Pharmaceutical composition for treating synucleinopathy comprising rifapentin, amphotericin b, cetylpyridinium, domifene, or tocofersolan containing long carbon chain as active ingredient

Abstract

The present invention relates to a pharmaceutical composition for preventing, alleviating, or treating synucleinopathy, comprising rifapentin, amphotericin B, cetylpyridinium, domifene, or tocofersolan as an active ingredient. The rifapentin, amphotericin B, cetylpyridinium, domifene, tocofersolan, or a pharmaceutically acceptable salt thereof of the present invention inhibits the fibrillation and oligomerization of alpha-synuclein, and thus can be effectively used in the treatment of synucleinopathy.

Description

Pharmaceutical composition for treating synucleinopathy comprising rifapentine, amphotericin B, cetylpyridinium, domiphen, and tocophersolane, which contain long carbon chains, as active ingredients

[0001] The present invention was made under the support of the Ministry of Science and ICT of the Republic of Korea under the research project number 2021R1A6A1A03038996, the research management specialized organization of the project is the National Research Foundation of Korea, the research project name is "University Key Research Institute Support Project", the research project name is "Development of Diagnosis and Treatment Technology for Geriatric Diseases", the main organization is Gachon University, and the research period is 2021.06.01-2030.05.31.

[0002] The present invention was also made possible by the support of the Ministry of Science and ICT of the Republic of Korea under the research project number RS-2023-00251396, the research management specialized organization of the project is the National Research Foundation of Korea, the research project name is "Individual Basic Research", the research project name is "Screening of Amyloid Beta Aggregation Inhibitor Compounds and Study of Mechanism of Action for Discovery of Alzheimer's Disease Treatment Candidates", the main organization is Gachon University, and the research period is 2023.06.01 - 2026.02.28.

[0003] This patent application claims priority to Republic of Korea Patent Application No. 10-2023-0180066, filed with the Korean Intellectual Property Office on December 12, 2023, the disclosure of which is incorporated herein by reference.

[0004] The present invention relates to a pharmaceutical composition for preventing, improving or treating synuclein disease, comprising rifapentine, amphotericin B, cetylpyridinium, domiphene or tocophersolane as an active ingredient.

[0005]

[0006] Synucleinopathies (α-synucleinopathies) are neurodegenerative diseases characterized by abnormal accumulation of alpha-synuclein protein fibrils or oligomers in neurons, nerve fibers, or glial cells.

[0007] Synucleinopathies include Parkinson's disease, Parkinson's disease dementia, Lewy body dementia, multiple system atrophy, and Alzheimer's disease, and are known to cause symptoms such as cognitive impairment, autonomic nervous system dysfunction, gaze paralysis, and dystonia.

[0008] Alpha-synuclein is a small protein composed of 140 amino acids. Due to its unstable structure, it can transform into various forms depending on the surrounding environment. Unbalanced physiological conditions, such as overexpression or mutations, can induce abnormal accumulation and aggregation of alpha-synuclein, leading to synucleinopathy.

[0009] Alpha-synuclein, similar to amyloid beta, which is known to be the cause of Alzheimer's disease, oligomerizes with itself to form oligomers, and when it continues to aggregate, fibrilization progresses to form fibrils.

[0010] Although extensive research has been conducted on treatments for synucleinopathy, only levodopa, which alleviates the symptoms of Parkinson's disease, is currently in clinical use. Levodopa, too, has not been shown to significantly alleviate symptoms of synucleinopathy other than Parkinson's disease. Therefore, the development of treatments for synucleinopathy remains a pressing need.

[0011] However, the challenges of new drug development are increasing due to rising initial development costs and failures in later stages of development stemming from strengthened drug safety regulations. Furthermore, the number of new drugs receiving approval is rapidly declining. To overcome this crisis, low-cost, rapid development methods are needed. Drug repurposing, which involves re-examining the indications of existing drugs to confirm their potential as new disease treatments, is emerging as a new approach to drug development.

[0012] The present inventors studied pharmaceutical compositions for treating synuclein disease and confirmed that rifapentine, used as a conventional anti-tuberculosis agent, amphotericin B, cetylpyridinium, and domiphen, used as preservatives, and tocofersolan, used as an antioxidant, have alpha-synuclein fibrillation inhibitory activity. In addition, by confirming the alpha-synuclein oligomerization inhibitory activity of each drug, they elucidated that rifapentine, amphotericin B, cetylpyridinium, domiphen, or tocofersolan can be used as pharmaceutical compositions for treating synuclein disease, thereby completing the present invention.

