WO2018111049A1 - Composition pharmaceutique destinée à prévenir ou à traiter des maladies associées à dyrk, comprenant un composé à base de pyridine comme principe actif - Google Patents

Composition pharmaceutique destinée à prévenir ou à traiter des maladies associées à dyrk, comprenant un composé à base de pyridine comme principe actif Download PDF

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WO2018111049A1
WO2018111049A1 PCT/KR2017/014893 KR2017014893W WO2018111049A1 WO 2018111049 A1 WO2018111049 A1 WO 2018111049A1 KR 2017014893 W KR2017014893 W KR 2017014893W WO 2018111049 A1 WO2018111049 A1 WO 2018111049A1
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cancer
hydrogen
straight
branched chain
chain alkyl
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PCT/KR2017/014893
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English (en)
Korean (ko)
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조성찬
최미리
이주연
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한국생명공학연구원
한국화학연구원
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Priority claimed from KR1020170172214A external-priority patent/KR102279347B1/ko
Application filed by 한국생명공학연구원, 한국화학연구원 filed Critical 한국생명공학연구원
Priority to CN201780086517.9A priority Critical patent/CN110325189A/zh
Priority to JP2019532126A priority patent/JP2020502167A/ja
Priority to EP17881667.4A priority patent/EP3542797A4/fr
Priority to US16/470,014 priority patent/US10765669B2/en
Publication of WO2018111049A1 publication Critical patent/WO2018111049A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating DYRK-related diseases containing a pyridine-based compound as an active ingredient.
  • DYRK Dual Specificity Tyrosine Phosphorylation Regulatory Kinase
  • DYRK1A is the most interested and widely studied in relation to Down syndrome and degenerative brain disease.
  • the gene of DYRK1A is located in human Chromosome Down Syndrome Danger Zone (DSCR), and has been attracting more attention as it turns out to be a determinant of cognitive impairment typically seen in Down syndrome patients.
  • DSCR Chromosome Down Syndrome Danger Zone
  • Alzheimer's disease is accompanied by two types of neuropathology: amyloid plaque, the formation of intracellular neurofibrillary tangles consisting of aggregates of hyperphosphorylated tau, and cellular accumulation of insoluble precipitates of amyloid ⁇ peptides.
  • DYRK1A is known to be associated with the development of Alzheimer's disease by directly phosphorylating Tau, amyloid ⁇ precursor protein (APP), and Presenilin 1 (PS1), which are key proteins for the formation of neuropathology.
  • DYRK1A plays an important role in other degenerative brain diseases.
  • transgenic mouse models that overexpress human or rat DYRK1A show a phenotype of Down's syndrome, including hippocampal spatial learning, motor neuron deficiency, and developmental delay, which is an important function of DYRK1A in mental retardation associated with Down's syndrome. Suggests.
  • the present inventors attempted to develop a drug targeting DYRK1A while studying a strategy for simultaneously controlling senile plaques and neurofibrillary tangles, and the pyridine-based compound according to the present invention was structurally different from a known DYRK1A inhibitor.
  • the present invention was completed by confirming that it was different, had better inhibitory effect, and had excellent selectivity for DYRK1A.
  • DYRK1A is of interest as a target for developing type 1 diabetes in addition to Down syndrome and degenerative brain disease.
  • DYRK1A is involved in the regulation of the proliferation of beta cells, which are insulin-producing cells of the pancreas through NFAT signaling. It has been confirmed by several groups that inhibit the proliferation of DYRK1A.
  • an effective inhibitor of DYRK1A activates the proliferation of pancreatic beta cells to promote insulin production and secretion, thereby providing a therapeutic effect in patients with type 1 diabetes.
  • DYRK1A is highly expressed in some cancers, and brain tumors and hematologic cancers are representative examples. DYRK1A has been reported to be involved in the generation and progression of cancer through phosphorylation of several factors (p27, cyclin D1, DREAM, c-myc, Sprouty) in the cell. Sprouty, in particular, is an important factor that controls the recyclining of EGFR, which is important for maintaining the stemness of cancer stem cells. Anti-cancer effects can be expected by inhibiting the stemness of cancer stem cells by inhibiting DYRK1A.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of DYRK-related diseases comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
  • the compound represented by the formula (1) according to the present invention not only has a strong DYRK1A inhibitory activity, but also has a high selectivity to the DYRK protein, thereby preventing or preventing DYRK-related diseases such as Down syndrome, degenerative brain disease, cancer disease, metabolic disease, or the like. It can be effectively used for treatment.
