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

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 α-glucosidase inhibitors derived from thalidomide. Here, to clarify the relationship between α-glucosidase inhibition and LXR modulation, we investigate the α-glucosidase-inhibitory activity of typical LXR ligands and the LXR-modulating activity of typical α-glucosidase inhibitors. Although there were some exceptions, co-existence of LXR-regulatory and α-glucosidase-inhibitory activities seemed to be rather general among the examined compounds. The LXR ligands were found to be non-competitive α-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 α-glucosidase inhibitor as well. Structural development of riccardin C afforded novel LXR antagonists lacking α-glucosidase-inhibitory activity, 19c and 19f, and a LXRα-selective antagonist, 22.