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Development of antidiabetic agents targeting PPARγ

Research Project

Project/Area Number 16590003
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionTokyo Medical and Dental University

Principal Investigator

YAMAMOTO Keiko  Tokyo Medical and Dental University, Institute of Biomaterials and Bioengineering, Associate Professor, 生体材料工学研究所, 助教授 (90147017)

Co-Investigator(Kenkyū-buntansha) YAMADA Sachiko  Tokyo Medical and Dental University, Institute of Biomaterials and Bioengineering, Professor Emeritus, 生体材料工学研究所, 名誉教授 (10014078)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsPPAR / unsaturated fatty acid / Mitsunobu Reaction / luciferase assay / drug design / nuclear receptor / metabolic syndrome / 糖尿病 / 脂肪酸
Research Abstract

We have reported that we designed docosahexaenoic acid (DHA) derivatives as PPARγ ligands based on the x-ray crystal structure of the ligand binding domain of PPARγ, and synthesized them from DHA. Furthermore, we found one of them, 4-OH derivative, has significant potency for PPARγ transactivation. In addition to 4-OH group, a conjugate diene structure around C(5)-position was found to be important for the transactivation indicating conformationally restricted analogs might show more potent activity. Thus, we designed new hybrid compounds composed of a head group of cinnamic acid and a tail group from polyunsaturated fatty acid. Side chain part of polyunsaturated fatty acid as a tail group was derived from eicosapentaenoic acid by iodolactonization, hydrolysis, glycol-cleavage, reduction and then bromination. Cinnamic acid derivative as a head group and the side chain bromide of polyunsaturated fatty acid as a tail group were bonded by Williamson ether production method or Mitsunobu reaction. Thus, we synthesized more than twenty new compounds. PPAR transactivation potency of these synthesized compounds was evaluated by the luciferase assay method. We found that PPARγ transactivation potencies of all compounds are weak while some of them significantly transactivate PPARα which is a subtype of PPARγ.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (8 results)

All 2006 2005 2004

All Journal Article (8 results)

  • [Journal Article] Synthesis of docosahexaenoic acid derivatives designed as novel PPARγ agonists and antidiabetic agents2006

    • Author(s)
      Toshimasa Ito
    • Journal Title

      Bioorganic Medicinal Chemistry 14

      Pages: 98-108

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis of docosahexaenoic acid derivatives designed as novel PPARγ agonists and antidiabetic agents.2006

    • Author(s)
      Toshimasa Itoh
    • Journal Title

      Bioorganic Medicinal Chemistry. 14

      Pages: 98-108

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis of docosahexaenoic acid derivatives designed as novel PPARγ agonists and antidiabetic agents.2006

    • Author(s)
      Toshimasa Itoh
    • Journal Title

      Bioorganic Medicinal Chemistry 14

      Pages: 98-108

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Identification of Putative Metabolites of Docosahexaenoic Acid as Potent PPARγ Agonists and Antidiabetic Agents2005

    • Author(s)
      Keiko Yamamoto
    • Journal Title

      Bioorganic Medicinal Chemistry Letters 15

      Pages: 517-522

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Identification of Putative Metabolites of Docosahexaenoic Acid as Potent PPARγ Agonists and Antidiabetic Agents.2005

    • Author(s)
      Keiko Yamamoto
    • Journal Title

      Bioorganic Medicinal Chemistry Letters. 15

      Pages: 517-522

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Identification of Putative Metabolites of Docosahexaenoic Acid as Pot ent PPARγ Agonists and Antidiabetic Agents.2005

    • Author(s)
      Keiko Yamamoto
    • Journal Title

      Bioorganic Medicinal Chemistry Letters 15

      Pages: 517-522

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Identification of Putative Metabolites of Docosahexaenoic Acid as Potent PPARγ Agonists and Antidiabetic Agents.2005

    • Author(s)
      Yamamoto_K, Itoh T, Abe D, Shimizu M, Kanda T, Kovama T, Ni
    • Journal Title

      Bioorganic Medicinal Chemistry Letters 15

      Pages: 517-522

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Two-dimensional alanine scanning mutational analysis of the interaction between the vitamin d receptor and its ligands : Studies of A2004

    • Author(s)
      Shimizu M, Yamamoto_K, Mihori M, Iwasaki Y, Morizono D, Yamada, S
    • Journal Title

      The Journal of Steroid Biochemistry and Molecular Biology 89-90

      Pages: 75-81

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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