WO2022050230A1 - アデノシン受容体の活性化を抑制する組成物 - Google Patents

アデノシン受容体の活性化を抑制する組成物 Download PDF

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WO2022050230A1
WO2022050230A1 PCT/JP2021/031777 JP2021031777W WO2022050230A1 WO 2022050230 A1 WO2022050230 A1 WO 2022050230A1 JP 2021031777 W JP2021031777 W JP 2021031777W WO 2022050230 A1 WO2022050230 A1 WO 2022050230A1
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adenosine
receptor
kappa
ifn
activity
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French (fr)
Japanese (ja)
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雅章 川野
祥 松下
理英 高木
美枝子 戸叶
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学校法人埼玉医科大学
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the present invention relates to a composition for suppressing the production of IL-22, IL-31 or IFN-kappa by suppressing the activation of the adenosine A2A receptor and / or the adenosine A2B receptor.
  • the present invention also treats, ameliorates, or prevents diseases caused by abnormal production of IL-22, IL-31, or IFN-kappa by suppressing the activation of adenosine A2A and / or adenosine A2B receptors.
  • the present invention relates to a method for evaluating a compound as an active ingredient of these compositions.
  • the living body responds to infections such as bacteria and viruses, tumors, cell damage, etc. by immune reaction.
  • the immune response is regulated by direct or indirect interactions between immunocompetent cells.
  • Various cytokines such as interleukin and interferon produced by macrophages, lymphocytes and the like play an important role in the regulation.
  • abnormal cytokine production leads to an abnormal immune response in the living body.
  • IL-22 is produced in large quantities in Th22 cells and the like, and is considered to form skin symptoms in the acute and chronic stages of atopic dermatitis (Non-Patent Document 1). More specifically, in adult atopic dermatitis patients classified as severe based on the diagnostic criteria (SCORAD), the ratio of Th22 in peripheral blood expressing homing receptors to the skin is higher than that in healthy subjects. (Non-Patent Document 2), and this finding suggests that Th22 may be involved in the pathogenesis of atopic dermatitis.
  • Non-Patent Document 3 IL-31 produced from Th2 cells is involved in the pruritus (itch) and is considered to be a cytokine that induces pruritus (Non-Patent Document 3).
  • IFN-kappa is remarkably produced, which suggests that it is involved in the pathological condition (Non-Patent Document 4).
  • IFN-kappa is confirmed to be expressed in epithelial cells, and its increase is confirmed in cutaneous lupus erythematosus and systemic lupus erythematosus.
  • it has been reported that the expression of IFN-kappa is enhanced by irradiation with IFN- ⁇ and ultraviolet rays in epithelial cells (Non-Patent Document 5).
  • adenosine which is one of the bases constituting DNA, is also used as a neurotransmitter in the living body.
  • Adenosine as a neurotransmitter is produced by modifying adenosine triphosphate (ATP) released from nerve cells with an adenosine-producing enzyme localized on the cell membrane surface. More specifically, extracellularly released ATP and adenosine diphosphate (ADP) are hydrolyzed by membrane-bound ectonucleoside triphosphate diphosphohydrolase-1 (CD39) to adenosine monophosphate. (AMP).
  • ATP adenosine triphosphate
  • ADP adenosine diphosphate
  • AMP is then converted to adenosine by a dephosphorylation reaction catalyzed by another adenosine-producing enzyme, ect-5'-nucleosidase (CD73). It is known that the extracellular adenosine thus produced acts on adenosine receptors, A1, A2a, A2b, and A3 on the surface of nerve cells to transmit signals into nerve cells.
  • CD73 ect-5'-nucleosidase
  • adenosine A2A receptor agonists have been reported to be effective in the treatment of asthma, chronic sinusitis, allergic dermatitis, etc. (Patent Document 1, paragraph 0004), and autoimmune diseases. , Asthma, atopic dermatitis, psoriasis and the like are reported to be effective (Patent Document 2, claims 10 and 12).
  • the present invention has been made in view of the problems of the prior art, and the present invention is to identify a substance involved in the production of IL-22, IL-31 or IFN-kappa, and to develop a drug targeting the substance. It is in.
  • adenosine which is a ligand for the adenosine A2A receptor, or an adenosine A2A receptor agonist (PSB0777) induces the production of IL-22 and IL-17F in a bidirectional mixed lymphocyte culture reaction system (2-way MLR). It became clear to do. Similarly, it was revealed that adenosine or PSB0777 induces the production of these cytokines in a culture system of CD4 + T cells activated by CD3 / CD28 stimulation. On the other hand, in the presence of an adenosine A2A receptor antagonist (istradefylline), the induction of production of these cytokines was suppressed.
  • an adenosine A2A receptor antagonist istradefylline
  • the present inventors have clarified that the production of the cytokine in 2-way MLR is induced not only by adenosine but also by ATP.
  • an inhibitor for an adenosine-producing enzyme CD39 inhibitor or CD73 inhibitor
  • CD39 inhibitor or CD73 inhibitor an inhibitor for an adenosine-producing enzyme
  • adenosine-induced IL-31 production was suppressed even in the presence of an adenosine A2B receptor antagonist (MRS1754). Furthermore, significant pathological suppression was observed by administering the antagonist to atopic dermatitis model animals.
  • the present inventors induce the production of IL-22, IL-31, and IFN-kappa by the production of ATP to adenosine involving adenosine-producing enzyme, and the subsequent activation of the adenosine receptor. Found to be done. Then, it was clarified that the production of these cytokines can be suppressed by suppressing the activation of such adenosine receptor or its pathway leading to it, and completed the present invention.
  • the present invention provides: [1] A composition for treating, ameliorating, or preventing a disease caused by suppression of IL-22, IL-31, or IFN-kappa production, or abnormal production of IL-22, IL-31, or IFN-kappa.
  • a composition comprising, as an active ingredient, a substance that suppresses the activation of the adenosine A2A receptor and / or the adenosine A2B receptor.
  • the test compound treats and improves the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or the disease caused by the abnormal production of IL-22, IL-31 or IFN-kappa.
  • it is a method for evaluating the probability of having a preventive activity. It comprises (a) contacting the test compound with the adenosine A2A receptor and (b) detecting the binding between the test compound and the adenosine A2A receptor.
  • the activity suppresses the production of IL-22, IL-31 or IFN-kappa, or the disease caused by the abnormal production of IL-22, IL-31 or IFN-kappa.
  • the test compound treats and improves the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or the disease caused by the abnormal production of IL-22, IL-31 or IFN-kappa.
  • it is a method for evaluating the probability of having a preventive activity. It comprises (a) contacting the test compound with the adenosine A2B receptor and (b) detecting the binding between the test compound and the adenosine A2B receptor.
  • the activity suppresses the production of IL-22, IL-31 or IFN-kappa, or the disease caused by the abnormal production of IL-22, IL-31 or IFN-kappa.
