Identification of putative metabolites of docosahexaenoic acid as potent PPARgamma agonists and antidiabetic agents.
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.
Yamamoto
Keiko
K
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
Itoh
Toshimasa
T
Abe
Daijiro
D
Shimizu
Masato
M
Kanda
Tomoatsu
T
Koyama
Takatoshi
T
Nishikawa
Masazumi
M
Tamai
Tadakazu
T
Ooizumi
Hiroshi
H
Yamada
Sachiko
S
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
D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D004281:Docosahexaenoic Acids