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WO2002048135A1 - Inhibiteurs tak1 - Google Patents

Inhibiteurs tak1 Download PDF

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Publication number
WO2002048135A1
WO2002048135A1 PCT/JP2001/010927 JP0110927W WO0248135A1 WO 2002048135 A1 WO2002048135 A1 WO 2002048135A1 JP 0110927 W JP0110927 W JP 0110927W WO 0248135 A1 WO0248135 A1 WO 0248135A1
Authority
WO
WIPO (PCT)
Prior art keywords
tak1
activation
inhibiting
inhibitor
kinase
Prior art date
Application number
PCT/JP2001/010927
Other languages
English (en)
Japanese (ja)
Inventor
Masayuki Tsuchiya
Toshihiko Ohtomo
Koichiro Ono
Masahiko Matsumoto
Tatsuya Ito
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Priority to AU2002222627A priority Critical patent/AU2002222627A1/en
Publication of WO2002048135A1 publication Critical patent/WO2002048135A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom

Definitions

  • the present invention provides a TAK1 inhibitor containing a specific zearalenone as an active ingredient, a TAK1 activation inhibitor containing a specific zearalenone as an active ingredient, and a TAK1 using a specific zearalenone as an active ingredient.
  • Inhibition method Use of specific zearalenones as an active ingredient
  • Inhibition of TAK1 activation Use of specific zearalenones to produce TAK1 inhibitors
  • the MAPK system is a conserved eukaryotic signaling system that converts receptor signals into various actions.
  • the MAPK system includes three types of protein kinases, namely, MAPKKK (Mitogen-Activated Protein Kinase Kinase), MAPKK (Mitogen-Activated Protein Kinase Kinase), and MAPK (Mitogen-Activated d. Protein Kinase).
  • MAPK is activated by phosphorylation by MAPKK.
  • MAPKK is activated by phosphorylation by MAPKKK (Trends Biochem. Sci. (1993) 18, 128; Trends Biochem. Sci. (1993) 19, 236; Trends Biochem. Sci. (1993) 19, 470; Cell (1995) 80, 179).
  • TAKl TGF-i8-Activated Kinase 1
  • MAPKKK MAPKKK family that functions in the intracellular signaling system
  • TAB1 TGF- / 3 signaling system that binds to and activates TAK1.
  • TAB1 binds to TAK1 to activate TAK1 kinase activity, and induces activation of c-Jun N-terminal kinase (JNK) and p38 MAPK through activation of MAPKK MKK4 and MKK3 / 6, and TGF- ; Signals such as 8 (J. Biol. Chem., (1996) 271, 13675-13679; J. Biol. Chem.,
  • TAK1 is also activated by various stresses such as stimulation of interleukin-1 (IL-1) and tumor necrosis factor (TNF) (J. Biol. Chem. (1997) 272, 8141-8144; J. Biol.
  • TAK1 is a MAPK cascade-mediated activation of JNK in IL-1 signaling, and nuclear factor- ⁇ It has been shown to be involved in the activation of NF- ⁇ through the activation of ⁇ ( ⁇ F— ⁇ ) -inducing kinase (NIK) and I ⁇ kinases (IKK) (Nature (1999) 398, 252) -256; Mol. Cell, (2000) 5, 649-658). Furthermore, LPS stimulation activated TAK1, induced NF- ⁇ F activation, and demonstrated that LPS is involved in signal transduction (FEBS Lett., (2000) 467, 160-164).
  • TGF-iS is a multifunctional factor that controls many cell functions, and one of them is TGF-J3, which is responsible for tissue repair and regeneration following various injuries (New Engl. J. Med., (1994) 331). , 1286-1292).
  • TGF-J3 is responsible for tissue repair and regeneration following various injuries.
  • TGF-jS may disrupt the balance of tissue repair and regeneration, resulting in pathological fibrosis.
  • TGF- ⁇ enhances the production of extracellular matrix proteins, inhibits the synthesis of extracellular matrix-degrading enzymes, and induces inhibitors of extracellular matrix-degrading enzymes. It has been shown to act as a major causative factor of fibrosis (New Engl. J. Med., (1994) 331, 1286-1292).
  • Inflammatory cytokines such as IL-1 and TNF play an important role as bioprotective factors such as inflammation due to invasion of foreign substances.However, it is known that excessive expression of this response causes various pathological conditions. Have been. IL-1 is thought to be an important mediator in immune and inflammatory responses, acting on various cells and enhancing their cellular functions.
  • TNF is released from cells such as macula phage activated by contact with foreign antigens that have invaded the living body, and not only enhances the chemotaxis and phagocytosis of macrophages, but also enhances the HLA of T lymphocytes. It enhances the expression of antigens, activates the function of T cells by increasing the expression of IL-2 receptor, and also enhances the chemotaxis and activation of neutrophils to remove foreign substances. It also promotes the proliferation of fibroblasts in inflamed areas and repairs their tissues. Furthermore, TNF Q! Promotes the expression of various cytokins in these cells, and is involved in the formation of cytokinetic networks, like IL-1.
