WO2020004404A1 - INHIBITEUR DE L'IL-1β - Google Patents

INHIBITEUR DE L'IL-1β Download PDF

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Publication number
WO2020004404A1
WO2020004404A1 PCT/JP2019/025204 JP2019025204W WO2020004404A1 WO 2020004404 A1 WO2020004404 A1 WO 2020004404A1 JP 2019025204 W JP2019025204 W JP 2019025204W WO 2020004404 A1 WO2020004404 A1 WO 2020004404A1
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disease
syndrome
active ingredient
inhibitor
medicament
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English (en)
Japanese (ja)
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龍佑 沈
直樹 外角
昭徳 西
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Kurume University
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Kurume University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to an IL-1 ⁇ inhibitor, a medicament for treating a disease caused by IL-1 ⁇ , a medicinal composition for treatment, a treatment method, and the like, which comprise a low molecular compound as an active ingredient.
  • compositions containing low-molecular-weight compounds as active ingredients have a simpler manufacturing process than pharmaceutical products such as antibodies, can reduce drug costs, and can be orally administered as tablets, capsules, etc. It is. Therefore, at least the problems 2) and 4) of the above-mentioned biological preparation can be solved by using a low molecular weight compound as an active ingredient. Therefore, development of an IL-1 ⁇ inhibitor containing a low molecular weight compound as an active ingredient is required.
  • IL-1 ⁇ increases in peripheral blood and acts on IL-1 ⁇ receptor of cerebrovascular endothelial cells in the brain. It is considered that one of the causes is invasion of macrophages and inflammatory cytokines (Non-patent Document 3). Therefore, it is considered that an IL-1 ⁇ inhibitor can also be used as a therapeutic agent for depression.
  • Non-muscle Mlck is required for ⁇ -catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1 ⁇ -mediated barrier dysfunction in brain endothelial cells, J Cell Sci. 2014 Apr 15; 127 (8): 1840-1853.
  • An object of the present invention is to provide an IL-1 ⁇ inhibitor, a medicament for treating a disease caused by IL-1 ⁇ , a pharmaceutical composition for treatment, a treatment method, and the like, which comprise a low molecular compound as an active ingredient.
  • a medicament for treating a disease caused by IL-1 ⁇ comprising 6-fluoro-3-[(1E) -2- (3-pyridinyl) ethenyl] -1H-indole as an active ingredient.
  • IL-1 ⁇ -induced diseases include familial Mediterranean fever, cryopyrin-associated periodic fever syndrome, NLRP12-associated periodic fever syndrome, IL-1 receptor antagonist deficiency, purulent aseptic arthritis, Majeed syndrome, Nakajo-Nishimura syndrome, CARD14 abnormality, juvenile-onset sarcoidosis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, Behcet's disease, Crohn's disease, gout / pseudogout, asbestosis / Silicosis, type 2 diabetes, Schnitzler syndrome, arteriosclerosis, stroke, depression, multiple sclerosis, Alzheimer's disease, rheumatic disease, malignancy, autoimmune disease, collagen disease, arteriosclerotic disease and allergic disease
  • the medicament according to [3] which is selected from the group consisting of:
  • FIG. 1 shows the effect of 680C91 on cytokine gene expression in Raw264.7 cells stimulated with LPS.
  • FIG. 2 shows the effect of 680C91 on cytokine gene expression in primary cultured macrophages from TDO wild type mice stimulated with LPS.
  • FIG. 3 shows the effect of 680C91 on cytokine gene expression of primary cultured macrophages from TDO gene deficient mice stimulated with LPS.
  • FIG. 4 shows the effect of 680C91 on weight loss in an inflammatory bowel disease model created by oral administration of dextran sodium sulfate (DSS).
  • FIG. 5 shows the effect of 680C91 on colon length shortening in an inflammatory bowel disease model created by oral administration of DSS.
  • FIG. 6 shows the effect of 680C91 on cytokine gene expression in colon tissue of an inflammatory bowel disease model created by oral administration of DSS.
  • FIG. 7 shows the effect of 680C91 on increasing the expression of IL-1 ⁇ protein in large intestine tissue of an inflammatory bowel disease model created by oral administration of DSS.
  • the present invention relates to an IL-1 ⁇ inhibitor comprising 6-fluoro-3-[(1E) -2- (3-pyridinyl) ethenyl] -1H-indole (680C91) as an active ingredient, and a disease caused by IL-1 ⁇ .
  • the present invention relates to a medicament for treatment, a pharmaceutical composition for treatment, a treatment method and the like.
  • the 680C91 has the following structural formula: Which is commercially available as a TDO inhibitor. 680C91 is known to have an antitumor effect. Hereinafter, 680C91 is also referred to as “the present compound”.
  • the compound may be a solvate, amorphous, crystal, polymorph, co-crystal or the like. Further, the present compound may be a compound in which one or more atoms are substituted with one or more isotope atoms. Examples of isotope atoms include deuterium ( 2 H), tritium ( 3 H), 13 C, 15 N, 18 O and the like.
  • the compound can suppress IL-1 ⁇ gene expression.
  • This IL-1 ⁇ inhibitory action is clearly different from the TDO inhibitory action. Therefore, the present invention provides an IL-1 ⁇ inhibitor comprising the present compound as an active ingredient.