  • Figure 1 is a schematic diagram showing a virtual screening (virtual screening) process for the discovery of DYRK1A inhibitor according to the present invention.
  • Figure 2 is a schematic diagram showing the discovery of three pyridine-based DYRK1A novel inhibitors according to the present invention.
  • Figure 3 shows the principle of operation of the NFAT signaling reporter cell-based DYRK1A efficacy evaluation system and the results of the secondary efficacy evaluation performed using the same.
  • FIG. 5A is a photograph showing the Tau phosphorylation inhibitory effect of the compound represented by the formula (2) according to the present invention at the mammalian cell level
  • Figure 5B is a Tau phosphorylation inhibition of the compound represented by formula (2) according to the present invention at the mammalian cell level It is a graph showing the efficacy.
  • FIG. 6 is a graph showing the in vitro CMGC kinase enzyme activity inhibitory effect of the compound represented by the formula (2).
  • FIG. 7 is a diagram showing a model for predicting the binding structure of the compounds represented by Formulas 2 and 3 with DYRK1A, Compound 1 is a compound represented by Formula 2, Compound 2 is a compound represented by Formula 3.
  • the present invention provides a compound represented by the following formula (1).
  • R 1 may be hydrogen or -NR 6 R 7 .
  • R 6 and R 7 may be independently of each other hydrogen, C 1 -C 5 linear or branched alkyl or benzyl, specifically R 6 and R 7 are independently of each other hydrogen or C 1 -C 3 It may be straight or branched chain alkyl of.
  • R 2 , R 3 and R 4 are independently of each other hydrogen, halogen, C 1 -C 5 straight or branched chain alkyl, -NR 8 R 9 , OR 8 , -CN, -NHC (O) R 8 , —SO 2 R 8 , —OS (O) 2 R 8 , pyrrolidine, piperidine or morpholine, specifically R 2 , R 3 and R 4 may independently be hydrogen, ⁇ F, -Cl, -Br, -I, C 1 -C 3 straight or branched chain alkyl, -NR 8 R 9 , OR 8 , -CN, -NHC (O) R 8 , -SO 2 R 8 ,- OS (O) 2 R 8 , pyrrolidine, piperidine or morpholine, more specifically R 2 , R 3 and R 4 are independently of each other hydrogen, -F, -Cl, -Br,- I, C 1 -C 3 may be straight or branched
  • R 8 and R 9 are each independently hydrogen, C 1 -C 5 straight or branched chain alkyl, C 1 -C 5 linear or branched alkynyl, C 1 -C 5 straight or branched chain of the Al alkenyl
  • C 6 may be aryl of C 6 -C 12 aryl substituted with halogen or tri-methyl substituted with a C 6 -C 12 aryl, halogen, -C 12, specifically, the R 8 and R 9 are independently of each other
  • R 5 may be hydrogen, C 1 -C 5 straight or branched chain alkyl, unsubstituted 4-piperidine or acetyl substituted 4-piperidine, specifically R 5 is hydrogen, C It can be 1- C 3 straight or branched chain alkyl, unsubstituted 4-piperidine or acetyl substituted 4-piperidine.
  • A may be carbon or nitrogen, and specifically, A may be nitrogen.
  • the compound represented by Formula 1 may be a compound represented by Formula 2, a compound represented by Formula 3, or a compound represented by Formula 4 below.
  • the compound represented by Formula 1 of the present invention has an effect of inhibiting the activity of DYRK.
  • the compound represented by Formula 1 strongly and selectively inhibits DYRK1A, and inhibits phosphorylation of Tau protein, which is a representative substrate protein of DYRK1A and a key factor in neurofibrillary tangle formation.
  • Molecular modeling confirmed that it inhibits ATP in a competitive manner. From the above results, it can be seen that the compound represented by the formula (1) of the present invention can be used as an active ingredient of the pharmaceutical composition for the prevention or treatment of DYRK-related diseases.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of DYRK-related diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • prevention refers to reducing the risk of developing a disease or disorder, that is, at least one clinical symptom of the disease is present in a subject that is susceptible to or at risk of disease but does not yet develop or exhibits symptoms of the disease. Indicates not to proceed.