  • TAK-] 3 IL-1, LPS, TNF, etc.
  • TAK-] 3 IL-1, LPS, TNF, etc.
  • TAK1 activation inhibitor no TAK1 kinase inhibitor or TAK1 activation inhibitor has been known to date.
  • An object of the present invention is to provide a TAK1 inhibitor or a TAK1 activation inhibitor.
  • the present inventors have conducted intensive studies to solve the above problems, and as a result, certain zearalenones have excellent TAK1 kinase inhibitory activity, and TGF-J3 and IL-1 mediated by activation of TAK1. The present inventors have found that such signal transduction is inhibited, and completed the present invention based on this finding.
  • the present invention provides a zearaleno having a hydroxyl group at each of the 8-position and the 9-position.
  • a TAK 1 inhibitor or a TAK 1 activation inhibitor comprising a pharmaceutically acceptable salt as an active ingredient.
  • the present invention also provides a method for inhibiting TAK1 or a method for inhibiting TAK1 activation, which comprises using an effective amount of a zearalenone having a hydroxyl group at each of the 8th and 9th positions.
  • the present invention provides the use of zearalenones having a hydroxyl group at both the 8-position and the 9-position for producing a TAK1 inhibitor or a TAK1 activation inhibitor.
  • the present invention provides a kit for inhibiting TAK1 or a kit for inhibiting TAK1 activation, which comprises a zearalenone having a hydroxyl group at each of positions 8 and 9 and an instruction manual.
  • FIG. 1 is a graph showing the inhibitory effect of compound (1) on signal transduction via TAK1.
  • zearalenones having a hydroxyl group at both the 8-position and 9-position include zearalenone (Zearal enone: the following formula (A)) or zearalenol (Ze arale nol: the following formula (B))
  • zearalenones having a hydroxyl group at both the 8-position and the 9-position include the compounds shown below:
  • Each of these compounds (1) to (13) is a compound known per se and described in the literature (for example, Int. J. Im Leak Pharmacol "21: 799-814, 1999; J. Org. Chem., 43: 2339). Chem. Pharm. Bull. 41: 373-375, 1993; J. Antibiotics, 52: 1077-1085, 1999; Biochem. Biophys. Res. Commun., 257: 19-23, 1999; Cytokine, 8: 751-761, 1996; Pharmacol. Commun., 7: 301-308, 1996; Japanese Patent Publication No. 8-40893; European Patent Publication No. 6 06444A; Biochemistry, 37: 9579-9585, 1998, etc.).
  • compounds (1) to (13) are preferable, compounds (1) to (3) are more preferable, and compound (1) is particularly preferable.
  • TAK1 inhibition means inhibiting the kinase activity of TAK1.
  • the TAK1 inhibitory activity can be measured, for example, by the method described in Example 1 below.
  • TAK1 activation inhibition refers to inhibiting TAK1-mediated intracellular signal transduction.
  • the TAK1 inhibitory activation inhibitory activity can be measured, for example, by the method described in Example 2 below.
  • the administration route and administration amount of the ⁇ kinase inhibitor or TAK1 activation inhibitor of the present invention are appropriately selected depending on the patient's body type, age, physical condition, type and degree of disease, elapsed time after onset, and the like. However, in the case of parenteral administration, a dose of 0.02 g to 2 mgZ body weight k days is generally expected, and in the case of oral administration, an effect of Sig SOOmgZ body weight k days is generally expected.
  • zearalenones having a hydroxyl group at both the 8-position and the 9-position may be used alone or in combination of two or more.
  • the TAK1 inhibitor or TAK1 activation inhibitor of the present invention may comprise one or more pharmaceutically acceptable diluents, wetting agents, emulsifiers, dispersants, adjuvants, preservatives, lubricants It can be administered as a pharmaceutical composition appropriately containing an impaction agent, a binder, a stabilizer and the like in an appropriate form depending on the intended administration route.
  • the kit of the present invention comprises a pharmaceutical composition
  • a pharmaceutical composition comprising a zearalenone having a hydroxyl group at each of the above-mentioned 8-position and 9-position, a diluent, and any one or more carriers including various carriers exemplified above. It contains the composition, as well as instructions for use.
  • TAK1 kinase activity was assessed by measuring TAK1 autophosphorylation and TAB1 phosphorylation. That is, a recombinant paculovirus vector containing the TAK1 and TAB1 genes (WO99 / 211010) was co-infected with insect cells Sf-9 and cultured for 3 days.
