WO2002048136A1 - Inhibiteurs de la proliferation des keratinocytes - Google Patents

Inhibiteurs de la proliferation des keratinocytes Download PDF

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Publication number
WO2002048136A1
WO2002048136A1 PCT/JP2001/010928 JP0110928W WO0248136A1 WO 2002048136 A1 WO2002048136 A1 WO 2002048136A1 JP 0110928 W JP0110928 W JP 0110928W WO 0248136 A1 WO0248136 A1 WO 0248136A1
Authority
WO
WIPO (PCT)
Prior art keywords
zearalenones
keratinocytes
proliferation
skin disease
keratinocyte
Prior art date
Application number
PCT/JP2001/010928
Other languages
English (en)
Japanese (ja)
Inventor
Masayuki Tsuchiya
Toshihiko Ohtomo
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 AU2002222628A priority Critical patent/AU2002222628A1/en
Publication of WO2002048136A1 publication Critical patent/WO2002048136A1/fr

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Classifications

    • 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
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • 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

Definitions

  • the present invention provides a keratinocyte proliferation inhibitor containing zearalenone as an active ingredient, a therapeutic or prophylactic agent for a skin disease associated with abnormal proliferation of keratinocytes, containing zearalenone as an active ingredient, and administering an effective amount of zearalenone.
  • a method of treating and preventing a skin disease associated with abnormal proliferation of keratinocytes which comprises administering an effective amount of zelarenones, the use of zelarenones for producing a keratinocyte proliferation inhibitor, and the use of keratinocytes.
  • zearalenones for the manufacture of a therapeutic or prophylactic agent for a skin disease associated with abnormal growth, an effective amount of zearalenones, a kit for inhibiting the growth of keratinocytes including instructions for use, and an effective amount of zearalenones Abnormal growth of keratinocytes, including Cormorants relates to a kit for the treatment or prevention of skin disorders.
  • keratinocytes which are skin epithelial cells
  • keratinocytes which are skin epithelial cells
  • the keratinocyte cell proliferation control mechanism has been disrupted, and skin thickening due to pathological abnormal proliferation of skin epithelial cells has been observed.
  • cytokins such as epidermal growth factor and other growth factors such as leukin 1, 4, 6, and 8
  • leukin 1, 4, 6, and 8 Although recognized (Gen. Pharmac., (1998) 5, 619-622), the detailed mechanism of keratinocyte proliferation in the above-mentioned diseases is unknown.
  • a substance that suppresses the pathological cell proliferation of keratinocytes it can be expected to be used as a therapeutic agent for various skin diseases characterized by abnormal proliferation of keratinocytes. Furthermore, any substance that does not affect the proliferation of stromal cells such as fibroblasts is expected to be useful in reducing side effects.
  • An object of the present invention is to provide a keratinocyte proliferation inhibitor. Another object of the present invention is to provide an agent for treating or preventing a skin disease associated with keratinocyte proliferation.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that certain zearalenones have a keratinocyte-specific cell growth inhibitory action, and completed the present invention based on this finding. .
  • the present invention provides a keratinocyte proliferation inhibitor comprising a zearalenone as an active ingredient. Further, the present invention provides a therapeutic or preventive agent for a skin disease associated with abnormal proliferation of keratinocytes, comprising a zearalenone as an active ingredient.
  • the present invention provides a method for inhibiting keratinocyte proliferation, which comprises administering an effective amount of a zearalenone to a patient in need thereof. Further, the present invention provides a method for treating and preventing a skin disease associated with abnormal proliferation of keratinocytes, which comprises administering an effective amount of zearalenones to a patient in need thereof.
  • the present invention relates to zearalenone for producing a keratinocyte proliferation inhibitor. Provides a kind of use.
  • the present invention also provides use of zearalenones for producing a therapeutic or prophylactic agent for a skin disease associated with keratinocyte overgrowth.
  • the present invention provides a kit for inhibiting the growth of keratinocytes, comprising an effective amount of zearalenones and instructions for use.
  • the present invention also provides a kit for treating or preventing a skin disease associated with keratinocyte overgrowth, comprising an effective amount of zearalenones and instructions for use.
  • FIG. 1 is a graph showing the inhibitory effect of compound (1) on human keratinocyte proliferation.
  • FIG. 2 is a graph showing the inhibitory effect of compound (1) on human keratinocyte proliferation.
  • FIG. 3 is a graph showing the effect of compound (1) on human keratinocyte. It is a graph which shows cytotoxicity.
  • FIG. 4 is a graph showing the effect of compound (1) on cell proliferation of human fibroblasts.
  • zearalenones include zearalenone and its derivatives, for example, as shown below:
  • compounds (1) to (3) are preferable, and compound (1) is particularly preferable.
  • Skin diseases associated with abnormal proliferation of keratinocytes include the failure of the cell proliferation control mechanism of keratinocytes and the pathological abnormal proliferation of skin epithelial cells. Includes various diseases with thickening. Non-limiting examples of such skin diseases include psoriasis, immune skin diseases, allergic skin diseases, inflammatory skin diseases, chronic wounds, and the like. Keratinocyte proliferation inhibitors are expected to be effective as therapeutic or prophylactic agents.
