Design, Synthesis, and Biological Evaluation of β‑Trifluoroethoxydimethyl Selenides as Potent Antiosteoporosis Agents

• Published in: Journal of medicinal chemistry 2024-05, Vol.67 (9), p.7585-7602
• Main Authors: Wu, Yao, Li, Bin, Ying, Linkun, Chen, Yao, Zhang, Yuxin, Hu, Chaoming, Zhang, Yichi, Yi, Lele, Xue, Weiwei, Huang, Shengbin, Song, Zengqiang
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00438

An efficient protocol for the synthesis of β-trifluoroethoxydimethyl selenides was achieved under mild reaction conditions, and 39 compounds were prepared. All compounds were evaluated for their abilities to inhibit RANKL-induced osteoclastogenesis, compound 4aa exhibited the most potent activity. Further investigations revealed that 4aa could inhibit F-actin ring generation, bone resorption, and osteoclast-specific gene expression in vitro. Western blot analyses demonstrated that compound 4aa abrogated the RANKL-induced mitogen-activated protein kinase and NF-kB-signaling pathways. In addition, 4aa also displayed a notable impact on the osteoblastogenesis of MC3T3-E1 preosteoblasts. In vivo experiments revealed that compound 4aa significantly ameliorated bone loss in an ovariectomized (OVX) mice model. Furthermore, the surface plasmon resonance experiment results revealed that 4aa probably bound to RANKL. Collectively, the above-mentioned findings suggested that compound 4aa as a potential RANKL inhibitor averted OVX-triggered osteoporosis by regulating the inhibition of osteoclast differentiation and stimulation of osteoblast differentiation.