Co-existence of alpha-glucosidase-inhibitory and liver X receptor-regulatory activities and their separation by structural development

Bioorg Med Chem. 2008 Apr 15;16(8):4272-85. doi: 10.1016/j.bmc.2008.02.078. Epub 2008 Feb 29.


Liver X receptors (LXR), which were originally reported as oxysterol-activated nuclear receptors, were recently found to recognize glucose as a physiological ligand. On this basis, we have already developed novel LXR antagonists based upon alpha-glucosidase inhibitors derived from thalidomide. Here, to clarify the relationship between alpha-glucosidase inhibition and LXR modulation, we investigate the alpha-glucosidase-inhibitory activity of typical LXR ligands and the LXR-modulating activity of typical alpha-glucosidase inhibitors. Although there were some exceptions, co-existence of LXR-regulatory and alpha-glucosidase-inhibitory activities seemed to be rather general among the examined compounds. The LXR ligands were found to be non-competitive alpha-glucosidase inhibitors, suggesting that it might be possible to separate the two activities. To test this idea, we focused on riccardin C, a naturally occurring LXR ligand, which we found here to be a potent alpha-glucosidase inhibitor as well. Structural development of riccardin C afforded novel LXR antagonists lacking alpha-glucosidase-inhibitory activity, 19c and 19f, and a LXRalpha-selective antagonist, 22.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / chemistry
  • Cell Line
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / metabolism*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glycoside Hydrolase Inhibitors*
  • Humans
  • Ligands
  • Liver X Receptors
  • Molecular Structure
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Structure-Activity Relationship
  • alpha-Glucosidases / metabolism*


  • Aldehydes
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Glycoside Hydrolase Inhibitors
  • Ligands
  • Liver X Receptors
  • NR1H3 protein, human
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear
  • alpha-Glucosidases