  • the administration form of the medicament containing the keratinocyte proliferation inhibitor of the present invention is not particularly limited, and may be oral administration, parenteral administration, systemic administration, or local administration.
  • the medicament of the present invention can be generally administered parenterally, can be administered transdermally as a spray, talmes, lotions, ointments, etc., or intravenously or intramuscularly as an injection Or it can be administered subcutaneously.
  • the dose can be appropriately selected depending on the patient's body type, age, physical condition, type and degree of the disease, elapsed time after onset, and the like.In the case of parenteral administration, the dose is generally from 0.01 to 0.1 gg. A dose of O mgZ body weight kg / day, and in the case of oral administration, a dose of 1 ng to 10 g / body weight kgZ day can generally be expected to be effective.
  • zearalenones may be used alone or in combination of two or more.
  • the keratinocyte proliferation inhibitor and the therapeutic or prophylactic agent for a skin disease associated with keratinocyte abnormal growth of the present invention comprise one or more pharmaceutically acceptable diluents, wetting agents, emulsifiers, dispersants, and auxiliary agents.
  • the composition can be administered as a pharmaceutical composition appropriately containing an agent, a preservative, a buffer, a binder, a stabilizer and the like in an appropriate form depending on the intended administration route.
  • kit of the present invention includes a pharmaceutical composition comprising zearalenones, a diluent, and any one or more carriers including the various carriers exemplified above, and instructions for use.
  • Example 1 Effect of the compound of the present invention on cell proliferation of normal human keratinocytes
  • Normal human keratinocytes manufactured by Sanko Junyaku Co., Ltd.
  • compound (1) is finalized.
  • WST-8 manufactured by Nacalai Tesque
  • the reaction was stopped by adding 1/10 volume. Immediately thereafter, the absorbance at 450 nm (reference wavelength: 655 nm) was measured using a microplate reader. A background obtained by performing the same treatment on a medium containing no cells was used as a background, and a value obtained by subtracting the background from the measured value was calculated.
  • Compound (1) is 10- 7 ⁇ : L0- 5 mol / L concentration significantly inhibited the growth of Hitokerachinosai Bok of (multiple comparisons Dunnett, ⁇ 0.00l), the IC 5. The value was 4.8 ⁇ 10 ⁇ 8 mol / L.
  • compound (1) is 10 ⁇ 7 ⁇ : L0- 5 mol / at a concentration of L significantly inhibited [3 H] thymidine uptake of human keratinocytes (multiple comparisons Dumiett, p rather 0.001), its IC50 The value was 3.2 ⁇ 10 ′ 8 mol / L.
  • compound (2) and compound (3) are 10 ⁇ 7 ⁇ : L0- 5 mol / at a concentration of L significantly inhibited [3 H] thymidine uptake of human keratinocytes (multiple comparisons Dumiett, p rather 0.001), its IC50 The value was 3.2 ⁇ 10 ′ 8 mol / L.
  • compound (2) and compound (2) is 10 ⁇ 7 ⁇ : L0- 5 mol / at a concentration of L significantly inhibited [3 H] thymidine uptake of human keratinocytes (multiple comparisons Dumiett, p rather 0.001), its IC50 The value was 3.2 ⁇ 10
  • Example 2 Examination of cytotoxicity of the compound of the present invention in normal human keratinocytes The cytotoxicity of compound (1) was evaluated by measuring the amount of LDH leaked out of cells. That is, seeded with KGM-2 medium normal human keratinocytes in a 96-well plate at 2X 10 3 per 1 Ueru, final concentration 10, 9-10, 5 Compound (1) after the cells have adhered mol / L. After culturing for 3 days, LDH activity leaked into the medium was measured by LDH-cytotoxicity test ⁇ KO (manufactured by Wako Pure Chemical Industries, Ltd.) using 50 L of 200 L of the culture supernatant. As a positive control, the final concentration of the control was 0.1 ° /. Tween 20 was added to the mixture, and the mixture was treated at 37 ° C. for 15 minutes. The LDH activity of the medium without cells alone was used as the background, and the value obtained by subtracting the background from the measured value was calculated.
  • LDH activity of the medium without cells alone
  • Compound (1) showed cytotoxicity to human keratinocytes at concentrations of 10- 5 mol / L (multiple comparisons Dunnett, p ⁇ 0.001), was almost completely inhibited keratinocyte proliferation concentrations ( At 10 ⁇ 7 to 10 ⁇ 6 mol / L), no cytotoxicity was observed.
  • Example 3 Investigation of the effect of the compound of the present invention on the cell proliferation of normal human fibroblasts A 96-well microplate was prepared so that the number of human fibroblast cell lines WI-38 cells (ATCC) was 2 x 10 3 cells / well. (Falcon) using DMEM medium containing 10% fetal bovine serum. After overnight incubation to allow the cells to be attached thereto were added the compound (1) in such a way that 10- 9 ⁇ 10 6 mol / L , or DMSO as a control such that the final concentration of 1%. After culturing for 3 days, a viable cell counting reagent SF (WST-8, manufactured by Nacalai Tesque) was added to 1/10 of the medium.
  • WI-38 cells ATCC
  • DMEM medium containing 10% fetal bovine serum
  • Fig. 4 shows the results.
  • keratinocytes since it has an activity of specifically suppressing the cell proliferation action of keratinocytes, various diseases characterized by abnormal proliferation of keratinocytes (for example, psoriasis, inflammatory, allergic skin diseases, chronic wounds, etc.) ) Is expected to be useful as a therapeutic or prophylactic agent. Further, since it does not substantially affect the proliferation of stromal cells such as fibroblasts, it is expected to be useful as an agent for treating or preventing the above-mentioned diseases with few side effects.
  • diseases characterized by abnormal proliferation of keratinocytes for example, psoriasis, inflammatory, allergic skin diseases, chronic wounds, etc.
  • stromal cells such as fibroblasts

