Pharmaceutical composition for preventing or treating cognitive dysfunction comprising histone deacetylase inhibitor

Abstract

The present invention relates to a composition for treating cognitive dysfunction, specifically Alzheimer's disease. The composition according to one aspect can inhibit or reduce the accumulation of amyloid aggregates and phosphorylated tau aggregates, and improve memory and cognitive function.

Description

Pharmaceutical composition for preventing or treating cognitive dysfunction comprising a histone deacetylase inhibitor

[0001] It relates to the therapeutic use of histone deacetylase inhibitors.

[0002] This invention is a technology developed with the support of the Global Innovation Special Zone Innovation Business Promotion (R&D) Overseas Joint Demonstration R&D Project (RS-2024-00488530) supported by the Korean government (Ministry of SMEs and Startups).

[0003] When the neural function of one or more parts of the central nervous system gradually declines due to the degeneration and death of nerve cells, diseases such as Alzheimer's Disease (AD) develop. Alzheimer's disease is the most common degenerative brain disease, affecting approximately 7.5% of the population over 65 years of age. Dementia has a prevalence rate of approximately 10% in the population over 65 years of age, and 75% of these people have Alzheimer's disease.

[0004] As we enter a super-aging society, the high prevalence and incidence of Alzheimer's disease among the elderly will lead to a socioeconomic burden and a rapidly expanding potential market for treatments. Global pharmaceutical companies are actively pursuing the development of these treatments. The global Alzheimer's disease treatment market, estimated at $7.2 billion in 2022, is projected to grow at a compound annual growth rate of 6.11% from 2023 to 2028, according to IMARC Research. Despite the recent approval of two new Alzheimer's drugs, treatment development remains active. Aducanumab and recanemab, for example, have received approval from the US Food and Drug Administration, and donanemab is also a strong candidate for approval. Conversely, gantenerumab and crenezumab, which had shown promise in preclinical and phase 2 clinical trials, failed in phase 3 clinical trials.

[0005] Despite extensive research over many years, the precise pathogenesis or cause of Alzheimer's disease remains unknown. To date, there is no fundamental treatment, and clinical trials for candidate therapeutics continue to face challenges. To address these issues, the inventors sought to discover the potential uses of histone deacetylase (HDAC) inhibitors, specifically CXD 101, as a treatment for cognitive impairment, including Alzheimer's disease.

[0006] Histones are basic proteins that bind to cellular DNA, and can regulate the transcriptional activity of specific genes depending on the degree of binding to DNA. Histones can undergo reversible acetylation reactions, and the transcriptional activity of specific genes is regulated depending on the degree. In eukaryotes, histones 1, 2A, 2B, 3, and 4 are known based on their amino acid sequences. Of these, excluding histone 1, which is a linking histone, four types combine in pairs to form a core histone, for a total of eight molecules. The core histone surrounds DNA to form a nucleosome. Histone deacetylases (HDACs) are enzymes that remove acetyl groups from lysine, which constitutes histone proteins, and histone deacetylase inhibitors are a general term for compounds that inhibit its activity. Histone deacetylases are divided into four subgroups (classes I, II, III, and IV) based on the similarity of their amino acid sequences.

[0007] Numerous previous studies have reported that increased enzyme activity leads to a decrease in acetylated histones in cancer cells and brain diseases (G Sadri-Vakili et al, 2007; EA Thomas et al, 2014; AJ Wilson et al, 2006; M Haberland et al, 2009). For this reason, histone deacetylases are being studied as therapeutic targets for these diseases, and related development research is being extensively conducted (KJ Janczura et al, 2018). Recently, CKD-504 and T-518, which are class IIb histone deacetylase 6 inhibitors, were reported to be effective in improving various pathological phenomena and behaviors of Alzheimer's disease (H Choi et al, 2016; T Onishi et al, 2021).

[0008] CXD101 (Zabadinostat), the IPB-A01 used in this patent, is a Class I HDAC inhibitor, and is currently undergoing phase 1 and 2 clinical trials as a treatment for lymphoma (SW Booth et al, 2021), and several patents are pending in relation to cancer or immune checkpoint inhibitors (WO-2021058974-A1, US-2021093625-A1), but it is not known whether it can exhibit an effective effect as a treatment for Alzheimer's disease. The present researchers completed the present invention by confirming the efficacy of CXD101 in reducing the number of amyloid beta aggregates and the number of phosphorylated tau proteins.

[0009] One aspect is to provide a pharmaceutical composition for preventing or treating cognitive dysfunction, comprising a compound represented by the following chemical formula 1 (CXD 101) or a pharmaceutically acceptable salt thereof:

[0010] [Chemical Formula 1]

[0011]

[0012] Another aspect is to provide a health functional food for improving memory or cognitive function comprising CXD 101 or a salt thereof.

[0013] Another aspect is to provide a feed composition for improving memory or cognitive function comprising CXD 101 or a salt thereof.

[0014] Another aspect is to provide a method for preventing, improving or treating cognitive dysfunction; or improving memory or cognitive function, comprising administering to a subject in need thereof an effective amount of CXD 101 or a pharmaceutically acceptable salt thereof.

[0015] Another aspect provides the use of CXD101 or a pharmaceutically acceptable salt thereof for the preparation of a formulation for preventing, improving or treating cognitive dysfunction; or for improving memory or cognitive function.

[0016] One aspect provides the use of CXD 101 for the prevention, improvement or treatment of cognitive dysfunction.

[0017] As used herein, the term "prevention" refers to any action that inhibits or delays the onset of a disease by administering the composition of the present invention to a subject. For preventive purposes, the composition may be administered to a subject at risk of developing a specific disease, condition, or symptom, or to a subject reporting one or more physiological symptoms of a disease, even if the disease, condition, or symptom has not yet manifested.

