Identification, synthesis, and characterization of new glycogen phosphorylase inhibitors binding to the allosteric AMP site.

Article Details

Citation

Kristiansen M, Andersen B, Iversen LF, Westergaard N

Identification, synthesis, and characterization of new glycogen phosphorylase inhibitors binding to the allosteric AMP site.

J Med Chem. 2004 Jul 1;47(14):3537-45.

PubMed ID
15214781 [ View in PubMed
]
Abstract

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 IC(50) value of 74 nM. This compound together with a closely related analogue was further characterized by enzyme kinetics and in primary rat hepatocytes.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
4-{2-[(3-Nitrobenzoyl)Amino]Phenoxy}Phthalic AcidGlycogen phosphorylase, muscle formIC 50 (nM)900N/AN/ADetails
AlvocidibGlycogen phosphorylase, muscle formIC 50 (nM)1000N/AN/ADetails
CP-320626Glycogen phosphorylase, muscle formIC 50 (nM)500N/AN/ADetails