[0013]

[0014] The present inventors have diligently researched and developed pharmaceutical compositions for the treatment of synuclein disease. As a result, we confirmed the alpha-synuclein fibrillation inhibitory activity of rifapentine, a conventional anti-tuberculosis drug; amphotericin B, cetylpyridinium, and domiphen, which are used as preservatives; and tocofersolan, which is used as an antioxidant. Furthermore, by confirming the alpha-synuclein oligomerization inhibitory activity of each drug, we have elucidated that rifapentine, amphotericin B, cetylpyridinium, domiphen, or tocofersolan can be used as pharmaceutical compositions for the treatment of synuclein disease, thereby completing the present invention.

[0015] Accordingly, the purpose of the present invention is to provide a pharmaceutical composition for preventing, improving or treating synuclein-related neurodegenerative diseases, which comprises rifapentine, amphotericin B, cetylpyridinium, domiphen, tocopherolane or a pharmaceutically acceptable salt thereof as an active ingredient.

[0016] Another object of the present invention is to provide a functional food composition for preventing or improving synuclein-related degenerative neurodegenerative diseases, comprising rifapentine, amphotericin B, cetylpyridinium, domiphen, tocopherolan or a pharmaceutically acceptable salt thereof as an active ingredient.

[0017] Other objects and advantages of the present invention will become more apparent from the detailed description, claims and drawings below.

[0018]

[0019] The present inventors have diligently researched and developed pharmaceutical compositions for the treatment of synuclein disease. As a result, they confirmed the alpha-synuclein fibrillation inhibitory activity of rifapentine, a conventional anti-tuberculosis drug, and amphotericin B, cetylpyridinium, domiphen, or tocophersolan, which are used as preservatives. Furthermore, by confirming the alpha-synuclein oligomerization inhibitory activity of each drug, they demonstrated that rifapentine, amphotericin B, cetylpyridinium, domiphen, or tocophersolan can be used as pharmaceutical compositions for the treatment of synuclein disease, thereby completing the present invention.

[0020] According to one aspect of the present invention, the present invention provides a pharmaceutical composition for preventing, improving or treating a synuclein-related neurodegenerative disease, comprising rifapentine, amphotericin B, cetylpyridinium, domiphen, tocofersolan or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the rifapentine is represented by the following chemical formula 1, the amphotericin B is represented by the following chemical formula 2, the cetylpyridinium is represented by the following chemical formula 3, the domiphen is represented by the following chemical formula 4, and the tocofersolan is represented by the following chemical formula 5:

[0021] [Chemical Formula 1]

[0022] ,

[0023] [Chemical Formula 2]

[0024] ,

[0025] [Chemical Formula 3]

[0026] ,

[0027] [Chemical Formula 4]

[0028] , and

[0029] [Chemical Formula 5]

[0030] .

[0031] In the present invention, "rifapentine" is an antibiotic of the rifamycin series, also called 3-[[(4-cyclopentyl-1-piperazinyl)imino]methyl]-rifamycin, is used for the treatment of tuberculosis, and has therapeutic efficacy against active tuberculosis and latent tuberculosis.

[0032] In the present invention, "amphotericin B" is a type of antifungal polyene antibiotic, and the amphotericin B is effective for the primary treatment of systemic fungal infections, fever of unknown origin in neutropenic patients, visceral leishmaniasis in adults and children with immune function, and visceral leishmaniasis in immunodeficient patients (such as HIV-positive patients).

[0033] In the present invention, "cetylpyridinium" is a cationic ammonium salt antibacterial agent, which is currently used as a main ingredient in oral hygiene products, and has an oral hygiene effect by removing oral odor and suppressing plaque that causes the odor.

[0034] In the present invention, "domiphen" is a quaternary ammonium salt bactericide that acts as a chemical preservative and cationic surfactant, and can be used for the auxiliary treatment of oral and throat infections and for the disinfection of skin and wound infections.

[0035] In the present invention, "tocofersolan" is a water-soluble derivative of vitamin E, which can be used as a vitamin E supplement or to treat vitamin E deficiency in individuals who cannot absorb fat, and can be used as an antioxidant in the cosmetics and pharmaceutical fields.

