Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 66, Issue 1, Pages 752-765Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01661
Keywords
-
Categories
Ask authors/readers for more resources
Osteoclasts have a higher demand for cholesterol, and the LXR# agonist can regulate cholesterol balance to inhibit osteoclast differentiation. By introducing privileged fragments from anti-osteoporosis agents, we synthesized a novel LXR# agonist. This agonist effectively inhibited osteoclast production and demonstrated potential for treating osteoporosis.
Osteoclasts have an additional demand for cholesterol compared to normal cells. Liver X receptors (LXRs) are famous for regulation of lipid and cholesterol metabolism. Therefore, we propose that the LXR# agonist can regulate the cholesterol balance in osteoclasts to inhibit osteoclast differentiation. Here, we designed and synthesized a novel LXR# agonist by introduction of the privileged fragments from anti-osteoporosis agents to the spiro[pyrrolidine-3,3 '-oxindole] scaffold which is a novel scaffold of LXR agonists in our previous research. As a result, seven LXR# agonists inhibited osteoclastogenesis with IC50 values ranging from 0.078 to 0.36 mu M. Especially, the most potent LXR# agonist B9 significantly inhibited RANKL-induced osteoclast differentiation and bone resorption in vitro and in vivo. Furthermore, B9 selectively activated LXR# to promote intracellular cholesterol exclusion in osteoclasts and reduce extracellular cholesterol uptake and thereby inhibited osteoclast production. This study provides a new strategy to develop LXR# agonists for osteoporosis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available