  • treatment refers to alleviating the disease or disorder, ie to arrest or reduce the progression of the disease or one or more clinical symptoms thereof.
  • the DYRK-related disease refers to a disease caused by overexpression and overactivation of DYRK, and may be, for example, Down syndrome, degenerative brain disease, cancer disease, metabolic disease, and the like.
  • the degenerative brain disease is one or more disease days selected from the group consisting of Pick disease, vascular dementia, Alzheimer's, Parkinson's disease, Lewy body dementia, prefrontal lobe dementia, Creutzfeldt-Jakob disease, Huntington's disease- chorea, multiple sclerosis, and Guillain-Barré syndrome Can be.
  • the cancer diseases include lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, rectal cancer, perianal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, and esophageal cancer.
  • Small bowel cancer endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penis cancer, prostate cancer, chronic or acute leukemia, lymphocyte lymphoma, bladder cancer, kidney or ureter cancer, renal cell cancer, renal cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma and pituitary adenoma.
  • CNS central nervous system
  • the metabolic disease may be selected from the group consisting of obesity, diabetes, hypertension, hyperlipidemia, hypercholesterolemia, arteriosclerosis, fatty liver, heart disease, diabetes, myocardial infarction, angina.
  • the compound represented by Formula 1 of the present invention effectively inhibits DYRK1A, thereby forming nerve fiber entanglement, senile plaque, lewy body formation by phosphorylation regulation of Tau, APP, PS1, ⁇ -synuclein, HIP1, etc. It has been shown that it can be used to control and eventually prevent or treat DYRK related diseases such as Alzheimer's and several degenerative brain diseases.
  • salts refer to salts of compounds of the invention that are pharmaceutically acceptable and that have the desired pharmacological activity of the parent compound.
  • Such salts may be prepared by conventional methods in the art, for example salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, formic acid, acetic acid, propionic acid, Salts with organic acids such as oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin), Salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arg
  • the pharmaceutical composition according to the present invention may be formulated by adding a non-toxic and pharmaceutically acceptable carrier, adjuvant and excipient, etc. according to conventional methods, for example oral such as tablets, capsules, troches, solutions, suspensions, etc. It may be prepared as a preparation for administration or as a preparation for parenteral administration.
  • excipients that may be used in the pharmaceutical composition according to the present invention include sweeteners, binders, solubilizers, dissolution aids, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like.
  • lactose for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, al A carboxylic acid, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.
  • the compounds of the present invention may be included at concentration levels ranging from 0.1% to 95% by weight relative to the total weight of the pharmaceutical composition, ie in an amount sufficient to achieve the desired effect.
  • compositions of the present invention may be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral dosage forms, external preparations, suppositories, or sterile injectable solutions according to conventional methods. .
  • compositions comprising a compound of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods. Specifically, when formulated, it may be formulated using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like that are commonly used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, or the like. Can be prepared by mixing. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used.
  • Oral liquid preparations include suspensions, solvents, emulsions, and syrups.In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used.
  • utopsol macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration may be administered by, for example, skin, oral, rectal, intravenous, abdominal, muscle, subcutaneous, intrauterine dural or intracerebroventricular injection, preferably either oral or intravenous It may be administered by the route of, but is not limited thereto.
  • the administration may contain one or more active ingredients exhibiting the same or similar function. It may further comprise one or more pharmaceutically acceptable carriers for administration.
  • Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, as necessary, including antioxidants, buffers, Other conventional additives such as bacteriostatic agents can be added.
  • the compounds according to the invention are easy to formulate a variety of formulations, for example, injectable formulations such as aqueous solutions, suspensions, emulsions, powders, tablets, capsules by additionally adding diluents, dispersants, surfactants, binders and lubricants. It may be formulated into a pill, pill, granule or injection solution.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, powders, tablets, capsules by additionally adding diluents, dispersants, surfactants, binders and lubricants. It may be formulated into a pill, pill, granule or injection solution.
  • the amount of the compound at the time of administration varies depending on the weight, age, sex, health condition, diet, time of administration, method of administration, excretion rate and severity of the disease.
  • the daily dosage of the compound of the present invention is 0.0001 to 100 mg / kg, preferably, the amount of 0.001 to 30 mg / kg may be administered once to several times a day. In addition, the administration period may be 1 day to 2 months, but may be administered without limitation until the prophylactic or therapeutic effect of the disease is exhibited.