  • the test compound treats and improves the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or the disease caused by the abnormal production of IL-22, IL-31 or IFN-kappa. Alternatively, it is a method for evaluating the probability of having a preventive activity.
  • the test compound inhibits the binding of the adenosine A2A receptor ligand to the adenosine A2A receptor, the activity suppresses the production of IL-22, IL-31 or IFN-kappa, or IL-22, IL-31 or IFN.
  • -A method that is evaluated to have the activity of treating, ameliorating, or preventing a disease caused by abnormal production of kappa.
  • the test compound treats and improves the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or the disease caused by the abnormal production of IL-22, IL-31 or IFN-kappa.
  • it is a method for evaluating the probability of having a preventive activity.
  • A The step of contacting the adenosine A2B receptor ligand with the adenosine A2B receptor in the presence of the test compound, and (b) the step of detecting the binding between the adenosine A2B receptor ligand and the adenosine A2B receptor.
  • test compound When the test compound inhibits the binding of the adenosine A2B receptor ligand to the adenosine A2B receptor, it has the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or IL-22, IL-31 or IFN.
  • -A method that is evaluated to have the activity of treating, ameliorating, or preventing a disease caused by abnormal production of kappa.
  • the test compound treats and improves the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or the disease caused by the abnormal production of IL-22, IL-31 or IFN-kappa. Alternatively, it is a method for evaluating the probability of having a preventive activity.
  • It comprises (a) contacting the test compound with cells expressing the adenosine A2A receptor and (b) detecting the activity of the adenosine A2A receptor.
  • the test compound reduces the activity of the adenosine A2A receptor as compared to the case where the test compound is not contacted, the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or IL-22, A method that is evaluated to have the activity of treating, ameliorating, or preventing a disease caused by abnormal production of IL-31 or IFN-kappa.
  • the test compound treats and improves the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or the disease caused by the abnormal production of IL-22, IL-31 or IFN-kappa.
  • it is a method for evaluating the probability of having a preventive activity. It comprises (a) contacting the test compound with cells expressing the adenosine A2B receptor and (b) detecting the activity of the adenosine A2B receptor.
  • the activity of the adenosine A2B receptor is reduced as compared to the case where the test compound is not contacted, the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or IL-22, IL-31 or A method that is evaluated to have the activity of treating, ameliorating, or preventing a disease caused by abnormal production of IFN-kappa.
  • the test compound treats and improves the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or the disease caused by the abnormal production of IL-22, IL-31 or IFN-kappa. Alternatively, it is a method for evaluating the probability of having a preventive activity.
  • It comprises (a) a step of contacting the test compound with an adenosine-producing enzyme, and (b) a step of detecting the binding between the test compound and the adenosine-producing enzyme.
  • the test compound treats and improves the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or the disease caused by the abnormal production of IL-22, IL-31 or IFN-kappa.
  • it is a method for evaluating the probability of having a preventive activity. It comprises (a) contacting the substrate of the adenosine-producing enzyme with the adenosine-producing enzyme in the presence of the test compound, and (b) detecting the binding between the substrate of the adenosine-producing enzyme and the adenosine-producing enzyme.
  • the test compound treats and improves the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or the disease caused by the abnormal production of IL-22, IL-31 or IFN-kappa. Alternatively, it is a method for evaluating the probability of having a preventive activity.
  • It comprises (a) a step of contacting the test compound with an adenosine-producing enzyme, and (b) a step of detecting the enzyme activity of the adenosine-producing enzyme.
  • the test compound reduces the enzymatic activity of the adenosine-producing enzyme, the production of IL-22, IL-31 or IFN-kappa, or IL-22, IL-31 or A method that is evaluated to have an activity of treating, ameliorating, or preventing a disease caused by an abnormal production of IFN-kappa.
  • the compositions of the present invention are useful as pharmaceuticals for the treatment, amelioration, or prevention of diseases caused by abnormal production of IL-22, IL-31, or IFN-kappa. Further, according to the present invention, it is also possible to efficiently evaluate and screen candidate compounds for such drugs by targeting adenosine A2A receptor, adenosine A2B receptor or adenosine producing enzyme.
  • the present invention is a composition for treating, ameliorating, or preventing a disease caused by suppression of IL-22, IL-31 or IFN-kappa production, or abnormal production of IL-22, IL-31 or IFN-kappa.
  • a composition comprising a substance that suppresses the activation of an adenosine A2A receptor and / or an adenosine A2B receptor as an active ingredient is provided.
  • the "adenosine receptor” is a G protein-coupled receptor molecule for adenosine, and in humans, there are four subtypes, A1, A2A, A2B, and A3.
  • A1, A2A, A2B, and A3 When the "adenosine receptor” is stimulated by the binding of its ligand, adenosine, on the cell surface, adenylate cyclase is activated in the cell, cAMP production is enhanced, and a signal is transmitted. (That is, the adenosine receptor is activated).
  • “Suppression of adenosine receptor activation” includes not only complete suppression (that is, inhibition) of the activation, but also partial suppression.
  • such inhibition competitively suppresses the binding of adenosine to the adenosine receptor, affects the binding constant of the adenosine receptor, and irreversibly binds to the receptor. It can be done non-competitively.
  • an adenosine A2A receptor antagonist can be mentioned as a "substance that suppresses the activation of the adenosine A2A receptor" according to the present invention.
  • the antagonist may be a known drug, or may be obtained by using, for example, the evaluation method of a test compound described later.
  • Known agents include, for example, Istradefylline, Preladenant, Vipadenant, Caffeine, SCH-58261, SCH-421348, SCH-442416, VER-6623, VER-6497, VER-7835, ST-1535, ZM-241385.
  • adenosine A2A receptor antagonist for example, xanthin exhibiting an antagonistic effect on the adenosine A2A receptor as disclosed in JP-A-6-21856 or JP-A-2016-003186.
  • Derivatives for example, Japanese Patent Publication No. 2013-523711, Japanese Patent Publication No. 2012-505264, Japanese Patent Publication No. 2011-513417, Japanese Patent Publication No. 2011-500833, Japanese Patent Publication No. 2011-500919, Japanese Patent Publication No. 2010-523497.
  • Japanese Patent Application Laid-Open No. 2008-297312 Japanese Patent Application Laid-Open No. 2009-508871, Japanese Patent Publication No.
  • a pyrimidine derivative that exhibits an antagonistic effect on the adenosine A2A receptor for example, an amino-quinoxalin derivative that exhibits an antagonistic effect on the adenosine A2A receptor as disclosed in JP-A-2011-514350; eg, a special feature.
  • examples thereof include an anti-adenosine A2A receptor antibody and a functional fragment thereof as disclosed in Japanese Patent Publication No. 2011-07869.
