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

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

Author information

1
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. dodo@iam.u-tokyo.ac.jp

Abstract

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.

PMID:
18343126
DOI:
10.1016/j.bmc.2008.02.078
[Indexed for MEDLINE]

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