  • the “IL-1 ⁇ inhibitor” in the present invention means an agent that suppresses gene expression of IL-1 ⁇ .
  • the present invention provides a medicament for treating a disease caused by IL-1 ⁇ , comprising the present compound as an active ingredient.
  • ⁇ disease caused by IL-1 ⁇ '' in the present invention a disease in which the involvement of IL-1 ⁇ is confirmed or indicated in the onset or progression, or a disease associated with overproduction of IL-1 ⁇ or abnormal activity expression
  • examples thereof include an autoinflammatory syndrome, a chronic inflammatory disease and the like (see YAKUGAKU ZASSHI 133 (6) 645-660 (2013) and the like). It is known that in these diseases, the pathology of hypercytokinemia (particularly hyperIL-1 ⁇ blood) can be observed.
  • Autoinflammatory syndromes include, for example, familial Mediterranean fever, cryopyrin-associated periodic fever syndrome, NLRP12-associated periodic fever syndrome, IL-1 receptor antagonist deficiency, purulent aseptic arthritis, Majeed syndrome, Nakajo-Nishimura Syndrome, CARD14 abnormality, juvenile-onset sarcoidosis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, Behcet's disease, Crohn's disease, gout / pseudogout, asbestosis / silicosis, type 2 Examples include diabetes, Schnitzler syndrome, arteriosclerosis, stroke, depression, multiple sclerosis, Alzheimer's disease, rheumatic diseases (rheumatoid arthritis, etc.).
  • various malignant tumors rectal cancer, colon cancer, renal cell carcinoma, non-small cell lung cancer, etc.
  • various autoimmune diseases glomerulonephritis, dilated cardiomyopathy, myocardium after infection with Cocksaki virus) Disease
  • collagen diseases scleroderma, etc.
  • various arteriosclerotic diseases arteriosclerotic diseases (atherosclerosis, etc.)
  • various allergic diseases allergic rhinitis, bronchitis, etc.
  • treatment includes prophylactic and therapeutic treatments, and includes any management measures such as prevention, treatment, alleviation of symptoms, reduction of symptoms, suppression of progression, and the like. .
  • the present invention also provides a method for treating a disease caused by IL-1 ⁇ , comprising administering an effective amount of the present compound to a subject.
  • the subject includes any mammal such as a human, monkey, dog, cat, rat, rat and the like.
  • the compounds may be administered systemically or locally.
  • the present compounds can be administered by oral administration, nasal administration, inhalation administration, intravenous injection (including infusion), subcutaneous injection, rectal administration, vaginal administration, transdermal administration, and the like.
  • the dose may vary depending on the type, age, body weight, symptom to be treated, desired therapeutic effect, administration route, treatment period and the like of the target mammal.
  • a satisfactory effect can be obtained by systemically or continuously administering an amount of 0.00001 to 500 mg / kg body weight per day, more preferably 0.0001 to 100 mg / kg body weight one to four times a day.
  • the pharmaceutical composition of the present invention may further contain a physiologically acceptable additive.
  • the additives include components used in combination with the present compound, and include, for example, excipients, diluents, extenders, solvents, lubricants, auxiliaries, binders, disintegrants, coating agents, encapsulating agents, ointments.
  • Base suppository base, aerosolizing agent, emulsifier, dispersing agent, suspending agent, thickener, isotonic agent, buffer, soothing agent, preservative, antioxidant, flavoring agent, fragrance
  • coloring agents include coloring agents, functional substances such as cyclodextrin, biodegradable polymers, and stabilizers.
  • the amount of the compound in the pharmaceutical composition of the present invention may vary depending on the formulation of the composition, and can generally be 0.000001 to 10.0%, more preferably 0.00001 to 5.0%, and most preferably 0.0001 to 1%.
  • Solid compositions for oral administration include tablets, troches, sublingual tablets, capsules, pills, powders, granules and the like.
  • Solid compositions may be prepared by mixing one or more active ingredients with at least one inert diluent.
  • the composition may further include additives other than the inert diluent, for example, lubricants, disintegrants and stabilizers.
  • Tablets and pills can be coated with enteric or gastrointestinal films, if necessary. Tablets and pills may be coated with two or more layers. They may be adsorbed on sustained release materials or may be microencapsulated.
  • the composition may be encapsulated with a readily degradable substance such as gelatin. They may be further dissolved in a suitable solvent such as a fatty acid or its mono-, di- or triglycerides to form soft capsules. If immediate action is required, sublingual tablets may be used.
  • liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs.
  • the composition may further comprise a conventionally used inert diluent, for example, purified water or ethyl alcohol.
  • the compositions may also contain additives other than inert diluents, for example, adjuvants such as wetting or suspending agents, sweetening, flavoring, flavoring and preserving agents.
  • the pharmaceutical composition of the present invention may be in the form of a spray composition, which can be prepared according to a known method.
