm [70 to 230 mesh]).
  • silica gel chromatography Karlgel 60; 0.063 to 0.2 mm [70 to 230 mesh]
  • the amyloid fibril formation inhibitor of the present invention contains the compound of the above formula 1 as an active ingredient, for example, the concentration of the compound of the above formula 1 in which R is a carboxyl group or a hydroxymethyl group is 0.2 mg / mL TTR 10 mM or more is preferable with respect to the protein, 40 mM or more is more preferable, and 100 mM or more is more preferable.
  • cyclodextrins include methylation, hydroxyalkylation such as hydroxyethyl and hydroxypropyl, glucosylation, maltosylation, alkylation, acylation, acetylation, sulfation, sulfobutylation, carboxymethylation Modification methods such as carboxyethylation, amination, carboxylation, tosylation, and dimethylacetylation, and a combination of these methods are known.
  • the modification of these cyclodextrins can be carried out with reference to, for example, the following literature: Cyclodextrins-Basics and Applications-, supervised by Fujio Toda, and industrial books.
  • the amyloid fibril formation inhibitor of the present invention may be a cyclodextrin derivative or a salt thereof.
  • the ratio of the cyclodextrin derivative or a salt thereof contained in the amyloid fibril formation inhibitor of the present invention is not particularly limited as long as it is an amount capable of suppressing amyloid fibril formation of TTR protein. For example, 80% to 100% Is preferred.
  • amyloid fibril formation inhibitor of the present invention can be used in either a solid or liquid form as long as it contains an effective amount of a cyclodextrin derivative or a salt thereof, and a pharmaceutically acceptable carrier or additive is added thereto. It can also be blended and prepared as a solid or liquid pharmaceutical composition.
  • amyloid fibril formation inhibitor of the present invention can be used for the purpose of suppressing amyloid fibril formation, and can be included in, for example, a medicament for the prevention and / or treatment of amyloidosis. Therefore, another aspect of the present invention is a medicament for preventing and / or treating amyloidosis, which comprises the amyloid fibril formation inhibitor of the present invention.
  • amyloidosis to which the medicament of the present invention is applied examples include, for example, familial amyloidosis polyneuropathy (FAP), neurodegenerative diseases such as Alzheimer's disease, bovine spongiform encephalopathy (BSE), Examples include Creutzfeldt-Jakob disease (CJD), laughing death syndrome, scrapie, and deformed Creutzfeldt-Jakob disease in humans.
  • FAP familial amyloidosis polyneuropathy
  • CJD Creutzfeldt-Jakob disease
  • laughing death syndrome scrapie
  • deformed Creutzfeldt-Jakob disease in humans.
  • familial amyloidosis polyneuropathy is a particularly suitable subject of the medicament of the present invention.
  • Amyloid fibrils by transthyretin which is a serum protein
  • TTR transthyretin
  • a serum protein is formed through the following three stages.
  • transthyretin present in serum as a tetrameric protein is decomposed into monomers by some action.
  • most of this monomer is decomposed and part is excreted out of the body as urine via a biological metabolic pathway, but part of the monomer is recombined to form a ⁇ -sheet structure.
  • this ⁇ -sheet structure is linearly polymerized to produce insolubilized fibrous amyloid fibrils.
  • Mutant transthyretin has the property that tetrameric proteins are easily dissociated into monomers, resulting in an increase in the production of amyloid fibrils.
  • the present inventors have found that amyloid fibrils can be obtained by using the cyclodextrin derivative of the present invention, which is an improved cyclodextrin that can include a hydrophobic molecule. It has been found that formation can be suppressed.
  • the cyclodextrin derivative of the present invention is a hydrophobic amino acid of transthyretin.
  • patients with mild symptoms can prevent the progression and worsening of symptoms by administering the medicament of the present invention.
  • a therapeutic effect can be expected even for patients with severe symptoms.
  • an individual having a mutant transthyretin is a potential patient who has a high possibility of developing FAP with aging, but the administration of the medicament of the present invention can prevent the onset of FAP.
  • the amyloid fibril formation inhibitor of the present invention may be used as it is.
  • the amyloid fibril formation inhibitor of the present invention which is usually an active ingredient or a mixture containing the same and one or more preparations It is desirable to prepare and use a form of a pharmaceutical composition containing a pharmaceutical additive.
  • amyloid fibril formation inhibitor of the present invention but also a nonsteroidal anti-inflammatory drug that stabilizes the transthyretin tetramer, such as diflunisal.
  • Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups.
  • Examples of the pharmaceutical composition suitable for parenteral administration include Injections, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches, transdermal absorbents, transmucosal absorbents, and the like.
  • Examples of pharmaceutical additives used in the production of the above pharmaceutical composition include excipients such as lactose and oligosaccharides, disintegrants or disintegrants, binders, lubricants, coating agents, dyes, and diluents.
  • solubilizers or solubilizers can be used by those skilled in the art depending on the form of the pharmaceutical composition. Can be selected as appropriate, and two or more of them may be used in combination.
  • an injection can be mentioned.
  • Injectables are usually substantially free of non-aqueous solvents (or water-soluble organic solvents) and can be dissolved or diluted with a solvent whose medium is substantially water.
  • lyophilized preparations can also be mentioned as a preferred form of the pharmaceutical product of the present invention. Even such lyophilized preparations can be dissolved in at least one liquid or solvent selected from water for injection (distilled water for injection), an infusion solution containing an electrolyte solution (such as physiological saline), and a nutritional infusion solution.
  • An injection solution can be easily prepared, and a glass container and a plastic container can be used as the container.
  • the amyloid formation inhibitor of the present invention can be contained in an amount of 0.01 parts by weight or more, preferably 0.1 to 10 parts by weight based on 100 parts by weight of the contents of the injection.
  • the dosage and number of administrations of the medicament of the present invention are not particularly limited, and can be appropriately selected according to conditions such as the age, weight, and sex of the patient, the type and severity of the disease, the purpose of prevention or treatment, etc. It is.
  • the amount of active ingredient is preferably 1 mg to 30 g per day, more preferably 10 mg to 10 g, and more preferably 100 mg to 5 g, but the dose is divided into several times a day. May be.
  • the amyloid fibril formation inhibitor of the present invention or the medicament of the present invention can be used not only as a pharmaceutical as described above, but also as a quasi-drug, cosmetic, functional food, nutritional supplement, food and drink, etc. .
  • a quasi-drug or cosmetic it can be used together with various adjuvants commonly used in the technical field such as quasi-drug or cosmetic, if necessary.
  • a functional food, nutritional supplement, or food and drink it is usually used in foods such as sweeteners, spices, seasonings, preservatives, preservatives, bactericides, and antioxidants as necessary. You may use with the additive used.
  • a desired shape such as solution, suspension, syrup, granule, cream, paste, jelly, etc., or as necessary.
  • the ratio contained in these is not specifically limited, It can select suitably according to a use purpose, a usage form, and a usage-amount.
  • TTR Experimental Material Transthyretin
  • CyD Cyclodextrin
  • GUI- ⁇ -CyD 6-O- ⁇ -maltosyl- ⁇ -CyD
  • G 2 - ⁇ -CyD was synthesized according to Ishiguro et al. (Toshihiro Ishiguro et. Al., (2001), Carbohydrate Research, 331, pp. 423-430).
  • Hydropropylated- ⁇ -CyD HP- ⁇ -CyD
  • SBE- ⁇ -CyD Sulfobutyl ether- ⁇ -CyD
  • Method for forming amyloid fibrils TTR was prepared with 20 mM acetate buffer (pH 3.0-6.5) containing 100 mM sodium chloride to a concentration of 0.2 mg / mL, and incubated at 37 ° C., protected from light. Amyloid fibrils were formed.
  • FIG. 8 shows the results of administering GUG- ⁇ -CyD to ATTR V30M rats and performing immunostaining with TTR antibody about three months later.
  • a decrease in the amount of deposited TTR amyloid was confirmed compared to the non-administered group.
  • amyloid fibril deposition Diseases that cause organ damage due to amyloid fibril deposition include FAP, Alzheimer's disease, Creutzfeldt-Jakob disease (mad cow disease), Huntington's disease, and other inherited diseases. Since the deposition of amyloid fibrils is due to the formation of insoluble fibrous aggregates of proteins, cyclodextrin derivatives can also be applied in the treatment of these various amyloidosis diseases.