  • Examples of the "substance that suppresses the activation of the adenosine A2B receptor" according to the present invention include an adenosine A2B receptor antagonist.
  • the antagonist may be a known drug, or may be obtained by using, for example, the evaluation method of a test compound described later.
  • Known agents include, for example, MRS-1754, Compound 38 (1,3-Dialkyl-8- (hetero) aryl-9-OH-9-deazaxansines), ATL-801, CVT-6883 (GS-6201), and the like. Examples thereof include, but are not limited to, MRS-1706, OSIP-339,391, PSB-603, PSB-0788, PSB-1115, PSB-1901, and ISAM 140.
  • the structural formulas of these known drugs are shown below in order.
  • adenosine A2B receptor antagonist for example, a xanthin derivative exhibiting an antagonistic effect on the adenosine A2B receptor as disclosed in Japanese Patent Publication No. 2005-516975; for example, Japanese Patent Publication No. 2008-506557.
  • examples thereof include pyrimidine derivatives exhibiting an antagonistic effect on adenosine A2B receptor; adenosine A2B receptor antibody and functional fragments thereof, as disclosed in Japanese Patent Publication No. 2020-532541.
  • the substance that suppresses the activation of the adenosine receptor may be a combination of the above-mentioned substance that suppresses the activation of the adenosine A2A receptor and the substance that suppresses the activation of the adenosine A2B receptor. good. Further, it may be a substance that suppresses the activation of both the adenosine A2A receptor and the adenosine A2B receptor, and examples thereof include an adenosine A2A receptor / adenosine A2B receptor dual antagonist.
  • the antagonist may be a known drug, or may be obtained by using, for example, the evaluation method of a test compound described later. Known agents include, but are not limited to, Etrumadenant (AB928), for example. The structural formula of this known drug is shown below.
  • the "substance that suppresses the activation of the adenosine A2A receptor and / or the adenosine A2B receptor" according to the present invention may suppress the activation of the adenosine A2A receptor and / or the adenosine A2B receptor, as described above.
  • the above are not limited to adenosine A2A receptor antagonists, adenosine A2B receptor antagonists, and adenosine A2A receptor / adenosine A2B receptor dual antagonists.
  • adenosine which is a ligand for the adenosine A2A receptor and the adenosine A2B receptor and induces its activation
  • adenosine triphosphate ATP
  • an adenosine-producing enzyme localized on the cell membrane surface. Generated. Therefore, by suppressing this adenosine production, it is possible to suppress the activation of the adenosine A2A receptor and the adenosine A2B receptor.
  • examples of the "substance that suppresses the activation of the adenosine A2A receptor and / or the adenosine A2B receptor" according to the present invention include compounds that inhibit the enzymatic activity of the adenosine-producing enzyme.
  • Adenosine-producing enzyme means an enzyme involved in adenosine production, and more specifically, CD39 and / or CD73 can be mentioned.
  • CD39 is a protein also called ectonucleoside triphosphate diphosphohydrolase-1, which catalyzes the hydrolysis of ATP and ADP to produce AMP.
  • CD73 is a protein also called ect-5'-nucleosidase that catalyzes the dephosphorylation reaction of AMP to produce adenosine.
  • these enzymes usually take a membrane-bound form having a transmembrane domain, but can also take a soluble form excluding the transmembrane domain.
  • the adenosine-producing enzymes of the invention also include such soluble CD39 and / or CD73.
  • the "compound that suppresses the enzyme activity of the adenosine-producing enzyme” (hereinafter, also referred to as “adenosine-producing enzyme inhibitor”), which is the active ingredient of the composition of the present invention, is any as long as it suppresses the enzyme activity of the adenosine-producing enzyme. There are no particular restrictions.
  • the “suppression” here also includes not only complete suppression (inhibition) but also partial suppression.
  • the "adenosine-producing enzyme inhibitor” may be a known drug, or may be obtained by using, for example, the evaluation method of a test compound described later.
  • Known inhibitors for CD39 include, but are not limited to, ARL67156, POM1 (H 2 Na 6 O 40 W 12 ), PSB06126, PSB069.
  • Known inhibitors for CD73 include, for example, AMP-CP (adenosine 5'-( ⁇ , ⁇ -methylene) diphosphate), AB-680, PSB-12379, CD73-IN-1. Not limited. The structural formulas of these known drugs are shown below in order.
  • a pyrimidine derivative that inhibits the enzymatic activity of CD73 JP-A-2020-515559, JP-A-2019-535720, or JP-A-2019-535720, as disclosed in JP-A-2020-517655, or Examples thereof include purine derivatives (adenosine derivatives and the like) that inhibit the enzymatic activity of CD73, as disclosed in JP-A-2017-513955.
  • Japanese Patent Laid-Open No. 2011-510953 Japanese Patent Application Laid-Open No. 2015-057405 or Japanese Patent Application Laid-Open No. 2019-509014, or Japanese Patent Application Laid-Open No. 2019-503709, Japanese Patent Application Laid-Open No. 2018-501197, Japanese Patent Application Laid-Open No. 2017-534648.
  • CD39 as disclosed in Gazette, Publication No. 2018-502051, WO2018 / 110555, WO2016 / 075176, WO2016 / 055609 or WO2016 / 081748.
  • antibodies and functional fragments thereof that bind to CD73 and inhibit the enzyme activity of each enzyme can also be used as adenosine-producing enzyme inhibitors.
  • short-chain oligonucleotides siRNA, shRNA, miRNA, antisense oligonucleotides
  • Nucleotides, etc. can also be used as adenosine-producing enzyme inhibitors.
  • the "substance that suppresses the activation of the adenosine A2A receptor and / or the adenosine A2B receptor” also includes a pharmacologically acceptable salt, hydrate or solvate as long as it has the suppressive activity.
  • a pharmacologically acceptable salt is not particularly limited and may be appropriately selected depending on the structure of each substance and the like.
  • an acid addition salt for example, a hydrochloride salt, a hydrogen bromide salt, a sulfuric acid
  • Inorganic acid salts such as salts, hydrogen sulfates, nitrates, carbonates, hydrogen carbonates, phosphates, monohydrogen phosphates, dihydrogen phosphates, acetates, propionates, lactates, citrates, Organic acid salts such as tartrate), base addition salts (eg, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, zinc salt, aluminum salt, ammonium salt, tetramethyl Ammonium salts), organic amine addition salts (eg, morpholin, piperidine and other addition salts), amino acid addition salts (eg, lysine, glycine, phenylalanine and other addition salts).
  • the hydrate or solvate is not particularly limited, and examples thereof include those in which 0.1 to 10 molecules of water or a solvent are added to one molecule of the substance or a salt thereof.
  • “substances that suppress the activation of adenosine A2A and / or adenosine A2B receptors” include tautomers, geometric isomers, and optical isomers based on asymmetric carbons, as long as they have the inhibitory activity. Includes all isomers and isomer mixtures, such as stereoisomers.