[0018] As used herein, the term "treatment" refers to any action that improves the symptoms of a disease or provides benefit by administering the composition of the present invention to a subject. As used herein, the terms "treatment," "palliation," and "improvement" may be used interchangeably. A therapeutic benefit refers to any therapeutically significant improvement or effect on one or more diseases, conditions, or symptoms under treatment.

[0019] The term “101” in this specification refers to N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]piperidin-4-yl)benzamide, a compound represented by the following chemical formula 1. It is also named Zabadinostat and was developed as a Class I HDAC inhibitor. It was reported that when taken orally, it actually functions as an HDAC inhibitor, resulting in increased expression of acetylated histone proteins (Blaszczak W., Liu G., et al. Immune modulation underpins the anti-cancer activity of HDAC inhibitors. Molecular Oncology. 2021. 15: 3280-3298.) In this specification, IPB-A01, a drug used by the inventors of the present invention, refers to CXD 101.

[0020] [Chemical Formula 1]

[0021]

[0022]

[0023] As used herein, the term "cognitive impairment" or "cognitive disorder" refers to a state in which memory, attention, language ability, visuospatial ability, and / or judgment are impaired, lost, or diminished. As used herein, "cognitive impairment" is used to comprehensively describe a wide range of cognitive impairments, from very mild cases, such as forgetfulness, to mild cognitive impairment, in which cognitive function, particularly memory, is reduced compared to that of similar age groups, but the ability to perform daily life remains, and to dementia, which interferes with daily life or social activities.

[0024] In one specific example, the cognitive dysfunction is amyloidosis, tauopathy, Alzheimer's disease, Parkinson's disease, dementia, dementia with Lewy bodies (DLB), multi-infarct dementia (MID), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), mild cognitive impairment (MCI), cerebral amyloid angiopathy, amyloid stroke, systemic amyloid disease, Dutch amyloidosis, frontotemporal lobar degeneration (FTLD), and Pick's disease. It can be any one selected from the group consisting of (Pick's disease).

[0025] In one specific example, the cognitive impairment may be caused by degenerative changes in the brain, particularly degeneration and death of brain and / or brain neurons.

[0026] In one specific example, the cognitive impairment may be caused by degeneration and death of neurons due to factors such as aggregation of amyloid-beta or tau protein. Specifically, it may be caused by deposition of amyloid plaques formed by aggregation of extracellular amyloid beta (Ab). Alternatively, it may be caused by an increase in neurofibrillary tangles formed by intracellular hyperphosphorylated tau protein tangles.

[0027] In one specific example, the Alzheimer's may be sporadic Alzheimer's or hereditary Alzheimer's.

[0028] In one specific example, the Alzheimer's disease may be genetically caused by mutations in the Amyloid Precursor Protein (APP), presenilin 1 (PS 1), or presenilin 2 genes. "" is a component of γ, a multi-subunit protease, and plays a major role in the sequential cleavage of amyloid precursor protein. The "" gene also performs the same enzymatic function as a component of the γ complex, like PS1, although less frequently.

[0029] In one specific example, the Alzheimer's disease may be caused by the expression of the APOE4 allele (APOEε), a specific isoform of apolipoprotein. Apolipoprotein plays a role in promoting the breakdown of amyloid-beta, but some isoforms, such as APOE4, are less effective than other isoforms and may act as a cause of excessive amyloid accumulation in the brain.

[0030] According to one specific example, the compound can prevent or treat damage or death of nerve cells. Specifically, it can prevent or treat damage or death of nerve cells caused by the accumulation of protein aggregates.

[0031] In one embodiment, the compound may inhibit or reduce the accumulation of protein aggregates.

[0032] In one specific example, the compound may inhibit or reduce the accumulation of amyloid-beta, tau protein, phosphorylated tau protein, and / or aggregates thereof. Specifically, the compound may reduce the expression of any one or more selected from the group consisting of 6E10, AT8, S396, and HT7. “” is a marker that can show the level of expression of amyloid-beta aggregates, “” and “” are markers that can show phosphorylated tau protein, and “” is a marker that can show total tau protein.

[0033] According to one specific example, the compound may increase the length of axons. Specifically, the compound may increase the expression of MAP2. “” is a neuronal cell marker representing axons.

[0034]

[0035] Another aspect provides a composition for preventing, improving or treating a disease comprising CXD 101 or a pharmaceutically acceptable salt thereof.

[0036] The composition is present in an amount of 0.00001 wt% to 80 wt%, for example, 0.00001 wt% to 60 wt%, 0.00001 wt% to 40 wt%, 0.00001 wt% to 30 wt%, 0.00001 wt% to 20 wt%, 0.00001 wt% to 10 wt%, 0.00001 wt% to 5 wt%, 0.05 wt% to 60 wt%, 0.05 wt% to 40 wt%, 0.05 wt% to 30 wt%, 0.05 wt% to 20 wt%, 0.05 wt% to 10 wt%, 0.05 wt% to 5 wt%, 0.1 wt% to 60 wt%, 0.1 wt% to 40 wt%, 0.1 It may comprise from 0.1 wt% to 30 wt%, from 0.1 wt% to 20 wt%, from 0.1 wt% to 10 wt%, or from 0.1 wt% to 5 wt% of the compound or its salt.

[0037] The above composition “comprising” a compound or a salt thereof means that the compound of the present specification or a pharmaceutically acceptable salt thereof is added to an extent capable of exhibiting the above-mentioned effect, and includes formulation in various forms by adding various components as auxiliary components for drug delivery and stabilization, etc.

[0038] As used herein, the term “pharmaceutically acceptable” means physiologically acceptable and does not typically cause allergic reactions such as gastrointestinal upset, dizziness, or similar reactions when administered to humans.