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Abstract

Cette invention concerne un inhibiteur de formation de fibrilles amyloïdes qui est très sûr et comprend une substance capable d'inhiber la formation de fibrilles amyloïdes de la protéine TTR à titre de principe actif. Plus spécifiquement, cette invention concerne un inhibiteur de formation de fibrilles amyloïdes comprenant un dérivé de cyclodextrine modifié par au moins un composant choisi dans le groupe constitué par un sucre, un peptide et un polyéthylène glycol qui peut être substitué et un sel du dérivé de cyclodextrine à titre de principe actif.
PCT/JP2010/002309 2010-03-30 2010-03-30 Inhibiteur de formation de fibrilles amyloïdes Ceased WO2011121645A1 (fr)

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Cited By (3)

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JP2016098173A (ja) * 2014-11-18 2016-05-30 学校法人中部大学 Ｇｌｐ−１分泌促進剤
EP3903822A4 (fr) * 2018-12-27 2022-08-31 National University Corporation Kumamoto University Ligand et support de médicament pénétrant dans le cerveau
JP7670278B2 (ja) 2019-10-04 2025-04-30 国立大学法人 熊本大学 薬物キャリア剤及びその製造方法

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JP2010090054A (ja) * 2008-10-07 2010-04-22 Kumamoto Univ アミロイド線維形成抑制剤

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JP2016098173A (ja) * 2014-11-18 2016-05-30 学校法人中部大学 Ｇｌｐ−１分泌促進剤
EP3903822A4 (fr) * 2018-12-27 2022-08-31 National University Corporation Kumamoto University Ligand et support de médicament pénétrant dans le cerveau
JP7670278B2 (ja) 2019-10-04 2025-04-30 国立大学法人 熊本大学 薬物キャリア剤及びその製造方法

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