[0036] The above rifapentine, amphotericin B, cetylpyridinium, domiphen, and tocopherolane have in common that they have long carbon chains.

[0037] The rifapentine, amphotericin B, cetylpyridinium, domiphen or tocopherolane according to the present invention can be used in the form of a pharmaceutically acceptable salt derived from an inorganic acid or an organic acid, and a preferred salt may be at least one selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid, but is not limited thereto.

[0038] The present invention may include rifapentine, amphotericin B, cetylpyridinium, domiphen, tocophersolane or pharmaceutically acceptable salts thereof, as well as hydrates, solvates and optical isomers that can be prepared therefrom.

[0039] The term "hydrate" as used herein refers to a compound of the present invention or a salt thereof, which contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate of the compound represented by Chemical Formulas 1 to 4 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain at least 1 equivalent, preferably 1 to 5 equivalents of water. Such a hydrate may be prepared by crystallizing a compound represented by Chemical Formulas 1 to 4 of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

[0040] The term "solvate" as used herein refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents include those that are volatile, non-toxic, and / or suitable for human administration.

[0041] The term "isomer" as used herein refers to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but is structurally or sterically different. Such isomers include structural isomers such as tautomers, stereoisomers such as R or S isomers having an asymmetric carbon center, geometric isomers (trans, sis), and optical isomers (enantiomers). All of these isomers and mixtures thereof are also included within the scope of the present invention.

[0042] In the present invention, the term "comprising as an active ingredient" means including an amount sufficient to achieve the pharmacological efficacy or activity of rifapentine, amphotericin B, cetylpyridinium, domiphen, tocophersolane or a pharmaceutically acceptable salt thereof of the present invention, and includes that various components may be additionally added for drug delivery, stabilization and formulation.

[0043] In the present invention, "alpha-synuclein (α-syn)" is a small protein composed of 140 amino acids that facilitates neurotransmission between brain cells. However, due to its unstable structure, alpha-synuclein can transform into various forms depending on the surrounding environment. Furthermore, unbalanced physiological conditions, such as overexpression or mutation, can induce abnormal accumulation and aggregation of alpha-synuclein, leading to synucleinopathy.

[0044] The "alpha-synuclein" of the present invention encompasses both the natural monomeric α-syn and its isoforms, and includes the natural α-syn consisting of 140 amino acids, the α-syn consisting of 126 amino acids produced by alternative splicing, the α-syn consisting of 112 amino acids, the α-syn in their monomeric form, the α-syn in their oligomeric form, the α-syn in their fibril form, and the α-syn in their phosphorylated form.

[0045] In the present invention, the term “monomer” means a single polypeptide of α-syn.

[0046] In one embodiment of the present invention, the drugs inhibit fibrillization or oligomerization of alpha-synuclein.

[0047] In the present invention, the term "fibrillization" refers to a process in which insoluble fibrils in which oligomers of α-syn are aggregated are formed.

[0048] In the present invention, the term “fibril” refers to an aggregate resulting from fibrillation of α-syn oligomers.

[0049] In the present invention, the term "oligomerization" refers to a process in which α-syn monomers themselves are aggregated to form soluble oligomers.

[0050] In the present invention, the term “oligomer” refers to an aggregate resulting from oligomerization of α-syn monomers.

[0051] In one embodiment of the present invention, the synuclein-related neurodegenerative disease may be selected from the group consisting of, but is not limited to, Parkinson's disease, Parkinson's disease dementia, Lewy body dementia, multiple system atrophy, or Alzheimer's disease.

[0052] In the present invention, synuclein-related neurodegenerative diseases, also called synucleinopathy, are closely related to the aggregation of alpha-synuclein proteins. Specifically, abnormalities in alpha-synuclein, a protein that facilitates neurotransmission between brain cells, lead to the formation of toxic protein aggregates such as oligomers and fibrils. These aggregates not only cause mitochondrial dysfunction but also lead to the death of brain neurons.

[0053] In the present invention, the term "degenerative neurological disease" means a disease that causes various symptoms as degenerative changes in the structure or function of the central nervous system or peripheral nervous system appear, and includes brain nerve diseases that cause impairment of cognitive function, learning or memory, or are accompanied by neuroinflammation.