[0039] As used herein, the term “pharmaceutically acceptable salt” refers to a salt according to one aspect of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Salts of the parent compound can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base, such as sodium, calcium, magnesium, or potassium, or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Typically, when practical, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used. The pharmaceutically acceptable salts include both acid or base addition salts and stereochemically isomeric forms thereof, and may be, for example, addition salts of organic or inorganic acids. The above salt includes any salt that maintains the activity of the parent compound in the subject of administration and does not cause undesirable effects, and is not particularly limited thereto.

[0040] These salts include inorganic and organic salts, for example, acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, lactic acid, bicarboxylic acid, bisulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium idet, carbonic acid, chlorobenzoic acid, citric acid, idetic acid, toluenesulfonic acid, fumaric acid, gluceptic acid, esilinic acid, pamoic acid, gluconic acid, methylnitric acid, malonic acid, hydrochloric acid, hydroiodoic acid, hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelic acid, mucic acid, It can be naphthylic acid, muconic acid, p-nitromethanesulfonic acid, hexamic acid, pantothenic acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, salicylic acid, sulfamic acid, sulfanilinic acid, or methanesulfonic acid.

[0041] In addition, the salt forms include salts of alkali and alkaline earth metals, such as ammonium salts, lithium salts, sodium salts, potassium salts, magnesium salts, and calcium salts, salts with organic bases, such as benzathine, N-methyl-D-glucamine, and hydrabamine salts, and salts with amino acids, such as arginine and lysine. In addition, the salt forms can be converted into free forms by treatment with a suitable base or acid.

[0042] The compound or its salt can be combined by reacting in the presence of a base and a solvent for 5 to 20 hours, for example, 10 to 20 hours, 15 to 20 hours, 15 to 19 hours, or 15 to 18 hours. The reaction can be performed at room temperature, and those skilled in the art can appropriately change the reaction time depending on the temperature.

[0043] The base may be NaH, lithium diisopropylamide (LDA), 4-dimethylaminopyridine (DMAP), triethylamine (TEA), pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azazurolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, 2,6-lutidine, morpholine, piperidine, piperazine, proton-sponge, ammonium hydroxide, triethanolamine, ethanolamine, or trizmal.

[0044] The solvent may be dimethylacetamide (DMAc), dichloromethane (DCM), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (ACN), DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexane, diethyl ether, dimethyl sulfoxide (DMSO), ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.

[0045]

[0046] The above composition may be a pharmaceutical composition.

[0047] The pharmaceutical composition of the present invention may be in any form suitable for the intended method of administration. In the pharmaceutical composition of the present invention, "administration" means introducing a predetermined substance into a patient by any suitable method, and the route of administration of the pharmaceutical composition may be administered through any common route as long as the drug can reach the target tissue. Administration may be by a method known in the art, and examples thereof include, but are not limited to, topical ocular administration (e.g., periocular (e.g., subTenon's), subconjunctival, intraocular, intravitreal, intracameral, subretinal, suprachoroidal, and retrobulbar administration), intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration. In addition, the active ingredient may be administered by any device capable of transporting to target cells, and the route of administration is preferably determined depending on the type of disease to which it is applied.

[0048] The above administration is 0.00001 mg to 1,000 mg of the composition according to one specific example per subject per day, for example, 0.00001 mg to 500 mg, 0.00001 mg to 100 mg, 0.00001 mg to 50 mg, 0.00001 mg to 25 mg, 1 mg to 1,000 mg, 1 mg to 500 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 25 mg, 5 mg to 1,000 mg, 5 mg to 500 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 10 mg to 1,000 mg, 10 mg to 500 mg, 10 mg to 100 mg, 10 mg to 50 mg, Alternatively, it may be administered in doses of 10 mg to 25 mg.

[0049] However, the dosage may be prescribed in various ways depending on factors such as formulation method, administration method, patient age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity, and a person skilled in the art can appropriately adjust the dosage by considering these factors. The frequency of administration may be once a day or twice or more within the range of clinically acceptable side effects, and the administration may be done in one or more sites, and the total number of administration days may be from 1 to 30 days per treatment, daily or at intervals of 2 to 5 days. If necessary, the same treatment may be repeated after an appropriate period. For animals other than humans, the same dosage as for humans per kg may be used, or the above dosage may be converted into an amount based on the volume ratio (e.g., average value) of the organs (e.g., heart) of the target animal and the human.

[0050] The pharmaceutical composition of the present invention may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., formulated according to conventional methods, or parenteral formulations such as suspensions, emulsions, lyophilized preparations, external preparations, suppositories, sterile injection solutions, and implantable preparations. The pharmaceutical composition may further comprise, in addition to the active ingredient, a pharmaceutically acceptable excipient that can be used in formulation.

[0051] The above excipients include carriers, vehicles, diluents, solvents, for example, monohydric alcohols, for example, ethanol, isopropanol, and polyhydric alcohols, for example, glycerol, and edible oils, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, oily esters, for example, ethyl oleate, isopropyl myristate; It may include at least one selected from the group consisting of binders, adjuvants, solubilizers, thickeners, stabilizers, disintegrants, glidants, lubricants, buffers, emulsifiers, wetting agents, suspending agents, sweeteners, coloring agents, flavoring agents, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-β cyclodextrin, polyvinylpyrrolidone, low melting point waxes, ion exchange resins, etc., but is not limited thereto.

[0052] The carriers mentioned above are those commonly used in formulations, and include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above ingredients, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweetening agents, flavoring agents, emulsifiers, suspending agents, preservatives, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

[0053] The pharmaceutical composition of the present invention may be formulated in the form of an oral administration dosage form, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, etc. These oral administration dosage forms may, in addition to the active ingredient according to the typical composition of each dosage form, contain pharmaceutically acceptable carriers, such as diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine, or lubricants such as silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol.

[0054] If the oral dosage form is a tablet, it may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidine, and in some cases, a disintegrating agent such as starch, agar, alginic acid or its sodium salt, an effervescent mixture and / or an absorbent, a coloring agent, a flavoring agent or a sweetening agent.

[0055] The pharmaceutical composition of the present invention being formulated in the form of a parenteral administration dosage form may mean that it is administered by a method such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In this case, in order to formulate the pharmaceutical composition in the parenteral administration dosage form, the active ingredient is mixed with a stabilizer or buffer in water to prepare a solution or suspension, and this solution or suspension can be prepared in a unit dosage form of an ampoule or vial.

[0056] In addition, the pharmaceutical composition may be sterilized or may further contain auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifying agents, salts for osmotic pressure control and / or buffers, and may further contain other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulating or coating.

[0057] The content of the compound or salt containing the compound in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the purpose of use of the pharmaceutical composition, the form of the formulation, etc., and may be, for example, 0.001 to 99 wt%, 0.001 to 90 wt%, 0.001 to 50 wt%, 0.01 to 50 wt%, 0.1 to 50 wt%, or 1 to 50 wt% based on the total weight of the pharmaceutical composition.

[0058] The pharmaceutical composition of the present invention can be administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount sufficient to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention, and may be adjusted according to factors including the type of the patient's disease, the severity of the disease, the type of active ingredient administered, the type of formulation, the patient's age, sex, weight, health condition, diet, sensitivity, the time and method of drug administration, the combination of the composition or concurrently used drugs, and other factors well known in the medical field.

[0059] The pharmaceutical composition of the present invention can prevent or treat a disease in a subject, including a step of administering to the subject an amount effective to prevent or treat the disease.

[0060] The dosage of the pharmaceutical composition for the prevention or treatment of diseases according to the present invention may range from 0.01 ug / kg to 10 g / kg per day, specifically from 0.01 mg / kg to 1 g / kg, depending on the patient's condition, weight, sex, age, severity of the condition, and route of administration. Administration may be administered once daily or divided into several doses. Such dosage should not be construed as limiting the scope of the present invention in any way.

[0061] The above entity may be a mammal. The mammal may be a human, a dog, a cat, a cow, a goat, or a pig.

[0062] The terms and methods described for the above compounds and diseases also apply to the above pharmaceutical compositions.

[0063]

[0064] The above composition may be a health functional food.

[0065] The term "health functional food" as used herein refers to a food manufactured or processed for health supplement purposes using specific ingredients as raw materials or by extracting, concentrating, refining, mixing, or other methods of specific ingredients contained in food raw materials. It refers to a food designed and processed so that the aforementioned ingredients can sufficiently exert bioregulatory functions on the body, such as biodefense, regulation of biological rhythms, and disease prevention and recovery, and can be used for the purpose of preventing or improving cognitive dysfunction.

[0066] There are no specific restrictions on the types of the above foods. Examples of the above foods include formulations selected from the group consisting of powders, granules, tablets, capsules, pills, gels, jellies, suspensions, emulsions, syrups, tea bags, infused teas, gums, candies, and health drinks, and include all health foods in the conventional sense.

[0067] The above health functional food may include food additives that are food-related and acceptable, and may include an appropriate carrier commonly used in the manufacture of health functional foods.

[0068] The terms and methods described for the above compounds and diseases also apply to the above health functional foods.

[0069]

[0070] The above composition may be a feed composition.

[0071] The feed composition can be prepared by adding the compound or its salt in an appropriate effective concentration range according to various feed preparation methods known in the art, and can be used for the purpose of preventing or improving cognitive dysfunction.

[0072] The above "feed" may mean any natural or artificial diet, meal, etc., or ingredients of the meal, which are suitable for or intended for an animal to eat, ingest, or digest. The type of feed is not particularly limited, and feed commonly used in the relevant technical field may be used. Non-limiting examples of the feed include plant feed such as grains, roots, fruits, food processing by-products, algae, fibers, pharmaceutical by-products, oils, starches, meal, or grain by-products; animal feed such as proteins, fat-free substances, oils, minerals, oils, single-cell proteins, zooplankton, or food.

[0073] The terms and methods described for the above compounds and diseases also apply to the above feed composition.

[0074]

[0075] Another aspect provides a method of preventing, ameliorating, or treating a condition of a subject comprising the step of treating or administering to the subject an effective amount of CXD 101 or a pharmaceutically acceptable salt thereof.

[0076] The condition of the above entity may be related to cognitive dysfunction.

[0077] The subject may be a mammal, such as a human, cow, horse, pig, dog, sheep, goat, or cat. The subject may be an individual in need of an improvement effect in a condition associated with cognitive dysfunction.

[0078] The terms and methods described for the above compounds and diseases also apply to the above method.

[0079]

[0080] Another aspect provides the use of CXD101 or a pharmaceutically acceptable salt thereof for the preparation of a formulation for preventing, improving or treating cognitive dysfunction; or for improving memory or cognitive function.

[0081] The terms and methods described for the above compounds and diseases also apply to the above method.

[0082]

[0083] The present invention is susceptible to various modifications and embodiments. Specific embodiments are illustrated in the drawings and described in detail in the following detailed description. However, this is not intended to limit the present invention to specific embodiments, but rather to encompass all modifications, equivalents, and alternatives falling within the spirit and technical scope of the present invention. In describing the present invention, detailed descriptions of related known technologies will be omitted if they are deemed to obscure the gist of the present invention.

[0084] The composition according to one aspect exhibits activity capable of inhibiting or reducing the accumulation of amyloid aggregates and phosphorylated tau aggregates, and improved memory and cognitive function in a mouse model of the disease with actual cognitive impairment. Therefore, the composition is useful as a treatment for Alzheimer's disease and, furthermore, for cognitive impairment.

[0085] Figure 1 is an immunohistochemical staining image showing changes in the expression of amyloid beta aggregate marker (6E10) according to IPB-A01 treatment.

[0086] Figure 2 is an immunohistochemical staining image showing the expression of phosphorylated tau protein aggregate marker (AT8) and changes in the length of nerve axons according to IPB-A01 treatment.

[0087] Figure 3 is a graph that quantifies and analyzes the change in expression of phosphorylated tau protein aggregate marker (AT8) according to IPB-A01 treatment.

[0088] Figure 4 is a graph that quantifies and analyzes the change in the length of nerve axons according to IPB-A01 treatment.

[0089] Figure 5 is a graph showing immunohistochemical staining images and quantitative analysis of the changes in the expression of amyloid beta aggregate marker (6E10) and phosphorylated tau protein aggregate marker (AT8) according to treatment with different concentrations of IPB-A01.

[0090] Figure 6 is a Western blotting image of amyloid beta aggregate marker and phosphorylated tau protein aggregate marker according to treatment with different concentrations of IPB-A01.

[0091] Figure 7 is a graph comparing the quantitative results of Western blotting of amyloid beta aggregate markers and phosphorylated tau protein aggregate markers according to concentration-specific treatment with IPB-A01.

[0092] Figure 8 is an image and graph analyzing the change in expression of phosphorylated tau protein aggregates according to IPB-A01 treatment using a filter trap analysis method.

[0093] Figure 9 is a graph showing the results of Y-maze behavioral evaluation according to the presence or absence of IPB-A01 treatment.

[0094] Figure 10 is a graph showing the results of the Morris water maze evaluation according to the presence or absence of IPB-A01 treatment.

[0095] Figure 11 is a schematic diagram showing the analysis location.

[0096] Figures 12 and 13 are immunohistochemical staining images showing changes in the expression of amyloid beta aggregate marker (6E10) and astrocyte marker (GFAP) according to IPB-A01 treatment, and graphs showing their quantitative analysis.

[0097] Figures 14 and 15 are immunohistochemical staining images showing changes in the expression of amyloid beta aggregate marker (6E10) and microglial cell marker (Iba-1) according to IPB-A01 treatment, and graphs showing their quantitative analysis.

[0098] The following examples are provided for more detailed description. However, these examples are provided solely to illustrate one or more specific examples, and the scope of the present invention is not limited to these examples.

[0099]

[0100] Example 1. Preparation of a PS 1 mutant patient-derived neuronal cell model

[0101] 1.1 Culturing induced pluripotent stem cells derived from Alzheimer's disease patients

[0102] Neuronal cells were differentiated from induced pluripotent stem cells (iPSCs) derived from patients with sporadic or hereditary Alzheimer's disease (AD). AD human iPSCs were derived from cells [AD-IPCS010; PS1-CHA07-S170F](15) of a 33-year-old male patient with familial Alzheimer's disease (fAD) carrying a PSEN1 (S170F) mutation.

[0103] Induced pluripotent stem cells were maintained in StemFit Basic 04 complete type medium (Ajinomoto; Cat. no. ASB04CT) supplemented with 1% antibiotic-antimycotic solution (Welgene; Cat. no. LS203-01) for 7 days, with medium replacement every other day. On day 7, iPSCs were subcultured by transferring to StemFit medium containing 10 μM Y-27632 ROCKi (Peprotech; Cat. no. 1293823).

[0104]

[0105] 1.2 Generation of neural progenitor cells

[0106] Induced pluripotent stem cells were cultured in neural precursor cell (NPC) induction medium [1X DMEM:F12 (Gibco; Cat.No.GIB-11320-082), 1% antibiotic antimycotic solution (Welgene; Cat.No.LS203-01), 1% non-essential amino acid (Gibco; Cat.No.GIB-11140-050), 0.1% B-mercaptoethanol (Gibco; Cat.No.GIB-21985-023), 20% KnockOut Serum Replacement (Gibco; Cat.No.GIB-10828-028), 10uM SB-431542 (Reagent Direct; Cat.No.21-A94), 100nM LDN-193189 (Sigma Aldrich; Cat.No.SML0559), 30uM Y-27632 ROCKi (Peprotech; Cat.No.1293823)] and cultured in a 96-well plate to form embryoid bodies, which were then cultured using the suspension culture method. After 24 hours, they were maintained in a neural progenitor cell induction medium without ROCKi.

[0107] On the 9th day, they were separated into single cells by treatment with 1 Cat.No.GIB-11140-050), 0.1% B-mercaptoethanol (Gibco; Cat.No.GIB-21985-023), 2% B-27 supplement without VitA (Gibco; Cat.No.GIB-12587-010), 1% MEM sodium pyruvate solution (Gibco; Cat.No.GIB-11360-070), 3mM D-glucose (Sigma After transferring to [Fluorocapsulated fibroblasts (Fluorocapsulated fibroblasts; Aldrich; Cat. No. G7021), 1% L-glutamine (Corning; Cat. No. 25-005-Cl), 10 mM bFGF (Peprotech; Cat. No. 100-188)], the cells were cultured as two-dimensional cells. NPCs were maintained by subculture at 6-day intervals, and differentiation into two-dimensional cerebral cortical neurons proceeded at the 6th subculture.