  • the cells are washed with PBS, and the extract solution is adjusted to 3.0 x 10 7 cells / mL (20 mM HEPES, pH 7.4, 150 mM NaCL 12.5 mM ⁇ -gycerophosphate, 1.5 mM MgCl 2 , 2 mM EGTA, 10 mM
  • the cells were suspended in mM NaF, 2 mM DTT, 1 mM Na 3 VO 4 1 mM PMSF, 20 ⁇ MAprotinin, 0.5% Triton X-100) to prepare a cell extract.
  • reaction was terminated by adding 50 L of a reaction stop solution (PBS containing 50% TCA) and further incubating at 4 for 10 minutes.
  • PBS containing 50% TCA a reaction stop solution
  • To remove free 33 P-ATP wash 5 times with PBS containing 0.05% Tween-20, add 50 ⁇ L of Supermix (Wallac), and incubate at room temperature for 30 minutes
  • TAK1 kinase activity was measured by measuring the amount of 33 P-ATP incorporated into TAK1 and TAB1 using micro-beta.
  • compounds (1) to (3) suppressed TAK1 kinase activity as shown in Table 1, and in particular, compound (1) exhibited IC 5 .
  • a TAK1 kinase inhibitory activity of 8.1 nM was shown.
  • Shimochi's Radicicol which is a compound that does not have a hydroxyl group at the position corresponding to the 8th and 9th positions of the compounds (1) to (3)
  • TAK1 activation of TAK1 induces activation of MAPK cascade and NF- ⁇ . Therefore, the effect of inhibition of TAK1 kinase activity on TAK1-mediated signal transduction was examined using the reporter Atsusei.
  • NFkB-Luc Genes Dev., 7, 1354-1363, 1993
  • NFkB-Luc incorporating a luciferase gene downstream of the response element was used to stimulate IL-1 or Activation of TAK1 was induced by forced expression of TAK1 / TAB1. That is, after seeding 1 x 10 6 293-IL1R cells (Mol. Cell, 5, 649-658, 2000), which forcibly expressed the IL-1 receptor in human embryonic kidney cell line 293 cells, and cultured overnight
  • a mixture of 2 g of NFkB-Luc and 10 FuGENE gene introduction reagents (Roche) was added to the cells, and the cells were further cultured for 8 hours to introduce the genes.
  • the cells into which the gene was introduced were detached with trypsin, the cells were seeded on a 96-well microplate (manufactured by Coaning Coaster) at 1 ⁇ 10 4 cells / well, and cultured overnight. After washing once with DMEM medium, compound (1) diluted with DMEM medium containing 0.2% fetal bovine serum was added in 50 portions. After incubating at 37 ° C for 1 hour, IL-1 (manufactured by PEPRO TECH) was added at 50 L each to a final concentration of 10 ng / mL, and the cells were further cultured for 24 hours. Luciferase activity is Steady Glo The measurement was performed using a Luciferase Assay Kit (promega).
  • FIG. 1 the vertical axis indicates the inhibitory activity ().
  • the horizontal axis represents the concentration of the compound (1) (M).
  • Closed squares indicate the inhibitory activity of p3TP-Lux Atsusei on TGF- / 3 signaling.
  • Closed triangles indicate the inhibitory activity of the IL-1 signaling system on NFkB-LucAssy.
  • the open triangle indicates the inhibitory activity of the signal transduction system by forced expression of TAK1 / TAB1 in NFkB-Luc assay.
  • compound (1) suppressed the expression of luciferase due to forced expression of TGF-3, IL-la, and TAK1 / TAB1 in a dose-dependent manner. This result suggests that inhibition of TAK1 kinase activity can inhibit downstream signal transduction.
  • the compound of the present invention has a TAK1 inhibitory activity, it inhibits various signal transduction systems through activation of TAK1 and various diseases involving activation of TAK1 as a cause of the disease, for example, TGF-j3, It is expected to be useful as an agent for treating and preventing various diseases known to be caused by IL-1, LPS, TNF- ⁇ and the like.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne des inhibiteurs TAK1 ou des inhibiteurs d'activation de TAK1 contenant, comme ingrédients actifs, des zéaralénones ayant des groupes hydroxyle au niveau des positions 8 et 9 ; une méthode permettant d'inhiber TAK1 ou d'inhiber l'activation de TAK1 en utilisant, comme ingrédients actifs, des zéaralénones ayant des groupes hydroxyle au niveau des positions 8 et 9 ; l'utilisation de zéaralénones ayant des groupes hydroxyle au niveau des positions 8 et 9 afin de produire des inhibiteurs TAK1 ou des inhibiteurs d'activation de TAK1 ; enfin des trousses permettant d'inhiber TAK1 ou des trousses permettant d'inhiber l'activation de TAK1, lesquelles trousses contiennent des zéaralénones ayant des groupes hydroxyle au niveau des positions 8 et 9 et un manuel.
PCT/JP2001/010927 2000-12-14 2001-12-13 Inhibiteurs tak1 WO2002048135A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002222627A AU2002222627A1 (en) 2000-12-14 2001-12-13 Tak1 inhibitors

