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Development of Novel Nuclear Receptor Modulators

Research Project

Project/Area Number 10557231
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section展開研究
Research Field 医薬分子機能学
Research InstitutionUniversity of Tokyo

Principal Investigator

KAGECHIKA Hiroyuki  University of Tokyo, Graduate School of Pharmaceutical Sciences Associate Professor, 大学院・薬学系研究科, 助教授 (20177348)

Co-Investigator(Kenkyū-buntansha) 首藤 紘一  厚生省, 国立医薬品食品衛生研究所・医薬品医療機器審査センター, センター長(研究職)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥8,100,000 (Direct Cost: ¥8,100,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1999: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1998: ¥3,200,000 (Direct Cost: ¥3,200,000)
Keywordsnuclear receptors / retinoid / retinoic acid / retinoid antagonist / retinoid synergist / thyroid hormone / RXR / チアゾリジン / チロイドホルモン
Research Abstract

Retinoic acid acts as a specific modulator of cellular differentiation and proliferation. Its natural and synthetic analogs, classified as retinoids, have already proven their efficacy in the treatment of dermatological diseases as well as skin cancer and leukemia. In this project we have designed and synthesized several kinds of novel compounds which regulate the activities of retinoids.
Dibenzodiazepine derivatives exhibited unique retinoid-reguratory activity, depending on the substituents. LE135is RARβ (and α)-selective retinoid antagonist. On the other hand, HX600, which is a strtuctural isomer of LE135, exhibited retinoid synergistic activity. Mechanistic investigation showed that HX600 binds to RXR site of RXR-RAR heterodimers to synergize with RAR ligands. During the investigation on the structure-activity relationships of retinoid synergists, we found a nitrated anaolg of HX600, yielding HX531, is an RXR antagonist which can inhibit the differentiation-inducing activities of retinoids. Diphenylamine derivatives are another class of retinoid synergists. In this series, size and bulkiness of the N-alkyl group are significant for the activity. Among them, DA023 and DA124 exhibited higher synergistic potency than LGD1069, a typical RXR agonist.
Finally, we developed several thiazolidine derivatives with retinoid agonistic or synergistic activities. Some thiazolidinedione derivatives are known as the specific ligands for peroxisome proliferator-activated receptor γ (PPARγ). Compounds such as TZ191 and TZ335 are RXR agonists and exhibited potent retinoid synergistic activity in HL-60 assay.
The compounds described here regulate specifically the action of retinoids. Especially, since retinoid synergists can potenciate retinoidal action at low concentration, they may find application in the field of retinoid therapy. RXR ligand can modulate the action of other nuclear receptor ligands besides retinoids. Further investigations on their actions are in progress.

