title: Identification of putative metabolites of docosahexaenoic acid as potent PPARgamma agonists and antidiabetic agents.
abstract: We found that putative metabolites of docosahexaenoic acid (DHA) are strong PPARgamma activators and potential antidiabetic agents. We designed DHA derivatives based on the crystal structure of PPARgamma, synthesized them and evaluated their activities in vitro and in vivo. The efficacy of 5E-4-hydroxy-DHA 2a as a PPARgamma activator was about fourfold stronger than that of pioglitazone. Furthermore, the 4-keto derivative (10b) showed antidiabetic activity in animal models without producing undesirable effects such as obesity and hepatotoxicity.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. yamamoto.mr@tmd.ac.jp
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Itoh
authors.forename: Daijiro
authors.initials: D
authors.lastname: Abe
authors.forename: Masato
authors.initials: M
authors.lastname: Shimizu
authors.forename: Tomoatsu
authors.initials: T
authors.lastname: Kanda
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Koyama
authors.forename: Masazumi
authors.initials: M
authors.lastname: Nishikawa
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Tamai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ooizumi
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D056486:Chemical and Drug Induced Liver Injury; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy; D004281:Docosahexaenoic Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D009765:Obesity / Q000139:chemically induced; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry; D051381:Rats
chemical_list: D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D004281:Docosahexaenoic Acids