[0108]

[0109] 1.3 Differentiation into cerebral cortex neurons

[0110] On the 1st day after the 6th subculture, the cell status was checked and then the cerebral cortical neuron differentiation induction medium [1X Neurobasal-A medium (Gibco; Cat. No. GIB-10888-022), 1% antibiotic antimycotic solution (Welgene; Cat. No. LS203-01), 2% B-27 supplement (Gibco; Cat. No. GIB-17504-044), 1% Glutamax (Gibco; Cat. No. GIB-35050-061), 1% N-2 supplement (Gibco; Cat. No. GIB-17502-048), 20ng / ml BDNF (Peprotech; Cat. No. 450-02), 20ng / ml GDNF (Peprotech; Cat. No. 450-10), 20ng / ml NT-3 (Peprotech; Cat.No.450 -03)] was replaced and differentiated.

[0111] Cells derived from a patient with a mutation in PS1 (S170F), a genetic disorder associated with familial Alzheimer's disease, were differentiated for 8 weeks and used. Cells were grown in 96-well plates, and the results were analyzed by treating three wells of each condition.

[0112]

[0113] Example 2. Preparation of a patient-derived cell model with the APOE4 / 4 genotype

[0114] Induced pluripotent stem cells were produced from cells derived from a 68-year-old Alzheimer's disease patient with the APOE4 / 4 genotype [SMC180; AD-APOE4-P38]. Neural progenitor cells were then produced from the induced pluripotent stem cells using the same method as in Example 1.

[0115] Cells derived from patients with the APOE4 / 4 genotype were differentiated for 14 weeks and used. Cells were grown in 96-well plates, and the results were analyzed by treating three wells of each condition.

[0116]

[0117] Example 3. Preparation of IPB-A01

[0118] IPB-A01 (CXD101, CAS No: 934828-12-3) was prepared by adding Dimethylsulfoxide (DMSO) and dissolving it to a concentration of 10 mM.

[0119]

[0120] Example 4. Confirmation of reduction in amyloid beta (Ab) aggregates

[0121] To confirm the change in the number of amyloid beta (Ab) aggregates according to IPB-A01 treatment, the following experiments were performed.

[0122] The neural cells of a patient with a mutation (S170F) in PS 1, a genetic disease of familial Alzheimer's disease obtained in Example 1, and the neural cells of a patient with an APOE4 / 4 genotype obtained in Example 2 were treated with 10 mM IPB-A01 of Example 3 for 2 days. Thereafter, in order to confirm the increase or decrease in amyloid beta aggregates, the expression level was confirmed by staining with GFAP antibody (DAKO, Z0334) that detects astrocytes and 6E10 antibody (BioLegend, 803015) that can see amyloid beta (Ab) aggregates, and the results are shown in Figure 1 (Red: GFAP, Green: 6E10, Blue: DAPI).

[0123] As shown in Fig. 1, it was confirmed that the number of amyloid beta (Ab) aggregates decreased when treated with IPB-A01.

[0124]

[0125] Example 5. Confirmation of reduction in tau protein aggregates

[0126] 5.1 Immunofluorescence staining

[0127] The change in the number of tau protein aggregates according to IPB-A01 treatment was confirmed using immunofluorescence staining.

[0128] The neural cells of a patient with a mutation (S170F) in PS 1, a genetic disease of familial Alzheimer's disease obtained in Example 1, and the neural cells of a patient with an APOE4 / 4 genotype obtained in Example 2 were treated with 10 mM IPB-A01 of Example 3 for 2 days. Thereafter, to confirm the increase or decrease in phosphorylated tau protein aggregates, the expression levels were confirmed by staining with MAP2 (Thermo Fisher Scientific, 13-1500), which indicates neuronal axons, and AT8 (Ser202, Thr205, Thermofisher Scientific, MN1020), which can show phosphorylated tau protein aggregates, and the results are shown in Fig. 2 (Red: MAP2, Green: p-Tau (AT8), Blue: DAPI).

[0129] Additionally, fluorescence imaging analysis was performed by contrasting the length of AT8, which can observe phosphorylated tau protein aggregates, and nestin, which can observe the length of neuronal axons. Fluorescence imaging analysis was analyzed by capturing 52 sites per well using ImageXpress Micro Confocal (IXMC, Molecular Devices), and MetaXpress software (version 6.6.3.55, Molecular Devices, United States) was used for quantitative analysis, and the final analysis data processed from this data were analyzed using Prism 8.0.1 software (GraphPad, San Diego, CA) using the ANOVA statistical method. The results are expressed as the mean ± standard error. The results are shown in Figures 3 and 4.

[0130] As shown in Figures 2 and 3, it was confirmed that the number of phosphorylated tau protein aggregates significantly decreased when IPB-A01 was treated, and as shown in Figure 4, it was confirmed that the length of the neuroaxon significantly increased compared to the control group.

[0131]

[0132] Additionally, after treating IPB-A01 of Example 3 at 0.1 mM and 1 mM for 2 days, the phosphorylated tau protein aggregates were stained with S396 antibody (Invitrogen, 44-752G) and the amyloid beta aggregates were stained with 6E10 antibody (BioLegend, 803015) to confirm the expression level, and the results are shown in Fig. 5 (Red: S396, Green: 6E10, Blue: DAPI).

[0133] As shown in Fig. 5, it was confirmed that the number of amyloid beta aggregates and phosphorylated tau protein aggregates was reduced when treated with IPB-A01.

[0134]

[0135] 5.2 Protein electrophoresis

[0136] Changes in the expression of amyloid beta aggregates and phosphorylated tau protein following IPB-A01 treatment were confirmed through Western blotting.

[0137] Specifically, the cell lysates of the control group treated with only DMSO in the neural cells of a patient with a mutation (S170F) in PS 1, a genetic disease of familial Alzheimer's disease obtained in Example 1, and the group treated with 0.1 mM, 1 mM, and 10 mM IPB-A01 of Example 3 were loaded on an SDS protein gel, electrophoresed, and the proteins in the gel were transferred to a PVDF (polyvinylidene difluoride) membrane. The target proteins on the membrane were probed with antibodies against an astrocyte marker (GFAP), a total tau protein marker (HT7), and a phosphorylated tau protein aggregate marker (p-Tau S396, AT8, Tau46), and the protein amount was quantified using an analysis system instrument (Biorad, ChemiDoc XRS+ system with Image Lab software #1708265). The results of Western blotting and the relative expression levels of the proteins were quantified and are shown in FIGS. 6 and 7.

