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

• Published in: Journal of medicinal chemistry Vol. 67; no. 19; pp. 17226 - 17242
• Main Authors: Li, Bin, Wu, Yao, Ying, Linkun, Zhu, Weiwei, Yang, Jingyi, Zhou, Lingling, Yi, Lele, Jiang, Tianle, Jiang, Haofu, Song, Xiangrui, Xue, Weiwei, Liang, Guang, Huang, Shengbin, Song, Zengqiang
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.10.2024
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01105

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 IC 50 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.