Design, synthesis, and evaluation of a new class of noncyclic 1,3-dicarbonyl compounds as PPARalpha selective activators |
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Authors: | Li Zhibin Liao Chenzhong Ko Ben C B Shan Song Tong Edith H Y Yin Zihui Pan Desi Wong Vincent K W Shi Leming Ning Zhi-Qiang Hu Weiming Zhou Jiaju Chung Stephen S M Lu Xian-Ping |
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Institution: | Chipscreen Biosciences, Ltd, Research Institute of Tsinghua University, Suite C301, PO Box 28, Shenzhen 518057, China. |
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Abstract: | Lipid accumulation in nonadipose tissues is increasingly linked to the development of type 2 diabetes in obese individuals. We report here the design, synthesis, and evaluation of a series of novel PPARalpha selective activators containing 1,3-dicarbonyl moieties. Structure-activity relationship studies led to the identification of PPARalpha selective activators (compounds 10, 14, 17, 18, and 21) with stronger potency and efficacy to activate PPARalpha over PPARgamma and PPARdelta. Experiments in vivo showed that compounds 10, 14, and 17 had blood glucose lowering effect in diabetic db/db mouse model after two weeks oral dosing. The data strongly support further testing of these lead compounds in other relevant disease animal models to evaluate their potential therapeutic benefits. |
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