Abstract

La présente invention concerne des inhibiteurs de la prolifération des kératinocytes qui renferment, en tant qu'ingrédient actif, une ou plusieurs zéaralénones; des remèdes ou des prophylactiques pour les maladies cutanées associées à une prolifération anormale des kératinocytes; une méthode permettant d'inhiber la prolifération des kératinocytes qui consiste à utiliser une ou plusieurs zéaralénones selon une posologie efficace; une méthode de traitement ou de prévention des maladies cutanées associées à la prolifération anormale des kératinocytes qui consiste à administrer une ou plusieurs zéaralénones selon une posologie efficace aux patients nécessitant un tel traitement; des trousses permettant d'inhiber la prolifération des kératinocytes qui renferment une ou plusieurs zéaralénones selon une posologie efficace et une notice; des trousses utiles pour traiter ou pour prévenir les maladies cutanées associées à la prolifération anormale des kératinocytes; et l'utilisation d'une ou plusieurs zéaralénones pour produire des inhibiteurs de la prolifération des kératinocytes ou bien des remèdes ou encore des prophylactiques destinés aux maladies cutanées associées à la prolifération anormale des kératinocytes.
PCT/JP2001/010928 2000-12-14 2001-12-13 Inhibiteurs de la proliferation des keratinocytes WO2002048136A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002222628A AU2002222628A1 (en) 2000-12-14 2001-12-13 Keratinocyte proliferation inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-379994 2000-12-14
JP2000379994A JP2004292314A (ja) 2000-12-14 2000-12-14 ケラチノサイト増殖抑制剤

Publications (1)

Publication Number Publication Date
WO2002048136A1 true WO2002048136A1 (fr) 2002-06-20

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Application Number Title Priority Date Filing Date
PCT/JP2001/010928 WO2002048136A1 (fr) 2000-12-14 2001-12-13 Inhibiteurs de la proliferation des keratinocytes

Country Status (3)