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Kiminori Ohta: "Potent Retimid Synergists with A Diphenylamine Skeleton"Biol.Pharm.Bull.. 21. 544-546 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Masayuki Ebisawa: "Novel Thiazolidinedione Derivatives with Retinoid Synergistic Activity"Biol.Pharm.Bull.. 21. 547-549 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Masayuki Ebisawa: "Thiazolidinediones with thyroid hormone receptor agonistic activity"Chem.Pharm.Bull.. 47. 1348-1350 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Masayuki Ebisawa: "Retinoid X Receptor-Antagonistic Diazepinyl benzoic Acids"Chem.Pharm.Bull.. 47. 1778-1786 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yasuyuki Endo: "Polymethylcarborane as a novel bioactive moiety : derivatives with potent retinoid antagonistic activity"Bioory.Med.Chem.Lett.. 10. 1733-1736 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kiminori Ohta: "Retinoidal Piporidinecarbixylic Acids, Unexpected Diaza-Substituent Effects in Retinobenzoic Acids"Chem.Pharm.Bull.. 48. 1504-1513 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohta, K. ; Tsuji, M. ; Kawachi, E. ; Fukasawa, H. ; Hashimoto, Y. ; Shudo, K. ; Kagechika, H.: "Potent Retinoid Synergists with A Diphenylamine Skeleton"Bio.Pharm.Bull.. 21. 544-546 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ebisawa, M. ; Kawachi, E. ; Fukasawa, H. ; Hashimoto, Y. ; Itai, A. ; Shudo, K. ; Kagechika, H.: "Novel Thiazolidinedione Derivatives with Retinoid Synergistic Activity"Bio.Pharm.Bull.. 21. 547-549 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iijima, T. ; Endo, Y. ; Tsuji, M. ; Kawachi, E. ; Kagechika H. ; Shudo, K.: "Dicarba-clso-dodecaboranes as a Pharmacophore. Retinoidal Antagonists and Potential Agonists"Chem.Pharm.Bull.. 47. 398-404 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Endo, Y. ; Iijima, T. ; Kagechika, H. ; Ohta, K. ; Kawachi E. ; Shudo, K.: "Dicarba-closo-dodecaboranes as a Pharmacophore. Novel Potent Retinoidal Agonists"Chem.Pharm.Bull.. 47. 585-587 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Li, Y. ; Hashimoto, Y. ; Agadir, A. ; Kagechika, H. ; Zhang, X.-K.: "Identification of a Novel Class of RARb-selective Retinoid Antagonists and their Inhibitory Effects on AP-1 activity and Retinoic Acid-induced Apoptosis in Human Breast Cancer Cells"J.Biol.Chem.. 274. 15360-15367 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ebisawa, M. ; Umemiya, H. ; Ohta, K. ; Fukasawa, H. ; Kawachi, E. ; Christoffel, G. ; Gronemeyer, H. ; Tsuji, M. ; Hashimoto, Y. ; Shudo, K. ; Kagechika, H.: "Retinoid X Receptor-Antagonistic Diazepinylbenzoic Acids"Chem.Pharm.Bull.. 47. 1778-1786 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ebisawa, M. ; Inoue, N. ; Fukasawa, H. ; Sotome, T. ; Kagechika, H.: "Thiazolidinediones with Thyroid Hormone Receptor Agonistic Activity"Chem.Pharm.Bull.. 47. 1348-1350 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Endo, Y. ; Yaguchi, K. ; Kawachi, E. ; Kagechika, H.: "Polymethylcarborane as a novel bioactive moiety : derivatives with potent retinoid antagonistic activity."Bioorg.Med.Chem.Lett.. 10. 1733-1736 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohta, K. ; Kawachi, E. ; Inoue, N. ; Fukasawa, H. ; Hashimoto, Y. ; Itai, A. ; Kagechika, H.: "Retinoidal Piperidinecarboxylic Acids. Unexpected Diaza-Substituent Effects in Retinobenzoic Aicds."Chem.Pharm.Bull.. 48. 1504-1513 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kagechika, H.: "Therapeutic Application of Synthetic Retinoids"IDrug. 3. 73-83 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hiroyuki Kagechika: "Therapeutic Application of Synthetic Retinoids"IDruga. 3(1). 73-83 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yasuyuki Endo: "Polymethylcarborane as a novel bioactive moiety : derivatiues with potent retinoid antagonistic activity."Bioorg.Med.Chem.Lett.. 10(15). 1733-1736 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kiminori Ohta: "Retinoidal Piperidinecarboxylic Acids. Unexpected Diaza-Substituent Effets in Retinobenzoic Acids"Chem.Pharm.Bull.. 48(10). 1504-1513 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yin Li: "Indentification of a novel class of RARβ-selective Retinoid Antagonists and their inhibitory effects on AP-1 activity and retinoic acid -induced apoptosis in human breast cancer cell"Journal of Biological Chemistry. 274・22. 15360-15367 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masayuki Ebisawa: "Thiazolidinediones with thyroid hormone receptor agonistic activity"Chem.Pharm.Bull.. 47・9. 1348-1350 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masayuki Ebisawa: "Retinoid X Receptor-Antagonistic Diazepinyl benzoic Acids"Chem.Pharm.Bull.. 47・12. 1778-1786 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kiminori Ohta: "Potent Retinoid Synergisfs with A Diphanyl amine Skeleton" Bio.Pharm.Bull.21(5). 544-546 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Masayuki Ebisawa: "Novel Thiazolidinedivne Derivatives with Retinoid Synergistic Activity" Bio.Pharm.Bull.21(5). 547-549 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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