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 β agonist can regulate the cholesterol balance in osteoclasts
to inhibit osteoclast differentiation. Here, we designed and synthesized
a novel LXRβ 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 LXRβ agonists inhibited osteoclastogenesis
with IC50 values ranging from 0.078 to 0.36 μM. Especially,
the most potent LXRβ agonist B9 significantly inhibited
RANKL-induced osteoclast differentiation and bone resorption in vitro
and in vivo. Furthermore, B9 selectively activated LXRβ
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 LXRβ
agonists for osteoporosis.