A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis

被引：74

作者：

Gomez-Galeno, Jorge E. ^{[1
]}

Dang, Qun ^{[1
]}

Nguyen, Thanh H. ^{[1
]}

Boyer, Serge H. ^{[1
]}

Grote, Matthew P. ^{[1
]}

Sun, Zhili ^{[1
]}

Chen, Mingwei ^{[1
]}

Craigo, William A. ^{[1
]}

van Poelje, Paul D. ^{[1
]}

MacKenna, Deidre A. ^{[1
]}

Cable, Edward E. ^{[1
]}

Rolzin, Paul A. ^{[1
]}

Finn, Patricia D. ^{[1
]}

Chi, Bert ^{[1
]}

Linemeyer, David L. ^{[1
]}

Hecker, Scott J. ^{[1
]}

Erion, Mark D. ^{[1
]}

机构：

[1] Metabasis Therapeut Inc, La Jolla, CA 92037 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2010年 / 1卷 / 09期

关键词：

5-(5-Hydroxy-isoxazol-3-yl)-furan-2-phosphonic acid; AMPK activator; lipogenesis; hepatocytes; PROTEIN-KINASE ACTIVATORS; METABOLIC SYNDROME; SKELETAL-MUSCLE; DRUG TARGET; RAT-LIVER; DISCOVERY; FRUCTOSE-1,6-BISPHOSPHATASE; PRODRUGS; TISSUES; CELL;

D O I：

10.1021/ml100143q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

AMP-activated protein kinase (AMPK) is a heterotrimeric kinase that regulates cellular. energy metabolism by affecting energy-consuming pathways such as de novo. lipid biosynthesis and glucose production as well as energy-producing pathways such as lipid oxidation and glucose uptake. Accordingly, compounds that activate AMPK represent potential drug candidates for the treatment of hyperlipidemia and type 2 diabetes. Screening of a proprietary library of AMP mimetics identified the phosphonic acid 2 that bears little structural resemblance to AMP but is capable of activating AMPK with high potency (EC(50) = 6 nM vs AMP EC(50) = 6 mu M) and specificity. Phosphonate prodrugs of 2 inhibited de novo lipogenesis In cellular and animal models of hyperlipidemia.

引用

收藏

页码：478 / 482

页数：5

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