Discovery of Spiro[pyrrolidine-3,3′-oxindole] LXRβ Agonists for the Treatment of 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.