A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis

• Published in: ACS medicinal chemistry letters Vol. 1; no. 9; pp. 478 - 482
• Main Authors: Gómez-Galeno, Jorge E, Dang, Qun, Nguyen, Thanh H, Boyer, Serge H, Grote, Matthew P, Sun, Zhili, Chen, Mingwei, Craigo, William A, van Poelje, Paul D, MacKenna, Deidre A, Cable, Edward E, Rolzin, Paul A, Finn, Patricia D, Chi, Bert, Linemeyer, David L, Hecker, Scott J, Erion, Mark D
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 09.12.2010
• Subjects: Letter; 5-(5-Hydroxy-isoxazol-3-yl)-furan-2-phosphonic acid; lipogenesis; AMPK activator; hepatocytes
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml100143q

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 (EC50 = 6 nM vs AMP EC50 = 6 μM) and specificity. Phosphonate prodrugs of 2 inhibited de novo lipogenesis in cellular and animal models of hyperlipidemia.