  • nasal formulations may be aqueous or oily solutions, suspensions, or emulsions.
  • the compositions may be in the form of a suspension, solution or emulsion capable of providing an aerosol, or in the form of a powder suitable for dry powder inhalation.
  • Compositions for administration by inhalation may additionally contain conventional propellants.
  • injectable compositions for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Diluents for aqueous solutions or suspensions include, for example, distilled water for injection, saline and Ringer's solution.
  • Non-aqueous diluents for solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbates.
  • the composition may further include additives such as preservatives, wetting agents, emulsifiers, dispersants and the like.
  • compositions may be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating a sterilizing agent, or by gas or radioisotope irradiation sterilization.
  • injectable compositions may be presented as sterile powder compositions that are dissolved in a sterile vehicle for injection before use.
  • external preparations include all external preparations used in the fields of dermatology and otolaryngology, and include, for example, ointments, creams, lotions and sprays.
  • the present invention also provides the present compounds for use in inhibiting IL-1 ⁇ or for treating a disease caused by IL-1 ⁇ .
  • the present invention also provides the use of the present compound for producing an IL-1 ⁇ inhibitor or for producing a medicament or a pharmaceutical composition for treating a disease caused by IL-1 ⁇ .
  • the present invention provides a medicament or a pharmaceutical composition containing the present compound as an active ingredient, and the medicament or the pharmaceutical composition can be used for inhibiting IL-1 ⁇ , or treating a disease caused by IL-1 ⁇ .
  • Example 1 ⁇ Method ⁇ Raw264.7 cells were spread on a 35 mm culture plate, and the following day, the medium was replaced with a medium containing 680C91 (1, 10 ⁇ M). After 30 minutes, lipopolysaccharide (LPS; Lipopolysaccharide (from E. coli o26), Wako BioWindow (Osaka, 0.1 ⁇ g / ml was added to the medium. Five hours later, total RNA was collected from the cells, and the gene expression of inflammatory cytokines IL-1 ⁇ , IL-6, and TNF- ⁇ was measured by real-time PCR.
  • LPS lipopolysaccharide
  • Wako BioWindow Osaka, 0.1 ⁇ g / ml
  • cDNA was purified from total RNA using the QuantiTect Reverse Transcription Kit (Qiagen, Valencia, USA) and real-time PCR was performed using LightCycler 480 System II (Roche, Basel, Switzerland) and GeneAce SYBR qPCR MIX ⁇ No. This was performed using ROX (NIPPON GENE, Toyama, Japan).
  • Example 2 ⁇ Method ⁇ 680C91 target molecule TDO wild type mouse and gene-deficient mouse (male, 9-11 weeks old, Molecular Brain 2009, 2: 8 doi: 10.1186 / 1756-6606-2-8, prepared by the method described in Asahikawa Intraperitoneal macrophages were collected from each of the medical devices according to a standard method. After intraperitoneal administration of 4% thioglycolate, 3-4 days later, macrophages infiltrating into the intraperitoneal cavity were collected and spread on a culture plate, and then 680C91 (1, 10, 50 ⁇ M) and LPS were added in the same manner as in Example 1. Added to the medium. Five hours later, total RNA was recovered from the cells, and the gene expression of inflammatory cytokines IL-1 ⁇ , IL-6, and TNF- ⁇ was measured by real-time PCR as in Example 1.
  • Example 3 ⁇ Method ⁇ C57BL / 6N mice (male, 10 weeks old, Japan SLC, Inc.) were used for the test of ulcerative colitis model.
  • the mice were divided into a DSS + 680C91 group, a DSS group, and a control group (6 mice per group).
  • a DSS + 680C91 group and the DSS group 3% dextran sulfate sodium (hereinafter, referred to as DSS; molecular weight: 36.000 to 50.000, MP bio) was allowed to freely drink to prepare an ulcerative colitis model.
  • the control group was allowed to freely drink tap water.
  • DSS + 680C91 680C91 dissolved in a vehicle was subcutaneously injected at a dose of 8 mg / kg once a day for 8 days (day 8) from the first day of DSS drinking (day 1).
  • the vehicle was similarly administered to the DSS group and the control group.
  • the vehicle was prepared by dissolving 0.2% DMSO (dimethyl sulfoxide) and 40% PEG400 (polyethylene glycol 400) in physiological saline.
  • mice After the treatment period (day 8), the mice were weighed and then dissected, the large intestine was collected, and the length was measured. The change in body weight was evaluated as the ratio of the weight loss after administration to that before the start of DSS administration (weight after 8 days / body weight before administration ⁇ 100).
  • cDNA was collected from the collected large intestine and purified from total RNA using the QuantiTect Reverse Transcription Kit (Qiagen, Valencia, USA), and the inflammatory cytokines IL-1 ⁇ , IL-6, and TNF were used as in Example 1.
  • - ⁇ gene expression was measured by real-time PCR.
  • protein expression was measured by Western blotting.
  • Protein was extracted from the collected large intestine, subjected to polyacrylamide electrophoresis (SDS-PAGE), transferred to a Nitrocellulose membrane, and detected using an antibody against Pro IL-1 ⁇ (IL-1 ⁇ precursor). Note that ⁇ -actin was used as an internal standard.

