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2003 Fiscal Year Final Research Report Summary

Development of Novel Nuclear Receptor Regulators and Their Clinical Utility

Research Project

Project/Area Number 13557208
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 InstitutionThe University of Tokyo

Principal Investigator

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

Project Period (FY) 2001 – 2003
Keywordsnuclear receptors / retinoids / bioisoster / tropolone / floxane / carborane / synergist / antidiabetes
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. LE135 is RARβ (and α)-selective retinoid antagonist. On the other hand, HX600, which is a structural 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 LGD1O69, 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.

  • Research Products

    (10 results)

All Other

All Publications (10 results)

  • [Publications] Ebisawa, M.: "Novel Retinoidal Tropolone Derivatives. Bioisosteric Relationship of Tropolone Ring with Benzoic Acid Moiety in Retinoid Structure"Chem.Pharm.Bull.. 49. 501-503 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kagechika, H.: "Novel Synthetic Retinoids and Separation of the Pleiotropic Retinoidal Activities"Curr.Med.Chem.. 9. 591-608 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takahashi, B.: "Novel Retinoid X Receptor Antagonists : Specific Inhibition of Retinoid Synersism in RXR-RAR Heterodimer Actions"J.Med.Cher.. 45. 3327-3330 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamakoshi, Y.: "Determination of Endogenous Levels of Retinoic Acid Isomers in Type II Diabetes Mellitus Patients. Possible Correlation with HbA 1c Values"Biol.Pharm.Bull.. 25. 1268-1271 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Endo, Y.: "Utility of Boron Clusters for Drug Design. Relation Between Estrogen Receptor Binding Affinity and Hydrophobicity of Phenols Bearing Various Types of Carboranyl Groups"Bioorg.Med.Chem.Lett.. 13. 4089-4092 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ebisawa, M.; Ohta, K.; Kawachi, E.; Fukasawa, H.; Hashimoto, Y.; Kagechika, H.: "Novel Retinoidal Tropolone Derivatives. Bloisosteric Relationship of Tropolone Ring with Benzoic Acid Moiety in Retinoid Structure."Chem. Pharm. Bull.. 49. 501-503 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kagechika, H.: "Novel Synthetic Retinoids and Separation of the Pleiotropic Retinoidal Activities"Curr Med. Chem.. 9. 591-608 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takahashi, B.; Ohta, K.; Kawachi, E.; Fukasawa, H.; Hashimoto, Y.; Kagechika, H.: "Novel Retinoid X Receptor Antagonists: Specific Inhibition of Retinoid Synersism in RXR-RAR Heterodimer Actions."J. Med. Chem. 45. 3327-3330 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamakoshi, Y.; Fukasawa, H.; Yamauchi, T.; Waki H.; Kadowaki, T.; Shudo, K.; Kagechika, H.: "Determination of Endogenous Levels of Retinoic Acid Isomers in Type II Diabetes Meilitus Patients. Possible Correlation with HbA1c Values"Biol. Pharm. Bull.. 25. 1268-1271 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Endo, Y.; Yamamoto, K.; Kagechika, H.: "Utility of Boron Clusters for Drug Design. Relation Between Estrogen Receptor Binding Affinity and Hydrophobicity of Phenols Bearing Various Types of Carboranyl Groups"Bioorg. Med. Chem. Lett.. 13. 4089-4092 (2003)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2005-04-19  

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