[0054] In the present invention, the term "Parkinson's disease" refers to one of the degenerative neurological diseases in which nerve cells that secrete the neurotransmitter dopamine in the substantia nigra of the brain are gradually lost, resulting in motor symptoms such as slow movement, tremors, rigidity, and gait disturbance due to dopamine deficiency, and non-motor symptoms such as cognitive decline and psychiatric symptoms, and it is known that the cause is the accumulation of alpha-synuclein protein in nerve cells that produce dopamine.

[0055] In the present invention, the term "Lewy body" refers to an abnormal protein aggregate that develops within the nerve cells of patients with Parkinson's disease, Lewy body dementia, and other degenerative neurological diseases, and Lewy bodies are known to be formed by the deposition of alpha-synuclein.

[0056] The term "Lewy body dementia" used in the present invention refers to a degenerative dementia that is the second most common cause of dementia after Alzheimer's disease, caused by the accumulation of Lewy bodies. Clinical symptoms include cognitive decline, hallucinations, REM sleep behavior disorder, and parkinsonism, with other symptoms including postural instability, repetitive falls, fainting, autonomic nervous system disorders, hypersomnia, decreased sense of smell, hallucinations, and mood disorders.

[0057] In the present invention, the term "multiple system atrophy" is a disease that clinically presents with Parkinsonian symptoms such as resting tremor, rigidity, bradykinesia, and postural instability, and is accompanied by autonomic nervous system symptoms such as gastrointestinal disorders, drooling, dysphagia, and orthostatic hypotension, or cerebellar symptoms such as gait disturbance, speech disorder, and eye movement disorder.

[0058] The term "Alzheimer's disease" in the present invention refers to a degenerative neurological disease accompanied by progressive memory loss, cognitive decline, and dementia. Clinical symptoms include cognitive impairment symptoms such as memory loss, language impairment, decreased spatial and temporal perception, decreased judgment and ability to perform daily life tasks, gait disturbance, and movement disorder. Amyloid plaques accumulated in brain regions such as the cerebral cortex and hippocampus are known to be the main cause, but recently, accumulation of Lewy bodies has been found in Alzheimer's patients, and alpha-synuclein is also attracting attention as a cause of Alzheimer's disease.

[0059] In the present invention, the term "prevention" means any act of inhibiting or delaying the onset of a synuclein-related degenerative neurodegenerative disease by administering a composition comprising rifapentine, amphotericin B, cetylpyridinium, domiphen, tocopherolane or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient.

[0060] The term "improvement" in the present invention means any act of at least reducing the degree of symptoms of a synuclein-related degenerative neurodegenerative disease by administering a composition comprising rifapentine, amphotericin B, cetylpyridinium, domiphen, tocopherolane or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient.

[0061] The term "treatment" in the present invention means any act in which the symptoms of a synuclein-related degenerative neurodegenerative disease are improved or beneficially changed by administering a composition comprising rifapentine, amphotericin B, cetylpyridinium, domiphen, tocophersolane or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient.

[0062] The pharmaceutical composition of the present invention may be formulated as a powder, granule, tablet, coated tablet, pill, sugar tablet, capsule, liquid, suspension, gel, syrup, slurry, suppository, enema, emulsion, paste, ointment, cream, lotion, powder, spray or suspension.

[0063] The pharmaceutical composition of the present invention may further comprise a suitable carrier, excipient or diluent commonly used in the manufacture of pharmaceutical compositions. Examples thereof include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, mannitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or mineral oil.

[0064] In addition to the above ingredients, the pharmaceutical composition of the present invention may further include excipients, stabilizers, diluents, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. Suitable pharmaceutically acceptable carriers, vehicles, excipients, stabilizers, or diluents are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

[0065] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to achieve preventive, alleviative, or therapeutic efficacy for a disease or pathological symptom caused by alpha-synuclein. The effective dosage level may be determined based on factors including the type and severity of the patient's disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, concurrently used drugs, and other factors well known in the medical field. The amount of the composition used may vary depending on the patient's age, sex, and weight, but may be administered once or several times daily in an amount sufficient to achieve a blood concentration of the compound useful for the treatment of alpha-synuclein disease.

[0066] The pharmaceutical composition of the present invention can be manufactured in a unit dose form or can be manufactured by inserting it into a multi-dose container by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains, and the method can be performed. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granules, tablet or capsule, and may additionally include a dispersing agent or stabilizer.

[0067] The dosage of the above composition may be increased or decreased depending on the route of administration, severity of the disease, gender, weight, age, etc. Therefore, the above dosage does not limit the scope of the present invention in any way.

