Synthesis and Antiosteoporotic Characterization of Diselenyl Maleimides: Discovery of a Potent Agent for the Treatment of Osteoporosis by Targeting RANKL

To discover new osteoclast-targeting antiosteoporosis
agents, we
identified forty-six diselenyl maleimides, which were efficiently
prepared using a novel, simple, and metal-free method at room temperature
in a short reaction time. Among them, 3k showed the most
marked inhibition of osteoclast differentiation with an IC50 value of 0.36 ± 0.03 μM. Moreover, 3k significantly suppressed RANKL-induced osteoclast formation,
bone resorption, and osteoclast-specific genes expression in vitro.
Mechanistic studies revealed that 3k remarkably blocked
the RANKL-induced mitogen-activated protein kinase (MAPK) and NF-κB
signaling pathways. In ovariectomized mice, intragastric administration
of 3k significantly alleviated bone loss, exhibiting
an effect similar to that of alendronate. Surface plasmon resonance
assay and microscale thermophoresis assay results suggested that RANKL
might be a potential molecular target for 3k. Collectively,
the findings presented above provided a novel candidate for further
development of bone antiresorptive drugs that target RANKL.