[0138] As shown in Figures 6 and 7, it was confirmed that the expression of astrocyte marker (GFAP) and phosphorylated tau protein aggregate marker (p-Tau S396, AT8, Tau46) proteins decreased when treated with IPB-A01.

[0139]

[0140] 5.3 Filter trap analysis

[0141] Taking advantage of the characteristics of diseases caused by abnormal protein accumulation, the change in insoluble protein aggregates following IPB-A01 treatment was confirmed using filter trap analysis.

[0142] Specifically, the neural cells of a patient with a mutation (S170F) in PS 1, a genetic disease of familial Alzheimer's disease obtained in Example 1, were treated with 0.1 mM, 1 mM, and 10 mM of IPB-A01 of Example 3 for 2 days. The control group treated with only DMSO and the group treated with IPB-A01 were placed at 100 ug in a 96-well Bio-Dot microfiltration unit (Bio-Rad #1706545) and pressure was applied to pass through the membrane. After all the liquid passed through the filter, AT8 (Ser202, Thr205, Thermofisher Scientific, MN1020), an antibody that indicates the amount of phosphorylated tau aggregates on the membrane, and HT7 antibody (Thermo Fisher Scientific, MN1000) that indicates the amount of total tau protein were used to observe proteins larger than a certain size that did not pass through the filter, and the results are shown in Fig. 8.

[0143] As shown in Fig. 8, it was confirmed that the number of proteins that did not pass through the filter, i.e. the number of aggregates, was reduced when IPB-A01 was treated.

[0144]

[0145] Experimental Example 6. Verification of Effects in a Mouse Model

[0146] The disease treatment effect of compound treatment according to one specific example was verified in a mouse disease model.

[0147]

[0148] 6.1 Preparation of the mouse model

[0149] All animals were handled strictly in accordance with the National Institute of Health (NIH) Guide for the Humane Care and Use of Laboratory Animals, and experiments were performed in accordance with the Institute for Laboratory Research (ILAR) Guide for the Care and Use of Laboratory Animals.

[0150] 5XFAD (five familial mutation) mice, an animal model of Alzheimer's disease, were maintained on a 12:12 hour light / dark cycle, and were fed ad libitum while maintaining a constant room temperature and acclimating for 2 weeks. The IPB-A01 composition was prepared immediately before use using the method described in Example 3. The IPB-A01 composition, excipients, or donepezil was administered once a day at 24-hour intervals to 6-month-old 5XFAD mice. IPB-A01 was administered orally at 20 mg / kg, and donepezil was administered intraperitoneally at 2 mg / kg. The total period was 12 weeks, and the composition was administered by adopting a method of administering for 5 days followed by 2 days of rest.

[0151]

[0152] 6.2 Y-maze behavioral assessment

[0153] We aimed to investigate whether IPB-A01 has an effect on improving cognitive function in mice using a Y-maze.

[0154] The purpose of this study was to compare the model group (Tg) with the group (Tg_Vehicle) that only added the drug-dissolving agent and IPB-A01, and donepezil, which is known to be effective in Alzheimer's disease, was set as the experimental group to compare the efficacy of the positive control drug. The lighting in the behavioral analysis room was set to 20-30 lux, and the Y-maze test apparatus was divided into three branches made of acrylic, and each maze was placed at a constant angle of 120° to each other. After designating each branch as A, B, and C, the experimental animal was placed in one branch and allowed to move freely for 8 minutes, and then recorded using a camera installed on the ceiling (KR Stover et al, 2015). The analysis was performed using Ethovision XT by Noldus, and the results are shown in Fig. 9.

[0155] As shown in Figure 9, it was confirmed that behavioral improvement was significantly increased when treated with IPB-A01 compared to negative mice (Tg_Vehicle) that were administered only the excipient, and this was confirmed to be similar to that of the positive control group, donepezil.

[0156]

[0157] 6.3 Morris water maze behavioral assessment

[0158] The Morris water maze is a method for measuring the time it takes to recognize an escape route and escape a stressful situation while passively swimming. Using this method, we evaluated whether spatial learning and cognitive ability were improved by IPB-A01 treatment.

[0159] Specifically, the tank used in the experiment was circular, measuring 950 cm x 60 cm, with an escape platform installed in the center, and water was filled 1 cm above the surface of the escape platform. The illumination was set to 30 lux, and the water temperature was set to 20 to 22 degrees Celsius. On the first day of the experiment, the animal model was allowed to swim freely for 1 minute. If it could not find the escape platform, it was artificially helped to find it and was made to stay there for 10 seconds. After a one-hour rest period, the second trial was also conducted for 1 minute, similar to the first trial. The third and fourth trials were conducted in the same manner as the second trial.

[0160] From the second to the sixth day, the fourth trial was conducted in the same manner as the first day, but the starting position each day was randomly designated as different from the starting position of the previous day, and the behavior was recorded. On the seventh day, the escape platform that had been there was removed, and the animals were allowed to swim freely for 1 minute, and their behavior was recorded. The analysis was performed on the second to sixth days, and the time to reach the escape platform was recorded, and the value that did not reach within 1 minute was recorded as 60 seconds (JPC de Bruin et al, 1997, Laura BT et al, 2018). The behavioral experiment conducted on the seventh day was graphed to show how quickly the animals reached the location where the existing escape platform was, and this is shown in Figure 10.

