Antidiabetic and Antiobesity Effects of Ampkinone (6f), a Novel Small Molecule Activator of AMP-Activated Protein Kinase

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• 作者：Sangmi Oh ; Sung Jin Kim ; Jung Hwan Hwang ; Hyang Yeon Lee ; Min Jeong Ryu ; Jongmin Park ; Soung Jung Kim ; Young Suk Jo ; Yong Kyung Kim ; Chul-Ho Lee ; Ki Ryang Kweon ; Minho Shong ; Seung Bum Park
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：October 28, 2010
• 年：2010
• 卷：53
• 期：20
• 页码：7405-7413
• 全文大小：958K
• 年卷期：v.53,no.20(October 28, 2010)
• ISSN：1520-4804

文摘

Adenosine 5'-monophosphate (AMP) activated protein kinase (AMPK) has emerged as an attractive target molecule for the treatment of metabolic disorders, including obesity and type 2 diabetes. In this study, we identified a novel small molecule, ampkinone (6f), as an indirect AMPK activator, which was derived from the small molecule library constructed by diversity-oriented synthesis. Ampkinone stimulated the phosphorylation of AMPK via the indirect activation of AMPK in various cell lines. Ampkinone-mediated activation of AMPK required the activity of LKB1 and resulted in increased glucose uptake in muscle cells. In addition, ampkinone-treated DIO mice significantly reduced total body weight and overall fat mass. Histological examination and measurement of lipid parameters showed that ampkinone effectively improved metabolic abnormalities in the DIO mice model. Our results demonstrate that ampkinone, a small molecule with a privileged benzopyran substructure, has a potential as a new class of therapeutic agent for antidiabetic and antiobesity treatment via the indirect stimulation of AMPK.