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 |
|---|---|
| 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 |
| Externally published | Yes |
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Keywords
- Antagonist
- Glucosidase
- Inhibitor
- Liver X receptor
- Structural development
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Organic Chemistry
- Drug Discovery
- Pharmaceutical Science
Cite this
Co-existence of α-glucosidase-inhibitory and liver X receptor-regulatory activities and their separation by structural development. / Dodo, Kosuke; Aoyama, Atsushi; Noguchi-Yachide, Tomomi; Makishima, Makoto; Miyachi, Hiroyuki; Hashimoto, Yuichi.
In: Bioorganic and Medicinal Chemistry, Vol. 16, No. 8, 15.04.2008, p. 4272-4285.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Co-existence of α-glucosidase-inhibitory and liver X receptor-regulatory activities and their separation by structural development
AU - Dodo, Kosuke
AU - Aoyama, Atsushi
AU - Noguchi-Yachide, Tomomi
AU - Makishima, Makoto
AU - Miyachi, Hiroyuki
AU - Hashimoto, Yuichi
PY - 2008/4/15
Y1 - 2008/4/15
N2 - 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.
AB - 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.
KW - Antagonist
KW - Glucosidase
KW - Inhibitor
KW - Liver X receptor
KW - Structural development
UR - http://www.scopus.com/inward/record.url?scp=42149184935&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=42149184935&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2008.02.078
DO - 10.1016/j.bmc.2008.02.078
M3 - Article
C2 - 18343126
AN - SCOPUS:42149184935
VL - 16
SP - 4272
EP - 4285
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 8
ER -