[0161] As shown in Fig. 10, it was confirmed that behavioral improvement was significantly increased compared to negative mice (Tg_Vehicle) that were administered only the excipient on the 4th and 6th days of IPB-A01 treatment, and it was confirmed that this was similar to the positive control group, donepezil.

[0162]

[0163] 6.4 Confirmation of decreased expression of amyloid-beta aggregate protein

[0164] Activated microglia and reactivated astrocytes surrounding amyloid plaques are known pathological hallmarks of Alzheimer's disease. To examine changes in amyloid-beta protein expression and astrocyte and microglia activity following IPB-A01 treatment in an animal model, the following experiments were conducted.

[0165] Specifically, immunohistochemical staining was performed. Mice were anesthetized with 100 mg / kg ketamine and 10 mg / kg xylazine, and then perfused whole body with phosphate-buffered saline (PBS, pH 7.4) via the heart to remove blood from the body. The brains were then fixed by perfusion with 4% paraformaldehyde (PFA), and then removed from the mice. The removed brains were immersed in the PFA solution and refrigerated for 24 hours, then placed in a 30% sucrose solution and refrigerated until the brains sank. After the brains sank, the 30% sucrose solution was replaced once more and refrigerated until the brains completely sank. The brains were then sectioned horizontally into 30 μm-thick sections using a cryotome (microtome) and used in the experiment. After washing the tissue sections with phosphate-buffered saline (PBS), non-specific binding other than the target protein was blocked with 3% hydrogen peroxide (H2O2) and normal serum. Afterwards, the sections were incubated with primary antibodies against 6E10, an amyloid-beta aggregate protein marker, at 4°C for 24 hours, followed by incubation with biotinylated anti-mouse IgG secondary antibodies at room temperature for 1 hour. Afterwards, the sections were incubated with antibodies against Iba1, an immune-related microglia marker, or GFAP, an astrocyte marker, at 4°C for 24 hours, followed by incubation with biotinylated anti-rabbit IgG secondary antibodies at room temperature for 1 hour. After washing the tissue sections with PBS, the tissues were mounted on slides and the expression of specific markers was confirmed under a microscope.

[0166] Specifically, when IPB-A01 was treated in the cortex and hippocampus regions of the brain, the expression of 6E10 targeting amyloid-beta aggregate protein and the expression of astrocytes were confirmed, and the results of immunohistochemical staining are shown in Figures 11 to 15.

[0167] Figure 11 is a schematic diagram showing the analysis location. During the analysis, the dentate gyrus (DG), CA3, and CA1, which are subregions of the hippocampus, were analyzed, and among them, the molecular layer (ML), granular layer, and polymorphic layer (hilus) of the dentate gyrus were analyzed.

[0168] As shown in Figures 12 and 13, it was confirmed that the expression of 6E10 and astrocyte markers tended to decrease in the lower regions of the cerebral cortex and hippocampus of the model group (transgenic, Tg) mice by IPB-A01. In addition, it was confirmed that the expression tended to decrease compared to the donepezil treatment group, which was the positive control group.

[0169] As shown in Figures 14 and 15, the expression of amyloid-beta aggregation in the cerebral cortex and hippocampus tended to decrease in the group treated with IPB-A01 compared to the model group (Tg), and it was confirmed that it was significantly reduced in the cerebral cortex in particular.

[0170]

[0171] In summary, the composition comprising IPB-A01 according to one aspect has the activity of inhibiting or reducing the accumulation of amyloid aggregates and phosphorylated tau aggregates, and it was confirmed that cognitive function was actually improved when IPB-A01 was administered to Alzheimer's disease mice. In other words, IPB-H01 is useful as a treatment for Alzheimer's disease and, furthermore, for cognitive dysfunction with similar aspects.

[0172]

[0173] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. A pharmaceutical composition for preventing or treating cognitive dysfunction, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] .

2. A pharmaceutical composition according to claim 1, wherein the cognitive dysfunction includes loss or decline in memory.

3. In claim 1, the cognitive dysfunction is amyloidosis, tauopathy, Alzheimer's disease, Parkinson's disease, dementia, dementia with Lewy bodies (DLB), multi-infarct dementia (MID), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), mild cognitive impairment (MCI), cerebral amyloid angiopathy, amyloid stroke, systemic amyloid disease, Dutch amyloidosis, frontotemporal lobar degeneration (FTLD). A pharmaceutical composition, wherein the pharmaceutical composition is any one selected from the group consisting of: and Pick's disease.

4. A pharmaceutical composition according to claim 1, wherein the cognitive dysfunction is caused by a mutation in at least one gene selected from the group consisting of an amyloid precursor protein (APP) gene, a presenilin 1 gene, and a presenilin 2 gene, or by expression of an apolipoprotein E4 allele.

5. In claim 1, the pharmaceutical composition inhibits or reduces the accumulation of any one or more of amyloid-beta (Aβ Tau), phosphorylated Tau (p-Tau), and aggregates thereof.

6. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition reduces the expression of at least one selected from the group consisting of 6E10, AT8, S396, and HT7.

7. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition increases the length of a nerve axon.

8. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition increases the expression of MAP2.

9. Health functional food for improving memory or cognitive function, comprising a compound represented by the following chemical formula 1 or a salt thereof: [Chemical Formula 1] .

10. Feed composition for improving memory or cognitive function, comprising a compound represented by the following chemical formula 1 or a salt thereof: [Chemical Formula 1] .

11. A method for preventing, improving or treating cognitive dysfunction; or improving memory or cognitive function, comprising administering to a subject in need thereof an effective amount of a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] .

12. Use of a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof for the prevention, improvement or treatment of cognitive dysfunction; or for the manufacture of a preparation for improving memory or cognitive function: [Chemical Formula 1] .

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