[0068] The pharmaceutical composition of the present invention can be administered to a subject via various routes. All modes of administration are conceivable, including intracerebral administration, oral ingestion, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, intrathecal injection, sublingual administration, buccal mucosa administration, rectal insertion, vaginal insertion, ocular administration, otic administration, nasal administration, inhalation, oral or nasal spraying, dermal administration, and transdermal administration.

[0069] The pharmaceutical composition according to the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents. It can be administered sequentially or simultaneously with conventional therapeutic agents, or in single or multiple doses. Considering all of the above factors, it is important to administer an amount that achieves maximum efficacy with minimal side effects. This amount can be readily determined by those skilled in the art to which the present invention pertains.

[0070] According to one aspect of the present invention, the present invention provides a functional food composition for preventing or improving a synuclein-related degenerative neurodegenerative disease, comprising rifapentine, amphotericin B, cetylpyridinium, domiphen, tocofersolan or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the rifapentine is represented by the following chemical formula 1, the amphotericin B is represented by the following chemical formula 2, the cetylpyridinium is represented by the following chemical formula 3, the domiphen is represented by the following chemical formula 4, and the tocofersolan is represented by the following chemical formula 5.

[0071] [Chemical Formula 1]

[0072] ,

[0073] [Chemical Formula 2]

[0074] ,

[0075] [Chemical Formula 3]

[0076] ,

[0077] [Chemical Formula 4]

[0078] , and

[0079] [Chemical Formula 5]

[0080] .

[0081] The functional food composition for preventing or improving synuclein-related neurodegenerative diseases of the present invention comprises, as active ingredients, rifapentine, amphotericin B, cetylpyridinium, domiphen, tocophersolane or a food-scientifically acceptable salt thereof, as well as components commonly added during food manufacturing, such as proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents. Examples of the above-mentioned carbohydrates include monosaccharides such as glucose and fructose; disaccharides such as maltose, sucrose, oligosaccharides, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavoring agents (thaumatin, stevia extract, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.

[0082] The functional food composition of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc.

[0083] In the present invention, "functional food composition" means a food manufactured and processed using raw materials or ingredients having functionality useful to the human body according to Act No. 6727 on Health Functional Foods, and means ingestion for the purpose of obtaining a useful effect for health purposes such as regulating nutrients for the structure and function of the human body or physiological action.

[0084] The health functional food of the present invention may contain conventional food additives, and its suitability as a food additive is determined by the specifications and standards for the relevant item in accordance with the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety, unless otherwise specified. Items listed in the above 'Food Additives Codex' include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, sucrose pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, noodle additive alkaline agents, preservative preparations, and tar color preparations. For example, a health functional food in the form of a tablet may be prepared by mixing the active ingredient of the present invention with an excipient, a binder, a disintegrant, and other additives, granulating the mixture using a conventional method, and then adding a lubricant, etc., and compression molding, or directly compression molding the mixture. In addition, the health functional food in the form of tablets may contain a fermenting agent, etc., if necessary. Among the health functional foods in the form of capsules, hard capsules can be manufactured by filling a mixture of the active ingredient of the present invention with additives such as excipients into a conventional hard capsule, and soft capsules can be manufactured by filling a mixture of the active ingredient of the present invention with additives such as excipients into a capsule base such as gelatin. The soft capsules may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative, etc., if necessary. The health functional food in the form of a ring can be prepared by molding a mixture of the active ingredient of the present invention with an excipient, a binder, a disintegrant, etc., by a conventionally known method, and, if necessary, can be coated with white sugar or another coating agent, or the surface can be coated with a material such as starch or talc. A health functional food in granular form can be manufactured into a granular form by mixing a mixture of the active ingredient of the present invention, excipients, binders, disintegrants, etc., using a conventionally known method, and may contain a flavoring agent, a flavoring agent, etc., as needed.

[0085] In one embodiment of the present invention, the synuclein-related neurodegenerative disease may be selected from the group consisting of Parkinson's disease, Parkinson's disease dementia, Lewy body dementia, multiple system atrophy, or Alzheimer's disease, but is not limited thereto.

[0086] The matters mentioned in the composition of the present invention are applied to the same extent as each other, unless they are contradictory to each other, and the description of overlapping contents is omitted to avoid complexity of this specification.

