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 differ...

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Published inJournal 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
LanguageEnglish
Published United States American Chemical Society 10.10.2024
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Summary: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.
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content type line 23
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.4c01105