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Application Number Priority Date Filing Date Title
JP2000-379995 2000-12-14
JP2000379995A JP2004292315A (ja) 2000-12-14 2000-12-14 Ｔａｋ１阻害剤

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037255A3 (fr) * 2001-10-31 2004-01-22 Millennium Pharm Inc Procedes et compositions de diagnostic et de traitement de troubles hematologiques au moyen de 16319
WO2004083854A1 (fr) * 2003-03-17 2004-09-30 Novartis Ag Identification de composes organiques capables de moduler l'activite de tak1
WO2006036941A3 (fr) * 2004-09-27 2006-10-26 Kosan Biosciences Inc Inhibiteurs de kinases specifiques
US7235556B2 (en) 2003-04-16 2007-06-26 Alcon, Inc. Methods of treating dry eye disorders
WO2009105755A2 (fr) 2008-02-21 2009-08-27 Nexgenix Pharmaceuticals Composés de promédicaments macrocycliques utilisés comme agents thérapeutiques
US7601852B2 (en) 2006-05-11 2009-10-13 Kosan Biosciences Incorporated Macrocyclic kinase inhibitors
US7799827B2 (en) 2002-03-08 2010-09-21 Eisai Co., Ltd. Macrocyclic compounds useful as pharmaceuticals
US7915306B2 (en) 2002-03-08 2011-03-29 Eisai Co., Ltd. Macrocyclic compounds useful as pharmaceuticals
WO2011036299A1 (fr) * 2009-09-28 2011-03-31 Universite De Strasbourg Inhibiteurs irréversibles utilisés pour traiter des pathologies associées à une kinase
US8067412B2 (en) 2006-08-11 2011-11-29 Universite De Strasbourg Macrocyclic compounds useful as inhibitors of kinases and HSP90
US8507696B2 (en) 2007-12-07 2013-08-13 Eisai R&D Management Co., Ltd. Intermediates in the synthesis zearalenone macrolide analogs
US8609640B2 (en) 2007-07-25 2013-12-17 Eisai, Inc. Multikinase inhibitors for use in the treatment of cancer
WO2015052714A1 (fr) 2013-10-07 2015-04-16 Mor Research Applications Ltd. Traitements de vitréoréthinopathie proliférante
US10206900B2 (en) 2013-10-07 2019-02-19 Mor Research Applications Ltd. Treatments for fibrotic diseases

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008018517A1 (fr) * 2006-08-09 2008-02-14 Zeria Pharmaceutical Co., Ltd. Agent thérapeutique et/ou préventif pour une maladie s'accompagnant d'une croissance cellulaire exagérée, et polynucléotide utile en tant que principe actif
US8513440B2 (en) 2007-06-05 2013-08-20 Universite De Strasbourg Compositions and methods comprising analogues of radicicol A

