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
N1 - Funding Information:
The work described in this paper was partially supported by Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology, Japan, and the Japan Society for the Promotion of Science.
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
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U2 - 10.1016/j.bmc.2008.02.078
DO - 10.1016/j.bmc.2008.02.078
M3 - Article
C2 - 18343126
AN - SCOPUS:42149184935
SN - 0968-0896
VL - 16
SP - 4272
EP - 4285
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 8
ER -