[0087]

[0088] The features and advantages of the present invention are summarized as follows:

[0089] (a) The present invention provides a pharmaceutical composition for preventing, improving or treating a synuclein-related neurodegenerative disease, comprising rifapentine, amphotericin B, cetylpyridinium, domiphen, tocopherolane or a pharmaceutically acceptable salt thereof as an active ingredient.

[0090] (b) The present invention provides a functional food composition for preventing or improving synuclein-related degenerative neurodegenerative diseases, comprising rifapentine, amphotericin B, cetylpyridinium, domiphen, tocopherolane or a pharmaceutically acceptable salt thereof as an active ingredient.

[0091] (c) The rifapentine, amphotericin B, cetylpyridinium, domiphen, tocophersolane or a pharmaceutically acceptable salt thereof of the present invention can be usefully used in the treatment of synuclein disease by inhibiting fibrillation and oligomerization of alpha-synuclein.

[0092] Another object of the present invention is to provide a functional food composition for preventing or improving synuclein-related degenerative neurodegenerative diseases, comprising rifapentine, amphotericin B, cetylpyridinium, domiphen, tocopherolane or a pharmaceutically acceptable salt thereof as an active ingredient.

[0093]

[0094] Figure 1 shows the structure of rifapentine.

[0095] Figure 2 shows the structure of amphotericin B.

[0096] Figure 3 shows the structure of cetylpyridinium.

[0097] Figure 4 shows the structure of domiphen.

[0098] Figure 5 shows the structure of tocofersolan.

[0099] Figure 6 shows the inhibitory effect of rifapentine, amphotericin B, cetylpyridinium domiphene, or tocophersolane on alpha-synuclein fibrillation in a Thioflavin T assay.

[0100] Figure 7 shows the inhibitory effect of rifapentine, amphotericin B, cetylpyridinium, domiphene, or tocophersolane on alpha-synuclein oligomerization in the MDS assay.

[0101]

[0102] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0103]

[0104] Example

[0105]

[0106] Throughout this specification, "%" used to indicate the concentration of a particular substance is (weight / weight) % for solid / solid, (weight / volume) % for solid / liquid, and (volume / volume) % for liquid / liquid, unless otherwise noted.

[0107]

[0108] Example 1: Drug preparation

[0109] The drugs used in the experiment, rifapentine, amphotericin B, cetylpyridinium, domiphen, and tocophersolane, were dissolved in DMSO and prepared at a concentration of 1 mM. The drugs were stored at -20°C until use in the experiment. The chemical structures of rifapentine, amphotericin B, cetylpyridinium, domiphen, and tocophersolane used in the experiment are shown in Figures 1 to 5.

[0110]

[0111] Example 2: Confirmation of the drug's alpha-synuclein (α-syn) fibrillation inhibition effect using ThT assay

[0112] The present inventors performed a Thioflavin (ThT) assay to confirm the inhibitory effects of rifapentine, amphotericin B, cetylpyridinium, domiphen, and tocophersolan on α-syn fibrillation.

[0113] First, lyophilized α-syn was diluted in PBS, filtered, dispensed into 1.5 mL tubes, and stored at -80°C until use. The cells were then incubated with or without rifapentine, amphotericin B, cetylpyridinium, domiphene, and tocopherolan (1 mM) at 37°C for 24 h. Afterwards, 500 μM ThT (Sigma Aldrich, St. Louis, MO, USA) was added and incubated at 37°C for 15 min. After incubation, the fluorescence signal was measured using a Victor 3 microplate reader (PerkinElmer, Waltham, MA, USA), and the results are shown in Figure 6.

[0114] As shown in Fig. 6, it was confirmed that strong fibrillation inhibition activity was observed when treated with rifapentine, amphotericin B, cetylpyridinium, domiphen, and tocopherolan compared to the control group.

[0115] These results indicate that rifapentine, amphotericin B, cetylpyridinium, domiphene, and tocophersolane of the present invention can inhibit the production of alpha-synuclein fibrils accumulating in the brains of patients with synucleinopathy by inhibiting alpha-syn fibrillation.

[0116]

[0117] Example 3: Confirmation of the inhibitory effects of rifapentine, amphotericin B, cetylpyridinium, domiphen, and tocophersolane on α-syn oligomerization.

[0118] The present inventors performed a multiple detection system (MDS) analysis to confirm the inhibitory efficacy of rifapentine, amphotericin B, cetylpyridinium, domiphen, and tocophersolan on α-syn oligomerization.

