title: A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis.
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.
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Gómez-Galeno
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Qun
authors.initials: Q
authors.lastname: Dang
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Thanh H
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Serge H
authors.initials: SH
authors.lastname: Boyer
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Grote
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Mingwei
authors.initials: M
authors.lastname: Chen
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: William A
authors.initials: WA
authors.lastname: Craigo
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Poelje
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Deidre A
authors.initials: DA
authors.lastname: MacKenna
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Cable
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rolzin
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Finn
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Bert
authors.initials: B
authors.lastname: Chi
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: David L
authors.initials: DL
authors.lastname: Linemeyer
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hecker
authors.affiliation: Metabasis Therapeutics, Inc., La Jolla, California 92037.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
keywords: 5-(5-Hydroxy-isoxazol-3-yl)-furan-2-phosphonic acid; AMPK activator; hepatocytes; lipogenesis