jm031121n_si_001.pdf (87.63 kB)
Identification, Synthesis, and Characterization of New Glycogen Phosphorylase Inhibitors Binding to the Allosteric AMP Site
journal contributionposted on 2004-07-01, 00:00 authored by Marit Kristiansen, Birgitte Andersen, Lars Fogh Iversen, Niels Westergaard
Inhibition of glycogen phosphorylase (GP) has attracted considerable attention during the last five to 10 years as a means of treating the elevated hepatic glucose production seen in patients with type 2 diabetes. Several different GP inhibitors binding to various binding sites of the GP enzyme have been reported in the literature. In this paper we report on a novel class of compounds that have been identified as potent GP inhibitors. Their synthesis, mode of binding to the allosteric AMP site as well as in vitro data on GP inhibition are shown. The most potent inhibitor was found to be 4-[2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid (4j) with an IC50 value of 74 nM. This compound together with a closely related analogue was further characterized by enzyme kinetics and in primary rat hepatocytes.
enzyme kineticshepatic glucose productionNew Glycogen Phosphorylase Inhibitors Bindingglycogen phosphorylaseallosteric AMP sitebinding sitesGP inhibition10 years74 nM4 jGP inhibitors bindingrat hepatocytesGP enzymenovel classtype 2 diabetesIC 50 valueAllosteric AMP Site InhibitioncompoundGP inhibitors