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, <b>3k</b> showed the most marked inhibition of osteoclast differentiation with an <i>IC</i>₅₀ value of 0.36 ± 0.03 μM. Moreover, <b>3k</b> significantly suppressed RANKL-induced osteoclast formation, bone resorption, and osteoclast-specific genes expression in vitro. Mechanistic studies revealed that <b>3k</b> remarkably blocked the RANKL-induced mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways. In ovariectomized mice, intragastric administration of <b>3k</b> 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 <b>3k</b>. Collectively, the findings presented above provided a novel candidate for further development of bone antiresorptive drugs that target RANKL.