  • the substance undergoes metabolism such as oxidation, reduction, hydrolysis, amination, deamination, hydroxylation, phosphorylation, dehydration, alkylation, dealkylation, and conjugation in the living body, and its inhibitory activity is still present.
  • the present invention also includes compounds showing the above, and the present invention also includes compounds that undergo metabolism such as oxidation, reduction, and hydrolysis in vivo to produce the above-mentioned substances.
  • adenosine A2A receptor antagonist "adenosine A2B receptor antagonist”, “adenosine A2A receptor / adenosine A2B receptor dual antagonist” and "compound that suppresses the enzymatic activity of adenosine producing enzyme” are as described above. , Many compounds have been developed and are commercially available. Therefore, it can be obtained by purchasing. In addition, many reports have been made on methods for producing these compounds, even if they are not commercially available. Therefore, those skilled in the art can appropriately prepare according to the production method.
  • composition of the present invention is used for pharmaceutical compositions (pharmaceutical products, non-pharmaceutical products, veterinary drugs, etc.), foods and drinks (including animal feeds), or for research purposes (for example, in vitro or in vivo experiments). It can be in the form of a reagent to be used.
  • the composition of the present invention can be used for the treatment, amelioration, or prevention of diseases caused by abnormal production of IL-22, IL-31, or IFN-kappa.
  • the cells that produce these cytokines are not particularly limited, but are, for example, naive T cells (naive CD4 + T cells, etc.), effector T cells, memory T cells, or helpers generated by activation of these T cells. Examples include T cells, regulatory T cells, etc., or epithelial cells, endothelial cells, keratin-producing cells.
  • Disease caused by abnormal production of IL-22 includes, for example, neutrophil airway inflammation including neutrophil bronchial asthma, periodontal disease, psoriasis, ulcerative colitis, severe atopic dermatitis, and vulgaris. Examples include, but are limited to, psoriasis, endometriosis, chronic sinusitis, and various other autoimmune diseases (eg, rheumatoid arthritis, polysclerosis, type 1 diabetes, autoimmune nephritis). Not done.
  • Examples of the "disease caused by abnormal production of IL-31" include diseases mainly caused by prurigo dermatitis, and more specifically, prurigo nodularis, atopic dermatitis, contact eczema, and the like. Examples include, but are not limited to, chronic idiopathic urticaria, obesity dermatitis, and various other autoimmune disorders (eg, bullous pemphigoid, psoriasis, alopecia roundus).
  • Disease caused by abnormal production of IFN-kappa includes, for example, inflammatory skin disease, neoplastic skin disease, hereditary skin disease (more specifically, allergic disease such as atopic dermatitis, psoriasis, etc. Atopic dermatitis, drug rash, drug-induced photosensitivity, photocontact dermatitis, skin lymphoma, melanoma), but are not limited to these.
  • the dosage form is not particularly limited as long as it contains a substance that suppresses the activation of the adenosine A2A receptor and / or the adenosine A2B receptor as an active ingredient. ..
  • the pharmaceutical composition of the present invention can be formulated into various dosage forms including a pharmacologically acceptable carrier by a known pharmaceutical method.
  • the dosage form of the pharmaceutical composition is not particularly limited and may be appropriately selected depending on the desired administration method, for example, an oral solid preparation (tablet, coated tablet, granule, powder, capsule, etc.). , Oral solutions (internal solutions, syrups, elixirs, etc.), external preparations (suppositories, ointments, patches, gels, creams, external powders, sprays, inhalants, etc.), injections (solutions, suspensions, etc.) Turbid liquid, solid agent for errands, etc.), other oral agents (gum agent, troche agent, sublingual tablet, buccal tablet, adhesive, etc.), oral spray agent, oral semi-solid agent, dentifrice, gargle Examples include agents.
  • Oral solid preparations include, for example, substances that suppress the activation of adenosine A2A and / or adenosine A2B receptors, excipients, and if necessary, binders, disintegrants, lubricants, and colorants.
  • excipients that can be produced by a conventional method by adding additives such as flavoring and flavoring agents, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like. Can be mentioned.
  • binder examples include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shelac, calcium phosphate, polyvinylpyrrolidone and the like.
  • disintegrant examples include dried starch, sodium alginate, canten powder, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, stearate monoglyceride, lactose and the like.
  • lubricant examples include purified talc, stearate, borax, polyethylene glycol and the like.
  • colorant examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.
  • the oral solution is produced by a conventional method, for example, by adding additives such as a flavoring / flavoring agent, a buffering agent, and a stabilizer to a substance that suppresses the activation of adenosine A2A receptor and / or adenosine A2B receptor. be able to.
  • additives such as a flavoring / flavoring agent, a buffering agent, and a stabilizer
  • Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.
  • Examples of the buffer include sodium citrate and the like.
  • Examples of the stabilizer include tragant, gum arabic, gelatin and the like.
  • a substance that suppresses the activation of the adenosine A2A receptor and / or the adenosine A2B receptor for example, a substance that suppresses the activation of the adenosine A2A receptor and / or the adenosine A2B receptor, a known carrier for suppository preparation such as polyethylene glycol, lanolin, cacao butter, and fatty acid triglyceride, and a necessary carrier. It can be produced by a conventional method after adding a surfactant or the like such as Tween (registered trademark) accordingly.
  • a surfactant or the like such as Tween (registered trademark) accordingly.
  • a known base, stabilizer, wetting agent, preservative, etc. are blended with a substance that suppresses the activation of adenosine A2A receptor and / or adenosine A2B receptor, and mixed by a conventional method. , Can be manufactured.
  • Examples of the base include liquid paraffin, white petrolatum, bleached beeswax, octyldodecyl alcohol, paraffin and the like.
  • Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like.
  • a cream, gel, paste or the like as an ointment can be applied to a known support by a conventional method to produce the patch.
  • the support include cotton, rayon, a woven fabric made of chemical fibers, a non-woven fabric, a film such as soft vinyl chloride, polyethylene, and polyurethane, and a foam sheet.
  • a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. are added to a substance that suppresses the activation of adenosine A2A receptor and / or adenosine A2B receptor.
  • Injections for subcutaneous, intramuscular, intravenous, etc. can be produced by a conventional method.
  • Examples of the pH adjuster and buffer include sodium citrate, sodium acetate, sodium phosphate and the like.
  • examples of the stabilizer include sodium metabisulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
  • examples of the tonicity agent include sodium chloride, glucose and the like.
  • Examples of the local anesthetic include procaine hydrochloride, lidocaine hydrochloride and the like.
  • a pharmaceutical product to be applied to the oral cavity can also be formulated by a known pharmaceutical method according to its properties.