  • the present invention also provides a health functional food composition for preventing or ameliorating DYRK-related diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the health functional food composition according to the present invention comprises a compound of Formula 1 or a pharmaceutically acceptable salt thereof for the purpose of preventing or ameliorating DYRK related diseases such as Down syndrome, degenerative brain disease, cancer disease, metabolic disease, etc. It can be added to such health supplements.
  • DYRK related diseases such as Down syndrome, degenerative brain disease, cancer disease, metabolic disease, etc. It can be added to such health supplements.
  • Examples of foods to which the above-mentioned substances may be added include dairy products, various soups, drinks, meat, sausages, breads, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products, dairy products and the like, and includes all the health functional foods in the conventional sense.
  • the compound of formula 1 of the present invention may be added as is to food or used together with other food or food ingredients, and may be suitably used according to a conventional method.
  • the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
  • the amount of the compound in the health food can be added at 0.1 to 90 parts by weight of the total food weight.
  • the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
  • the health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratios, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of natural carbohydrates is generally from about 1 g to 20 g, preferably from about 5 g to 12 g per 100 g of the composition of the present invention.
  • the compound of formula 1 of the present invention may be used in various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, Alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.
  • the quinoline 4-one derivative of the present invention may contain fruit flesh for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but it is generally chosen that the quinoline 4-one derivative of the present invention is in the range of 0.1 to about 20 parts by weight per 100 parts by weight.
  • DYRK1A was selected using protein structure-based method (Structure-Based Virtual Screening, SBVS), and utilized 340,000 compound libraries owned by Korea Compound Bank.
  • the protein used to consider the spatial variation of the binding site, the conformational difference and the diversity of the inhibitor structure through the tertiary structure analysis of the protein is PDB code 4MQ1 (2.35).
  • c] quinoline carboxylic acid derivative is bound.
  • hydrogen bonding in the hinge region is expected to be an important functional pharmacophore. Therefore, in virtual search, two conditions are applied to each of the two selected protein structures. A total of 40,000 compound libraries were searched four times.
  • NFAT signaling reporter a well-established cell-based DYRK1A efficacy evaluation system (FIG. 3).
  • the NFAT signaling reporter is highly dependent on DYRK1A, and thus is effective in deriving DYRK1A inhibitor candidates.
  • DYRK1A is known to regulate calcineurin / nuclear factor of activated T cells (NFAT) signaling and play an important role in human developmental stages.
  • NFATc1 transcription factor is a protein that is usually phosphorylated in the cytoplasm. When the Ca 2+ concentration of the cell increases, NFATc1 is dephosphorylated by Ca 2+ dependent protein phosphatase calcineurin and NFATc1 is transferred into the nucleus. .
  • NFATc1 which enters the nucleus, forms a transcription complex with partner protein NFATn and binds to a promoter of the target gene to induce target gene expression.
  • DYRK1A phosphorylates NFATc1 to inhibit the migration of NFATc1 to the nucleus, resulting in suppression of target gene expression.
  • DYRK1A inhibitory effect of 570 candidates was confirmed by the transcriptional activity of NFATc1.
  • a luciferase reporter containing NFAT-RE NFAT response element
  • NFAT-RE-luciferase reporter was overexpressed in 293T cells and treated with ionomycin (IM) and phorbol 12-myristate 13-acetate (PMA) to increase intracellular Ca 2+ levels. Increased dramatically.
  • IM ionomycin
  • PMA phorbol 12-myristate 13-acetate
  • Overexpression of DYRK1A was found to be relatively suppressed luciferase expression. Candidates treated under these conditions inhibit DYRK1A, resulting in an increase in luciferase.
  • DYRK1A inhibitors have a common pyridine structure in which benzoxazolo and pyrazole are structurally combined, and in particular, Compound 3 represented by Formula 4 is the minimum unit of the compound having DYRK1A inhibitory activity. Judging.
  • the activity of luciferase gradually increased when the concentration gradient was applied under the same conditions, and DYRK1A was not overexpressed when 3 ⁇ M was treated. Higher than luciferase activity.