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JP (1) JP2004292314A (fr)
AU (1) AU2002222628A1 (fr)
WO (1) WO2002048136A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003076424A1 (fr) * 2002-03-08 2003-09-18 Eisai Co. Ltd. Composes macrocycliques utiles comme produits pharmaceutiques
EP1450784A2 (fr) * 2001-11-09 2004-09-01 Conforma Therapeutics Corporation Composes de zearalanol inhibant hsp90 et leurs procedes de production et d'utilisation
US7601852B2 (en) 2006-05-11 2009-10-13 Kosan Biosciences Incorporated Macrocyclic kinase inhibitors
US7915306B2 (en) 2002-03-08 2011-03-29 Eisai Co., Ltd. Macrocyclic compounds useful as pharmaceuticals
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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008150291A (ja) * 2005-03-22 2008-07-03 Kyowa Hakko Kogyo Co Ltd 乾癬治療剤
WO2014069510A1 (fr) 2012-10-31 2014-05-08 富山化学工業株式会社 Nouveau dérivé d'amine ou sel correspondant

Citations (5)

* 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
EP0646576A1 (fr) * 1993-10-01 1995-04-05 F. Hoffmann-La Roche Ag Analogues de la vitamine D3
JPH0840893A (ja) * 1993-08-31 1996-02-13 Takeda Chem Ind Ltd インターロイキン−１産生抑制剤
WO1996013259A2 (fr) * 1994-10-28 1996-05-09 Cor Therapeutics, Inc. Procede et combinaisons servant a inhiber les proteine kinases
WO1998004264A1 (fr) * 1996-07-30 1998-02-05 Geomed Inc Procedes et compositions permettant d'inhiber la proliferation de keratinocytes

Patent Citations (5)

* 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
JPH0840893A (ja) * 1993-08-31 1996-02-13 Takeda Chem Ind Ltd インターロイキン−１産生抑制剤
EP0646576A1 (fr) * 1993-10-01 1995-04-05 F. Hoffmann-La Roche Ag Analogues de la vitamine D3
WO1996013259A2 (fr) * 1994-10-28 1996-05-09 Cor Therapeutics, Inc. Procede et combinaisons servant a inhiber les proteine kinases
WO1998004264A1 (fr) * 1996-07-30 1998-02-05 Geomed Inc Procedes et compositions permettant d'inhiber la proliferation de keratinocytes

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7553979B2 (en) 2001-11-09 2009-06-30 Conforma Therapeutics Corporation HSP90-inhibiting zearalanol compounds and methods of producing and using same
EP1450784A2 (fr) * 2001-11-09 2004-09-01 Conforma Therapeutics Corporation Composes de zearalanol inhibant hsp90 et leurs procedes de production et d'utilisation
EP1450784A4 (fr) * 2001-11-09 2005-02-09 Conforma Therapeutics Corp Composes de zearalanol inhibant hsp90 et leurs procedes de production et d'utilisation
US7799827B2 (en) 2002-03-08 2010-09-21 Eisai Co., Ltd. Macrocyclic compounds useful as pharmaceuticals
AU2003224672B2 (en) * 2002-03-08 2010-02-04 Eisai R&D Management Co., Ltd. Macrocyclic compounds useful as pharmaceuticals
WO2003076424A1 (fr) * 2002-03-08 2003-09-18 Eisai Co. Ltd. Composes macrocycliques utiles comme produits pharmaceutiques
US7915306B2 (en) 2002-03-08 2011-03-29 Eisai Co., Ltd. Macrocyclic compounds useful as pharmaceuticals
EP2308861A1 (fr) * 2002-03-08 2011-04-13 Eisai R&D Management Co., Ltd. Composés macrocycliques utiles en tant qu'agents pharmaceutiques
US8329742B2 (en) 2002-03-08 2012-12-11 Eisai Co., Ltd. Macrocyclic compounds useful as pharmaceuticals
US7601852B2 (en) 2006-05-11 2009-10-13 Kosan Biosciences Incorporated Macrocyclic kinase inhibitors
US8609640B2 (en) 2007-07-25 2013-12-17 Eisai, Inc. Multikinase inhibitors for use in the treatment of cancer
US8937056B2 (en) 2007-07-25 2015-01-20 Eisai R&D Management Co., Ltd. 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

Also Published As

Publication number Publication date
AU2002222628A1 (en) 2002-06-24
JP2004292314A (ja) 2004-10-21

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