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0606044A1 (fr) * 1992-12-04 1994-07-13 Sandoz Ltd. Composés de lactones utiles comme agents pharmaceutiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0606044A1 (fr) * 1992-12-04 1994-07-13 Sandoz Ltd. Composés de lactones utiles comme agents pharmaceutiques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MATSUOKA MASATO ET AL.: "Inhibition of HgC12-induced mitogen-activated protein kinase by LL-Z1640 in CCRF-CEM cells", EUR. J. PHARMACOL., vol. 409, 2000, pages 155 - 158, XP002908835 *
RAWLINS PHILIP ET AL.: "Inhibition of endotoxin-induced TNF-alpha production in macrophages by 5Z-7-oxo-zeaenol and other fungal resorcyclic acid lactones", INTERNATINAL JOURNAL OF IMMUNOPHARMACOLOGY, vol. 21, 1999, pages 799 - 814, XP002908837 *
YAMAGUCHI KYOKO ET AL.: "Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction", SCIENCE, vol. 270, 1995, pages 2008 - 2011, XP002103399 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037255A3 (fr) * 2001-10-31 2004-01-22 Millennium Pharm Inc Procedes et compositions de diagnostic et de traitement de troubles hematologiques au moyen de 16319
US8329742B2 (en) 2002-03-08 2012-12-11 Eisai Co., Ltd. Macrocyclic compounds useful as pharmaceuticals
US7799827B2 (en) 2002-03-08 2010-09-21 Eisai Co., Ltd. Macrocyclic compounds useful as pharmaceuticals
US7915306B2 (en) 2002-03-08 2011-03-29 Eisai Co., Ltd. Macrocyclic compounds useful as pharmaceuticals
WO2004083854A1 (fr) * 2003-03-17 2004-09-30 Novartis Ag Identification de composes organiques capables de moduler l'activite de tak1
US7235556B2 (en) 2003-04-16 2007-06-26 Alcon, Inc. Methods of treating dry eye disorders
WO2006036941A3 (fr) * 2004-09-27 2006-10-26 Kosan Biosciences Inc Inhibiteurs de kinases specifiques
JP2008514635A (ja) * 2004-09-27 2008-05-08 コーザン バイオサイエンシス インコーポレイテッド 特異的キナーゼ阻害剤
US7601852B2 (en) 2006-05-11 2009-10-13 Kosan Biosciences Incorporated Macrocyclic kinase inhibitors
US8450305B2 (en) 2006-08-11 2013-05-28 Universite De Strasbourg Macrocyclic compounds useful as inhibitors of kinases and HSP90
US8067412B2 (en) 2006-08-11 2011-11-29 Universite De Strasbourg Macrocyclic compounds useful as inhibitors of kinases and HSP90
US8937056B2 (en) 2007-07-25 2015-01-20 Eisai R&D Management Co., Ltd. Multikinase inhibitors for use in the treatment of cancer
US8609640B2 (en) 2007-07-25 2013-12-17 Eisai, Inc. Multikinase inhibitors for use in the treatment of cancer
US11160783B2 (en) 2007-07-25 2021-11-02 Eisai R&D Management Co., Ltd. Multikinase inhibitors for use in the treatment of cancer
US8507696B2 (en) 2007-12-07 2013-08-13 Eisai R&D Management Co., Ltd. Intermediates in the synthesis zearalenone macrolide analogs
WO2009105755A2 (fr) 2008-02-21 2009-08-27 Nexgenix Pharmaceuticals Composés de promédicaments macrocycliques utilisés comme agents thérapeutiques
WO2011036299A1 (fr) * 2009-09-28 2011-03-31 Universite De Strasbourg Inhibiteurs irréversibles utilisés pour traiter des pathologies associées à une kinase
WO2015052714A1 (fr) 2013-10-07 2015-04-16 Mor Research Applications Ltd. Traitements de vitréoréthinopathie proliférante
EP3054942A4 (fr) * 2013-10-07 2017-03-08 Mor Research Applications Ltd. Traitements de vitréoréthinopathie proliférante
US10206900B2 (en) 2013-10-07 2019-02-19 Mor Research Applications Ltd. Treatments for fibrotic diseases
IL247063B (en) * 2013-10-07 2022-09-01 Mor Research Applic Ltd Treatments for Pi. Wee. R. (pvr)

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AU2002222627A1 (en) 2002-06-24

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