  • composition of the present invention When the composition of the present invention is used as a pharmaceutical composition, one or more other components effective for the treatment of diseases caused by abnormal production of IL-22, IL-31 or IFN-kappa may be used. Can be blended. It may also be used in combination with other pharmaceutical compositions effective for this purpose.
  • the administration target of the pharmaceutical composition is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include humans and non-human animals.
  • non-human animals include, but are not limited to, mice, rats, cows, pigs, monkeys, dogs, cats and the like.
  • the administration method can be appropriately selected depending on the dosage form and the like, and examples thereof include oral administration, external administration, and administration by injection.
  • the dose can be appropriately selected according to the type, age, body weight, sex, symptoms, etc. of the subject to be administered, and for example, the active ingredient adenosine A2A receptor and / or adenosine A2B receptor per day for human adults.
  • the amount of the substance that suppresses the activation of the body for example, an amount selected in the range of 0.04 to 500 mg is considered preferable.
  • the frequency of administration is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the daily dose may be administered once a day or divided into a plurality of doses. You may. It may also be administered, for example, 1 to 4 times a week instead of daily.
  • the food and drink may be, for example, a health food, a functional food, a food for specified health use, a nutritional supplement, a food for the sick, or a food additive.
  • Specific examples of foods and drinks include liquid foods such as drinks, soups, dairy drinks, soft drinks, tea drinks, alcoholic drinks, jelly-like drinks, and functional drinks; oils such as cooking oil, dressings, mayonnaise, and margarine.
  • the food and drink in the present invention can be manufactured by a manufacturing technique known in the art.
  • one or more components effective for diseases caused by abnormal production of IL-22, IL-31 or IFN-kappa may be blended.
  • it may be a multifunctional food or drink by combining it with other ingredients or other functional foods that exhibit this desired function.
  • the target of food and drink can be appropriately selected according to the purpose, and examples thereof include humans and non-human animals.
  • non-human animals include, but are not limited to, mice, rats, cows, pigs, monkeys, dogs, cats and the like.
  • the amount of intake can be appropriately selected according to the type, age, body weight, sex, symptoms, etc. of the subject to be ingested, and for example, the active ingredient adenosine A2A receptor and / or adenosine A2B receptor per day for human adults.
  • an amount selected in the range of 0.04 to 500 mg is considered preferable.
  • the frequency of intake can be appropriately selected depending on the intended purpose. For example, the daily intake may be taken once a day or may be divided into a plurality of times. It may also be taken, for example, 1 to 4 times a week instead of daily.
  • the product of the composition of the present invention (pharmaceutical composition, food and drink, reagent, device containing these, etc.) or its description is used to suppress the production of, for example, IL-22, IL-31 or IFN-kappa. , And / or may be labeled as being used for the treatment, amelioration, or prevention of diseases caused by abnormal production of IL-22, IL-31, or IFN-kappa.
  • "marked on the product or instruction manual” means that the label is attached to the main body, container, packaging, etc. of the product, or the instruction manual, package insert, advertisement, or other printed matter that discloses the information of the product. It means that the display is attached to.
  • the present invention treats and improves a disease caused by an activity in which a test compound suppresses the production of IL-22, IL-31 or IFN-kappa, or an abnormal production of IL-22, IL-31 or IFN-kappa. , Or provide a method for assessing the probability of having prophylactic activity.
  • the first aspect of the evaluation method of the present invention is a method using the binding of the test compound to the adenosine A2A receptor as an index, (a) a step of contacting the test compound with the adenosine A2A receptor, and (b). ) Includes a step of detecting the binding of the test compound to the adenosine A2A receptor.
  • the test compound comprises (a) a step of contacting the test compound with the adenosine A2B receptor, and (b) a step of detecting the binding between the test compound and the adenosine A2B receptor.
  • a method using the binding to the adenosine A2B receptor as an index can also be mentioned.
  • the second aspect of the evaluation method of the present invention is a method using the binding between the test compound and the adenosine-producing enzyme as an index, (a) a step of bringing the test compound into contact with the adenosine-producing enzyme, and (b) a subject.
  • the step of detecting the binding between the test compound and the adenosine-producing enzyme is included.
  • test compound to be the target of the evaluation method of the present invention is not particularly limited, and for example, a synthetic small molecule compound library, an expression product of a gene library, a peptide library, a polynucleotide library, an antibody, and a bacterial release.
  • examples include substances, extracts and culture supernatants of cells (microorganisms, plant cells, animal cells), purified or partially purified polypeptides, extracts from marine organisms, plants or animals, and the like.
  • the test compound may be synthesized based on the design in silico based on the three-dimensional structure of the adenosine A2A receptor, adenosine A2B receptor or adenosine-producing enzyme.
  • the "adenosine A2A receptor" used in the evaluation method of the present invention is, for example, a protein consisting of the amino acid sequence set forth in SEQ ID NO: 1 (NCBI Reference Sequence: NP_000666.2) or a partial peptide thereof. Can be mentioned. However, it should be understood that individual differences may occur in the amino acid sequence of the adenosine A2A receptor.
  • the "adenosine A2B receptor" used in the evaluation method of the present invention includes, for example, a protein consisting of the amino acid sequence set forth in SEQ ID NO: 10 (NCBI Reference Sequence: NP_000667.1) or a partial peptide thereof. Can be mentioned. However, it should be understood that the amino acid sequence of the adenosine A2B receptor may also vary from individual to individual.
  • the "adenosine-producing enzyme" used in the evaluation method of the present invention is, for example, a protein consisting of the amino acid sequence according to any one of SEQ ID NOs: 2 to 7 (NCBI Reference Sequence: NP_001767, NP_001091645, NP_001157650, NP_001157651, NP_001157653, or NP_001157654) and partial peptides thereof can be mentioned.
  • a protein consisting of the amino acid sequence set forth in SEQ ID NO: 8 or 9 NCBI Reference Sequence: NP_001191742 or NP_002517
  • a partial peptide thereof can be mentioned.
  • individual differences may occur in the amino acid sequence of adenosine-producing enzymes.
  • adenosine A2A receptor As the adenosine A2A receptor, adenosine A2B receptor, and adenosine-producing enzyme, in addition to the above-mentioned natural protein and its partial peptide, variants and modifications thereof can be used as needed.
  • other proteins eg, enzymes such as alkaline phosphatase (SEAP), ⁇ -galactosidase, fluorescent proteins such as green fluorescent protein (GFP), glutathione-S-transferase (GST)
  • SEAP alkaline phosphatase
  • GFP green fluorescent protein
  • GST glutathione-S-transferase
  • fusion proteins can be used.
  • the adenosine A2A receptor or adenosine-producing enzyme can also be used in the form expressed on the cell surface.
  • Contact between the test compound and the adenosine A2A receptor, adenosine A2B receptor or adenosine-producing enzyme can be performed by adding the test compound to the evaluation system or the like.