[0119] First, lyophilized α-syn was dissolved in PBS, and diluted α-syn was mixed with rifapentine, amphotericin B, cetylpyridinium, domiphen, and tocopherolan, respectively, and incubated at 37°C. After 1, 2, and 3 hours, the mixture was diluted in PBS and stored at -80°C to terminate aggregation.

[0120] A 96-well plate was plated with a diluted coating buffer containing an anti-α-synuclein antibody targeting α-syn, and the wells were coated with the antibody by incubating at 37°C for 1 hour. The wells were then washed with PBS-T, and blocking buffer (3% BSA) was added and stored at room temperature for 1 hour. After the reaction was complete, the prepared samples were diluted and incubated at room temperature for 1.5 hours. After that, the same antibody as the biotin-conjugated coating antibody was used as the α-syn target antibody, and the antibody solution diluted in the detection solution was added to each well and incubated at room temperature for 1.5 hours. After the incubation, the wells were treated with Streptavidin-HRP and reacted at room temperature for 30 minutes. The wells were washed, and 3,3'5,5'-tetramethylbenzidine solution (TMB) was added and reacted at room temperature for 30 minutes. After 15 minutes, the stop solution was added, and the colorimetric change was measured at a wavelength of 450 nm using a Victor 3 microplate reader (PerkinElmer, Waltham, MA, USA). The results are shown in Figure 6.

[0121] In Figure 7, A represents the relative amount of oligomers over time for rifapentine, B represents amphotericin B, C represents domiphen, D represents cetylpyridinium, and E represents tocophersolan.

[0122] As shown in Fig. 7, in the control group, the amount of oligomers increased as the incubation time increased, but a significant decrease in oligomerization was observed in the rifapentine, amphotericin B, cetylpyridinium, domiphen, and tocopherolan treatment groups.

[0123] These results indicate that rifapentine, amphotericin B, cetylpyridinium, domiphene, and tocophersolane of the present invention can inhibit the production of alpha-synuclein oligomers accumulating in the brains of patients with synuclein disease by inhibiting α-syn oligomerization.

[0124] While specific aspects of the present invention have been described in detail above, it is clear to those skilled in the art that these specific descriptions are merely preferred implementation examples and that the scope of the present invention is not limited thereto.

Claims

1. A pharmaceutical composition for preventing, improving or treating synuclein-related degenerative neurodegenerative diseases, comprising rifapentine, amphotericin B, cetylpyridinium, domiphen, tocofersolan or a pharmaceutically acceptable salt thereof as an active ingredient, A pharmaceutical composition wherein the rifapentine is represented by the following chemical formula 1, the amphotericin B is represented by the following chemical formula 2, the cetylpyridinium is represented by the following chemical formula 3, the domiphene is represented by the following chemical formula 4, and the tocophersolane is represented by the following chemical formula 5: [Chemical Formula 1] , [Chemical formula 2] , [Chemical Formula 3] , [Chemical Formula 4] , and [Chemical Formula 5] .

2. A pharmaceutical composition according to claim 1, characterized in that the drug inhibits fibrillization or oligomerization of alpha-synuclein.

3. A pharmaceutical composition according to claim 1, wherein the synuclein-related neurodegenerative disease is selected from the group consisting of Parkinson's disease, Parkinson's disease dementia, Lewy body dementia, multiple system atrophy, or Alzheimer's disease.

4. A functional food composition for preventing or improving synuclein-related degenerative neurodegenerative diseases, comprising rifapentine, amphotericin B, cetylpyridinium, domiphen, tocopherolane or a pharmaceutically acceptable salt thereof as an active ingredient, A functional food composition wherein the rifapentine is represented by the following chemical formula 1, the amphotericin B is represented by the following chemical formula 2, the cetylpyridinium is represented by the following chemical formula 3, the domiphene is represented by the following chemical formula 4, and the tocophersolane is represented by the following chemical formula 5. [Chemical Formula 1] , [Chemical formula 2] , [Chemical Formula 3] , [Chemical Formula 4] , and [Chemical Formula 5] .

5. A functional food composition in claim 4, wherein the synuclein-related degenerative neurodegenerative disease is selected from the group consisting of Parkinson's disease, Parkinson's disease dementia, Lewy body dementia, multiple system atrophy, or Alzheimer's disease.

Images