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Peroxisome proliferator activated receptor γ and oxidized docosahexaenoic acids as new class of ligand

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Abstract

PPARγ regulates the expression of numerous genes. In addition to their anti-diabetic activity, PPARγ agonists have been reported to have beneficial effects for cancer, inflammation including inflammatory bowel disease, atherosclerosis and brain inflammation, as well as bone turnover. To investigate a potential new class of ligands for PPARγ, we designed with reference to the crystal structure of the ligand-binding domain of PPARγ oxidized docosahexaenoic acid (DHA) derivatives, which have a hydrophilic substituent at the C(4)-position and are putative metabolites of DHA. We synthesized 14 compounds and evaluated their activities in vitro. We found that these DHA derivatives show PPARγ transactivation higher than, or comparable to, that of pioglitazone, which is a thiazolidinedione derivative used as an antidiabetic agent. Furthermore, one of them showed anti-diabetic activity in animal models. In this paper, we review the potential of PPARγ as a drug target and oxidized DHA as a new class of ligand for PPARγ.

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Acknowledgment

We thank Dr. John Schwabe of Department of Biochemistry, University of Leicester (Leicester, UK) for helpful comments.

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Authors and Affiliations

  1. Department of Biochemistry, University of Leicester, Leicester, UK

    Toshimasa Itoh

  2. Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo, 194-8543, Japan

    Keiko Yamamoto

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  1. Toshimasa Itoh
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  2. Keiko Yamamoto
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Correspondence to Keiko Yamamoto.

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Itoh, T., Yamamoto, K. Peroxisome proliferator activated receptor γ and oxidized docosahexaenoic acids as new class of ligand. Naunyn-Schmied Arch Pharmacol 377, 541–547 (2008). https://doi.org/10.1007/s00210-007-0251-x

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  • DOI: https://doi.org/10.1007/s00210-007-0251-x

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