鉴定二十二碳六烯酸的假定代谢产物作为有效的过氧化物酶体增殖物激活受体γ激动剂和抗糖尿病药物。
Identification of putative metabolites of docosahexaenoic acid as potent PPARgamma agonists and antidiabetic agents.
作者信息
Yamamoto Keiko, Itoh Toshimasa, Abe Daijiro, Shimizu Masato, Kanda Tomoatsu, Koyama Takatoshi, Nishikawa Masazumi, Tamai Tadakazu, Ooizumi Hiroshi, Yamada Sachiko
机构信息
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
出版信息
Bioorg Med Chem Lett. 2005 Feb 1;15(3):517-22. doi: 10.1016/j.bmcl.2004.11.053.
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.
我们发现，二十二碳六烯酸（DHA）的假定代谢产物是强效的过氧化物酶体增殖物激活受体γ（PPARγ）激动剂和潜在的抗糖尿病药物。我们基于PPARγ的晶体结构设计了DHA衍生物，合成了这些衍生物，并在体外和体内评估了它们的活性。5E-4-羟基-DHA 2a作为PPARγ激动剂的效力比吡格列酮强约四倍。此外，4-酮衍生物（10b）在动物模型中显示出抗糖尿病活性，且不会产生肥胖和肝毒性等不良影响。
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