  • a known method can be appropriately adopted for "detection of binding between the test compound and the adenosine A2A receptor, adenosine A2B receptor or adenosine-producing enzyme". For example, there is a method of contacting a test compound with a fixed adenosine A2A receptor, adenosine A2B receptor or adenosine producing enzyme to identify a compound that binds to the adenosine A2A receptor, adenosine A2B receptor or adenosine producing enzyme. ..
  • Various known means can be used as a means for detecting the binding between the test compound and the adenosine A2A receptor, adenosine A2B receptor or adenosine-producing enzyme, and as an example of a suitable means, surface plasmon resonance Biosensors that utilize the phenomenon can be mentioned.
  • test compound is a synthetic small molecule compound library
  • a high-throughput method by combinatorial chemistry technology (Writton NC et al., Science. 26; 273 (5274) 458-464 (1996), Verdine, GL Nature 384 11-13 (1996), Hogan JC, Jr Directed combinatorial chemistry. Nature. 384: 17-19 (1996) can be used.
  • test compound is a polynucleotide library
  • an in vitro selection method can be used (SELEX method) (Tuerk C. & Gold L., Science. 3; 249 (496): 505-. 510 (1990), Green R. et al., Methods Compan Methods Enzymol. 2: 75-86 (1991), Gold L. et al., Annu Rev Biochem 64: 763-97 (1995), Uphoff. et al., Curr. Opin. Struct. Biol. 6: 281-288 (1996)).
  • test compound a method using FRET (fluorescence resonance energy transfer), an immunoprecipitation method, a yeast two-hybrid system, etc. can also be used.
  • FRET fluorescence resonance energy transfer
  • immunoprecipitation method a method using immunoprecipitation method, a yeast two-hybrid system, etc.
  • test compound when the test compound binds to at least one protein of adenosine A2A receptor, adenosine A2B receptor and adenosine-producing enzyme, a partial peptide thereof, or a variant or a modification thereof, IL-22. , IL-31 or IFN-kappa production inhibitory activity, or IL-22, IL-31 or IFN-kappa production abnormal activity to treat, ameliorate, or prevent diseases. Will be done.
  • the third aspect of the evaluation method of the present invention is a method using the inhibition of the binding between the adenosine A2A receptor ligand and the adenosine A2A receptor by the test compound as an index, and (a) in the presence of the test compound. It comprises contacting the adenosine A2A receptor ligand with the adenosine A2A receptor and (b) detecting the binding of the adenosine A2A receptor ligand to the adenosine A2A receptor.
  • a step of contacting the adenosine A2B receptor ligand with the adenosine A2B receptor in the presence of the test compound and (b) the adenosine A2B receptor ligand and the adenosine A2B receptor.
  • a method using the inhibition of the binding between the adenosine A2B receptor ligand and the adenosine A2B receptor by the test compound as an index comprises a step of detecting the binding.
  • adenosine A2A receptor ligand or the “adenosine A2B receptor ligand”
  • adenosine which is a natural ligand
  • a fixed adenosine A2A receptor or adenosine A2B receptor an adenosine A2A receptor or adenosine A2B receptor expressed on the cell surface, and adenosine labeled with a radioactive substance or a fluorescent substance are used. Whether or not the test compound inhibits the binding to the drug may be detected using the label as an index.
  • the term "inhibition" as used herein includes both complete inhibition and partial inhibition.
  • IL when the test compound inhibits the binding between the adenosine A2A receptor ligand and the adenosine A2A receptor, and / or when the binding between the adenosine A2B receptor ligand and the adenosine A2B receptor is inhibited, IL. It is likely to have the activity of suppressing the production of -22, IL-31 or IFN-kappa, or the activity of treating, ameliorating or preventing the disease caused by the abnormal production of IL-22, IL-31 or IFN-kappa. Is evaluated as.
  • the fourth aspect of the evaluation method of the present invention is a method using the inhibition of the binding between the substrate of the adenosine-producing enzyme and the adenosine-producing enzyme by the test compound as an index, and (a) adenosine in the presence of the test compound. It comprises contacting the substrate of the producing enzyme with the adenosine producing enzyme, and (b) detecting the binding between the substrate of the adenosine producing enzyme and the adenosine producing enzyme.
  • adenosine-producing enzyme substrate examples include ATP and ADP when the adenosine-producing enzyme is CD39, and AMP, for example, when the adenosine-producing enzyme is CD73.
  • the test compound inhibits the binding between the fixed adenosine-producing enzyme or the adenosine-producing enzyme expressed on the cell surface and the labeled substrate such as a radioactive substance or a fluorescent substance. It may be detected by using the sign as an index.
  • test compound inhibits the binding between the substrate of the adenosine-producing enzyme and the adenosine-producing enzyme, the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or IL-22, IL- It is evaluated that there is a probability that it has an activity of treating, ameliorating, or preventing a disease caused by abnormal production of 31 or IFN-kappa.
  • the fifth aspect of the evaluation method of the present invention is a method using the suppression of the activity of the adenosine A2A receptor by the test compound as an index, and (a) the test compound is brought into contact with cells expressing the adenosine A2A receptor. It comprises (b) a step of detecting the activity of the adenosine A2A receptor.
  • adenosine by the test compound comprises (a) a step of contacting the test compound with a cell expressing the adenosine A2B receptor, and (b) a step of detecting the activity of the adenosine A2B receptor.
  • a method using suppression of A2B receptor activity as an index can also be mentioned.
  • Examples of the activity of the adenosine A2A receptor include various events that occur in signal transduction from the adenosine A2A receptor in response to a stimulus. Examples of such signal transduction include, but are not limited to, an increase in cAMP and activation of PKA. Examples of the activity of the adenosine A2B receptor, which is an index of the evaluation method of the present invention, include various events occurring in signal transduction from the adenosine A2B receptor in response to a stimulus.
  • Such signal transduction includes, for example, activation of adenylate cyclase, elevation of cAMP, activation of PKA, activation of phospholipase C, elevation of inositol 1,4,5-triphosphate, elevation of diacylglycerol, and the like. However, it is not limited to these.
  • a reaction in which adenosine A2A receptor and / or adenosine A2B receptor ligand on the cell surface is activated by stimulation with adenosine A2A receptor ligand and adenosine A2B receptor ligand.
  • the test compound may be applied to the system to evaluate whether the activity is inhibited. Methods for measuring these activities are known and may be measured using ordinary methods or measurement kits.
  • IL-22, IL-31 or IFN-kappa It is evaluated that there is a probability that it has an activity of suppressing the production of IL-22, or an activity of treating, ameliorating, or preventing a disease caused by an abnormal production of IL-22, IL-31, or IFN-kappa.
