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 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.
Original language | English |
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Pages (from-to) | 4272-4285 |
Number of pages | 14 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 16 |
Issue number | 8 |
DOIs | |
Publication status | Published - Apr 15 2008 |
Keywords
- Antagonist
- Glucosidase
- Inhibitor
- Liver X receptor
- Structural development
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry