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 (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.