  • the luciferase increase effect of the compounds represented by the formulas (2) and (3) shows an EC 50 that is about 10 times lower than the previously reported DYRK1A inhibitor, Harmin, CX-4945. It was confirmed (FIG. 4).
  • DYRK1A a representative substrate protein of DYRK1A and a major factor in the onset of Alzheimer's and Down syndrome.
  • Tau is a microtubule-associated protein.
  • DYRK1A phosphorylates Thr212 of Tau protein, and this phosphorylation has been clearly observed in hippocampal tissue of Down syndrome syndrome mice overexpressed DYRK1A.
  • DYRK1A In order to confirm whether the compound represented by Formula 2 directly inhibits DYRK1A, an in vitro kinase assay using purely purified DYRK1A protein was performed, as well as DYRK family kinase such as DYRK1B, DYRK3, and DYRK4. As well as the representative CMGC kinase including the selective efficacy of DYRK1A was confirmed.
  • the compound represented by the formula (2) showed the strongest inhibitory effect on DYRK1A, showed an inhibitory effect of about 95% at a concentration of 100 nM, and a strong inhibitory effect such that an IC 50 of approximately 10 nM was predicted (FIG. 6).
  • the compound represented by Chemical Formula 2 showed high inhibitory effect on GSK3 ⁇ after DYRK1A.
  • GSK3 ⁇ also exhibited amyloid plaque and neurofibrillary tangle, which are major neuropathologies of degenerative brain disease. Considering that it is an important kinase for formation, a synergistic effect can be expected.
  • the compounds represented by the formulas (2) and (3) were structurally fitted to the ATP binding site of DYRK1A, respectively, in particular, the nitrogen of the pyridine ring and Leu241 of the DYRK1A hinge region.
  • the hydrogen bonds formed between Glu239 and Glu239 are expected to play an important role.

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Abstract

La présente invention concerne une composition pharmaceutique destinée à prévenir ou à traiter des maladies associées à DYRK, comprenant un composé à base de pyridine comme principe actif. Selon la présente invention, le composé à base de pyridine, à utiliser comme principe actif de la composition pharmaceutique, inhibe l'activité de DYRK1A avec une efficacité très élevée et une sélectivité très élevée, ce qui lui permet d'être efficacement utilisé dans la prévention ou le traitement de maladies associées à DYRK telles que le syndrome de Down, les maladies cérébrales dégénératives, les maladies cancéreuses et les maladies métaboliques.
PCT/KR2017/014893 2016-12-15 2017-12-15 Composition pharmaceutique destinée à prévenir ou à traiter des maladies associées à dyrk, comprenant un composé à base de pyridine comme principe actif WO2018111049A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN201780086517.9A CN110325189A (zh) 2016-12-15 2017-12-15 含有吡啶类化合物作为活性成分的用于预防或治疗dyrk相关疾病的药物组合物
JP2019532126A JP2020502167A (ja) 2016-12-15 2017-12-15 ピリジン系化合物を有効成分として含有するｄｙｒｋ関連疾患の予防又は治療用薬学的組成物
EP17881667.4A EP3542797A4 (fr) 2016-12-15 2017-12-15 Composition pharmaceutique destinée à prévenir ou à traiter des maladies associées à dyrk, comprenant un composé à base de pyridine comme principe actif
US16/470,014 US10765669B2 (en) 2016-12-15 2017-12-15 Pharmaceutical composition for preventing or treating DYRK-related diseases, containing pyridine-based compound as active ingredient

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KR20160171495 2016-12-15
KR10-2016-0171495 2016-12-15
KR1020170172214A KR102279347B1 (ko) 2016-12-15 2017-12-14 피리딘계 화합물을 유효성분으로 함유하는 dyrk 관련 질환의 예방 또는 치료용 약학적 조성물
KR10-2017-0172214 2017-12-14

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Citations (5)

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US7348325B2 (en) * 2005-11-30 2008-03-25 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
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US7348325B2 (en) * 2005-11-30 2008-03-25 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
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WO2009126003A2 (fr) * 2008-04-10 2009-10-15 한국화학연구원 Nouveaux dérivés de pyridine à substitution pyrazole et benzoxazole ou leurs sels pharmaceutiquement acceptables, leur procédé de préparation, et composition pharmaceutique contenant ces dérivés/sels en tant que principes actifs pour prévenir et traiter des troubles impliquant une prolifération cellulaire aberrante

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