2005 Fiscal Year Final Research Report Summary
Development of antidiabetic agents targeting PPARγ
| Project/Area Number |
16590003
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Tokyo Medical and Dental University |
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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)
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| 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)
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| Project Period (FY) |
2004 – 2005
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| Keywords | PPAR / unsaturated fatty acid / Mitsunobu Reaction / luciferase assay / drug design / nuclear receptor / metabolic syndrome |
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| 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.
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