A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis

Jorge E Gómez-Galeno; Qun Dang; Thanh H Nguyen; Serge H Boyer; Matthew P Grote; Zhili Sun; Mingwei Chen; William A Craigo; Paul D van Poelje; Deidre A MacKenna; Edward E Cable; Paul A Rolzin; Patricia D Finn; Bert Chi; David L Linemeyer; Scott J Hecker; Mark D Erion

doi:10.1021/ml100143q

A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis

ACS Med Chem Lett. 2010 Aug 30;1(9):478-82. doi: 10.1021/ml100143q. eCollection 2010 Dec 9.

Authors

Jorge E Gómez-Galeno¹, Qun Dang¹, Thanh H Nguyen¹, Serge H Boyer¹, Matthew P Grote¹, Zhili Sun¹, Mingwei Chen¹, William A Craigo¹, Paul D van Poelje¹, Deidre A MacKenna¹, Edward E Cable¹, Paul A Rolzin¹, Patricia D Finn¹, Bert Chi¹, David L Linemeyer¹, Scott J Hecker¹, Mark D Erion¹

Affiliation

¹ Metabasis Therapeutics, Inc., La Jolla, California 92037.

Abstract

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.

Keywords: 5-(5-Hydroxy-isoxazol-3-yl)-furan-2-phosphonic acid; AMPK activator; hepatocytes; lipogenesis.