Synthesis and\nAntiosteoporotic Characterization of\nDiselenyl Maleimides: Discovery of a Potent Agent for the Treatment\nof Osteoporosis by Targeting RANKL

To discover new osteoclast-targeting antiosteoporosis\nagents, we\nidentified forty-six diselenyl maleimides, which were efficiently\nprepared using a novel, simple, and metal-free method at room temperature\nin a short reaction time. Among them, <b>3k</b> showed the most\nmarked inhibition of osteoclast differentiation with an <i>IC</i><sub>50</sub> value of 0.36 ± 0.03 μM. Moreover, <b>3k</b> significantly suppressed RANKL-induced osteoclast formation,\nbone resorption, and osteoclast-specific genes expression in vitro.\nMechanistic studies revealed that <b>3k</b> remarkably blocked\nthe RANKL-induced mitogen-activated protein kinase (MAPK) and NF-κB\nsignaling pathways. In ovariectomized mice, intragastric administration\nof <b>3k</b> significantly alleviated bone loss, exhibiting\nan effect similar to that of alendronate. Surface plasmon resonance\nassay and microscale thermophoresis assay results suggested that RANKL\nmight be a potential molecular target for <b>3k</b>. Collectively,\nthe findings presented above provided a novel candidate for further\ndevelopment of bone antiresorptive drugs that target RANKL.