  • the sixth aspect of the evaluation method of the present invention is a method using the suppression of the enzyme activity of the adenosine-producing enzyme by the test compound as an index, (a) a step of contacting the test compound with the adenosine-producing enzyme, and (b). ) Includes a step of detecting the enzymatic activity of an adenosine-producing enzyme.
  • the enzyme activity of the adenosine-producing enzyme which is an index of the evaluation method of the present invention, is the amount of the product (AMP for CD39, adenosine for CD73) obtained by the reaction catalyzed by each enzyme in the presence of each substrate. , Can be detected by measurement by a known method (for example, liquid chromatography mass analysis method).
  • AMP for CD39, adenosine for CD73
  • Such enzyme activity also includes various events that occur in signal transduction induced by the produced adenosine and the like. Examples of such signal transduction include, but are not limited to, an increase in cAMP and activation of PKA. Methods for measuring these activities are known and may be measured using ordinary methods or measurement kits.
  • test compound when the test compound reduces the activity of the adenosine-producing enzyme, the activity of suppressing the production of IL-22, IL-31 or IFN-kappa, or IL, as compared with the case where the test compound is not contacted. It is evaluated to have the potential to have the activity of treating, ameliorating, or preventing diseases caused by abnormal production of -22, IL-31, or IFN-kappa.
  • the evaluation method of the present invention has been described above, but the evaluation method of the present invention is carried out for a plurality of test compounds to bind to the above-mentioned adenosine A2A receptor and / or adenosine A2B receptor ligand, and adenosine.
  • adenosine IL-22, IL-31 or IFN-kappa can be selected by selecting a compound based on binding to adenosine, inhibition of binding of adenosine-producing substrate to adenosine-producing enzyme, or suppression of adenosine-producing enzyme activity.
  • Compounds can be screened that have the activity of suppressing the production of, or the activity of treating, ameliorating, or preventing diseases caused by abnormal production of IL-22, IL-31, or IFN-kappa. Therefore, the present invention also provides such a screening method.
  • -It is preferable to verify whether or not the disease has an activity of treating, ameliorating, or preventing a disease caused by abnormal production of kappa.
  • the suppression of IL-22, IL-31 or IFN-kappa production is evaluated by, for example, as described in this example, whether or not the production of these various cytokines is suppressed by using 2-way MLR or the like. be able to.
  • the activity of treating, ameliorating, or preventing diseases caused by abnormal production of IL-22, IL-31, or IFN-kappa can be evaluated in experiments using various model animals. Furthermore, in clinical trials, it is possible to actually evaluate the effect in humans.
  • the difference between the two groups was analyzed using Student's t-test. Differences between 3 groups or more are one-way ANOVA, one-way ANOVA, where p value (probability value, p value) is 0.05 or less, and there is a significant difference. When it was determined that there was a significant difference in the above, a Turkey test (Turkey honestly significant difference) was further performed to analyze the significant difference between the two groups.
  • the Kruskal-Wallis test determined that the p-value was 0.05 or less, and the Kruskal-Wallis test determined that there was a significant difference. In this case, Wilcoxon signed-rank test was further performed to analyze the significant difference between the two groups.
  • FIG. 1A medium, FIG. 1B; medium, FIG. 1C; medium + adenosine 100 ⁇ M, FIG. 2A; medium + CD3 / 28, FIG. 2B; medium + CD3 / 28, FIG. 2C; medium + adenosine 600 ⁇ M + CD3 / 28, FIG. 3; medium + CD3 /.
  • CD28 + adenosine (600 ⁇ M), FIG. 4A; medium + ATP (100 ⁇ M), FIG. 4B; medium + ATP (100 ⁇ M), FIG. 5; medium + CD3 / CD28 + adenosine (600 ⁇ M), FIG. 6A; medium + ATP (100 ⁇ M), FIG. 6B; medium + ATP. (100 ⁇ M), FIG. 7; medium + 600 ⁇ M adenosine + anti-CD3 / CD28 antibody.
  • Example 1 Effect of adenosine and isstradefylline on 2-way MLR 1 Mononuclear cells were isolated from the splenocytes of BALB / c and SJL / J mice with different H-2. Specifically, spleens are removed from 8-10 week-old female H-2 different BALB / c and SJL / J mice, and the spleens are added to homogenizers (GPE Scientific, Tenbroeck Style Homogenizer, Pestle diameter 15 mm).
  • PBMCs Peripheral blood mononuclear cells
  • DMEM fetal calf serum
  • D10 medium was added to the prepared mononuclear cells to adjust to 3 ⁇ 106 cells / ml each. Then, in order to induce the MLR reaction, the prepared BALB / c-derived mononuclear cells and SJL / J-derived mononuclear cells were mixed 1 ml each in a 12-well plate (total: 6 ⁇ 10 6 cells / 2 ml). ).
  • adenosine is added so that the final concentration becomes 100 to 1000 ⁇ M, and the cells are co-cultured.
  • the culture supernatant 7 days after the start of the culture is collected, and the concentrations of IL-17F and IL-22 contained in the culture supernatant are adjusted.
  • Quantified by ELISA method Quantified by ELISA method.
  • the ELISA method for quantifying IL-17F and IL-22 was performed using a Duo Set kit (manufactured by R & D Systems) according to the attached manual.
  • PSB0777 ammonium salt which is an adenosine A2A receptor agonist
  • TOCRIS PSB0777 ammonium salt
  • adenosine final concentration, 100 ⁇ M
  • istradefylline which is an adenosine A2A receptor antagonist
  • Example 2 Effect of adenosine and isstradefylline on CD4 + T cells 1
  • spleens were removed from 8-10 week old BALB / c mice and placed in a 6 cm dish containing 5 mL DMEM. The spleen was thoroughly kneaded in the medium using tweezers, and the solution containing the lymphocytes eluted in the medium was transferred to a 15 mL tube. The 6 cm dish was washed again with 5 mL DMEM. The supernatant was added to the 15 mL tube to give a total volume of 10 mL.
  • CD4 + T cells were prepared by positive selection using magnetic beads (mouse CD4 (L3T4) MicroBeads (Miltenyi Biotec, 130-049-201)).
  • Adenosine was added to the prepared mouse CD4 + T cells so that the final concentration was 100 to 1000 ⁇ M, and the anti-mouse CD3 ⁇ agonist antibody (BioLegend, Clone: 145-2C11) having a final concentration of 1 ⁇ g / mL and the final concentration were 0.5 ⁇ g / mL anti-mouse CD28 agonist antibody (BioLegend, Clone: 37.51) was added, seeded and cultured on a 24-well plate at 1 ⁇ 10 6 cells / 500 ⁇ L, and cultured on cells 7 days after the start of culture. Qing was recovered. The concentrations of IL-17F and IL-22 contained in the collected cell supernatant were quantified by the ELISA method.