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Abstract

L'invention concerne un inhibiteur de l'IL-1β, et un médicament, une composition pharmaceutique et une méthode, chacun d'entre eux étant destiné au traitement de maladies associées à l'IL-1β, et autres, dans chacun desquels un composé de faible poids moléculaire est utilisé en tant que principe actif. La présente invention concerne un inhibiteur de l'IL-1β contenant du 6-fluoro-3-[(1E)-2-(3-pyridinyl)éthényl]-1H-indole en tant que principe actif.
PCT/JP2019/025204 2018-06-26 2019-06-25 INHIBITEUR DE L'IL-1β Ceased WO2020004404A1 (fr)

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JP2020527548A JP7290223B2 (ja) 2018-06-26 2019-06-25 ＩＬ－１β阻害薬

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JP2018121098 2018-06-26
JP2018-121098 2018-06-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021162650A1 (fr) * 2020-02-12 2021-08-19 Istanbul Universitesi Dérivés de 5-fluoro/5-trifluorométhoxy-1h-indole-2,3-dione 3-(4-phénylthiosemicarbazone) utilisés en tant qu'antagonistes de l'interleukine 1 (il-1) et agents antipyrétiques et/ou anti-inflammatoires destinés à être utilisés dans le traitement, par exemple, de la maladie de behçet

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Title
BABAK, M. ET AL.: "Engagement of the aryl hydrocarbon receptor in M. tuberculosis-infected macrophages has pleiotropic effects on innate immune signaling", INFLAMMATION RESEARCH, vol. 64, no. 2, 2015, pages S188, XP055667965 *
BOSTIAN, A. ET AL.: "Aberrant activation of the kynurenine pathway in gliomas increases polymerase kappa expression and promotes genomic instability and chemoresistance", FASEB J, vol. 30, 2016, [retrieved on 20190821] *
BREDA, C. ET AL.: "Tryptophan-2, 3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites", PNAS, vol. 113, no. 19, 2016, pages 5435 - 5440, XP055667970 *
GIBNEY, S. M. ET AL.: "Inhibition of stress- induced hepatic tryptophan 2, 3-dioxygenase exhibits antidepressant activity in an animal model of depressive behavior", INT J NEUROPSYCHOPHARMACOL, vol. 17, no. 6, 2014, pages 917 - 928, XP055667967 *
HSU, Y. L. ET AL.: "Lung cancer-derived galectin-1 contributes to cancer associated fibroblast- mediated cancer progression and immune suppression through TD02/kynurenine axis", ONCOTARGET, vol. 7, no. 19, 2016, pages 27584 - 27598, XP055667975 *
REED, M. R. ET AL.: "Inhibition of kynurenine signaling decreases glioblastoma multiforme genomic instability and sensitizes cells to chemotherapeutic treatment", FASEB J, vol. 31, 2017, pages 754, [retrieved on 20190821] *
URAIA, Y. ET AL.: "IL -Ibeta increases expression of tryptophan 2,3-dioxygenase and stimulates tryptophan catabolism in endometrioma stromal cells", AM J REPROD IMMUNOL, vol. 72, no. 5, 2014, pages 496 - 503 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021162650A1 (fr) * 2020-02-12 2021-08-19 Istanbul Universitesi Dérivés de 5-fluoro/5-trifluorométhoxy-1h-indole-2,3-dione 3-(4-phénylthiosemicarbazone) utilisés en tant qu'antagonistes de l'interleukine 1 (il-1) et agents antipyrétiques et/ou anti-inflammatoires destinés à être utilisés dans le traitement, par exemple, de la maladie de behçet

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JPWO2020004404A1 (ja) 2021-07-08

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