  • PSB0777 ammonium salt which is an adenosine A2A receptor agonist
  • PSB0777 ammonium salt was added to the prepared mouse CD4 + T cells so that the final concentration was 0.01 to 10 ⁇ M, and the final concentration was 1 ⁇ g / mL.
  • Anti-mouse CD3 ⁇ agonist antibody BioLegend, Clone: 145-2C11
  • anti-mouse CD28 agonist antibody BioLegend, Clone: 37.51
  • the cells were seeded on a 24-well plate at / 500 ⁇ L and cultured, and the cell supernatant was collected 7 days after the start of the culture.
  • the concentrations of IL-17F and IL-22 contained in the collected cell supernatant were quantified by the ELISA method.
  • adenosine A2A receptor antagonist istradefylline was added to the prepared mouse CD4 + T cells together with adenosine (final concentration, 600 ⁇ M) so that the final concentration was 0.01 to 1 nM.
  • Add an anti-mouse CD3 ⁇ agonist antibody BioLegend, Clone: 145-2C11
  • an anti-mouse CD28 agonist antibody BioLegend, Clone: 37.51
  • BioLegend, Clone: 37.51 an anti-mouse CD28 agonist antibody
  • the cells were seeded on a 24-well plate at 1 ⁇ 10 6 cells / 500 ⁇ L and cultured, and the cell supernatant 7 days after the start of the culture was collected.
  • the concentrations of IL-17F and IL-22 contained in the collected cell supernatant were quantified by the ELISA method.
  • adenosine induces the production of IL-17F and IL-22, which is induced by the adenosine A2A receptor antagonist Istradefylline. It was shown to be suppressed by phosphorus in a concentration-dependent manner (Fig. 2C).
  • CD4 + T cells were prepared in the same manner as described in Example 2. Adenosine was added to the prepared mouse CD4 + T cells so that the final concentration was 600 ⁇ M, and the anti-mouse CD3 ⁇ agonist antibody (BioLegend, Clone: 145-2C11) having a final concentration of 1 ⁇ g / mL and the final concentration of 0.
  • the anti-mouse CD3 ⁇ agonist antibody BioLegend, Clone: 145-2C11
  • adenosine induces IL-31 production in CD4 + T cells activated by CD3 / CD28 stimulation (see “medium” in FIG. 3).
  • adenosine A2A receptor antagonist istradefylline was added to the prepared mouse CD4 + T cells together with adenosine (final concentration, 600 ⁇ M) so that the final concentration was 0.01 to 1 nM.
  • Add an anti-mouse CD3 ⁇ agonist antibody BioLegend, Clone: 145-2C11
  • an anti-mouse CD28 agonist antibody BioLegend, Clone: 37.51
  • BioLegend, Clone: 37.51 an anti-mouse CD28 agonist antibody
  • the cells were seeded on a 24-well plate at 1 ⁇ 10 6 cells / 500 ⁇ L and cultured, and the cell supernatant 7 days after the start of the culture was collected.
  • the concentration of IL-31 contained in the collected cell supernatant was quantified by the ELISA method.
  • Example 4 Effect of CD39 inhibitor and / or CD73 inhibitor on 2-way MLR 1 Mononuclear cells were isolated from the spleen cells of BALB / c and SJL / J mice with different H-2 in the same manner as in Example 1 and adjusted to 3 ⁇ 106 cells / ml each. Each cell was mixed 1 ml each in a 12-well plate (overall: 6 x 106 cells / 2 ml).
  • a CD39 inhibitor ARL67156 trisodium salt (TOCRIS)
  • a CD73 inhibitor adenosine 5'-( ⁇ , ⁇ -methylene) diphosphate (AMP).
  • -CP) sodium salt TOCRIS
  • FIGS. 4A and 4B it was clarified that the production of IL-31 was induced by adding ATP to mononuclear cells (“medium” in FIGS. 4A and 4B).
  • CD4 + T cells were prepared in the same manner as described in Example 2. Adenosine was added to the prepared mouse CD4 + T cells so that the final concentration was 600 ⁇ M, and the anti-mouse CD3 ⁇ agonist antibody (BioLegend, Clone: 145-2C11) having a final concentration of 1 ⁇ g / mL and the final concentration of 0.
  • the anti-mouse CD3 ⁇ agonist antibody BioLegend, Clone: 145-2C11
  • adenosine final concentration, 600 ⁇ M
  • adenosine A2A receptor antagonist istradefylline were added to the prepared mouse CD4 + T cells so that the final concentration was 1 ⁇ M, and the final concentration was increased.
  • Example 6 Effect of CD39 inhibitor and / or CD73 inhibitor on 2-way MLR 2 Mononuclear cells were isolated from the spleen cells of BALB / c and SJL / J mice with different H-2 in the same manner as in Example 1 and adjusted to 3 ⁇ 106 cells / ml each. Each cell was mixed 1 ml each in a 12-well plate (overall: 6 x 106 cells / 2 ml).
  • a CD39 inhibitor ARL67156 trisodium salt (TOCRIS)
  • a CD73 inhibitor adenosine 5'-( ⁇ , ⁇ -methylene) diphosphate (AMP).
  • -CP) sodium salt TOCRIS
  • Example 7 Effect of MRS1754 on CD4 + T cells
  • istradefylline which is an adenosine A2A receptor antagonist
  • MRS1754 which is an adenosine A2B receptor antagonist
  • the concentration of IL-31 contained in the culture supernatant of the cells was quantified by the ELISA method.
  • Example 8 Effect of MRS1754 on atopic dermatitis model mice
  • the back of NC / Nga mice was shaved with hair clippers, and 2% 2,4,6-trinitrochlorobenzene (TNCB) (ethanol and acetone 4: 1).
  • Atopic dermatitis model mice were prepared by dropping 150 ⁇ L of TNCB dissolved in a liquid mixed with the above.
  • a cream was prepared by mixing MRS1754 with petrolatum to a concentration of 5%, each cream was applied to the back, and the change in the pathological condition was observed. Then, the observed pathological conditions were scored (the pathological condition items and scores are shown in the margin of Table 1), and the effect of MRS1754 was evaluated.
  • IL-22 is produced in large quantities from Th22 cells and the like, and is considered to be involved in the formation of its pathological condition (Non-Patent Documents 1 and 2). Furthermore, in atopic dermatitis, IL-31 produced from Th2 cells is considered to be a cytokine that induces strong itch (Non-Patent Document 3).
  • the antagonist to the adenosine A2A receptor and / or the adenosine A2B receptor can exert not only the effect of suppressing inflammation and the like shown in the above model animal, but also the effect of suppressing strong itching.
  • the present invention is useful for the treatment of diseases caused by abnormal production of IL-22, IL-31 or IFN-kappa, and mainly contributes to the medical field.
  • the present invention also contributes to basic research for regulating the production of IL-22, IL-31 or IFN-kappa.

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