Synthesis of N-methylpyridine-chlorofuranformamide analogs as novel OPG up-regulators and inhibitors of RANKL-induced osteoclastogenesis.
Synthesis of N-methylpyridine-chlorofuranformamide analogs as novel OPG up-regulators and inhibitors of RANKL-induced osteoclastogenesis.
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DOI：
10.1016/j.bioorg.2021.105361
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发表时间：
2021-09
影响因子：
5.1
通讯作者：
Chao Liu;Yining Li;Ren Sheng;Xiaowan Han;Li Bao;Chenyin Wang;Weizhi Wang;Xinhai Jiang;Jiangxue Han;Lijuan Lei;Ni Li;Jing Zhang;Minghua Chen;Yan Li;Ye-xiang Wu;Shunwang Li;Y. Ren;Yanni Xu;S. Si
中科院分区：
文献类型：
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作者：
Chao Liu;Yining Li;Ren Sheng;Xiaowan Han;Li Bao;Chenyin Wang;Weizhi Wang;Xinhai Jiang;Jiangxue Han;Lijuan Lei;Ni Li;Jing Zhang;Minghua Chen;Yan Li;Ye-xiang Wu;Shunwang Li;Y. Ren;Yanni Xu;S. Si
OPG/RANKL/RANK通路是设计用于治疗骨质疏松症的治疗剂的有前景的靶点。具有N-甲基吡啶-氯呋喃甲酰胺结构骨架的E09241先前被鉴定为通过增加骨保护素（OPG）表达来减少骨丢失，从而保护卵巢切除大鼠免受骨质疏松症。本研究合成了36个E09241（3a）衍生物。介绍了该类化合物的合成、OPG活性上调、构效关系和细胞毒性等方面的研究进展。具有良好上调OPG活性的化合物可以抑制RANKL（核因子-kappa B配体的受体激活剂）诱导的RAW 264.7细胞破骨细胞生成。特别地，化合物3cand 3 i 1通过抑制RANKL诱导的RAW 264. 7细胞中的NF-κB和MAPK途径而显著降低NFATc 1和MMP-9蛋白表达。化合物3c、3v和3 i 1能显著促进成骨培养基中MC 3 T3-E1细胞的成骨分化，并能显著增加MC 3 T3-E1细胞OPG蛋白的表达和分泌。此外，研究了化合物3a、3c、3e、3v和3 i 1的药代动力学特征、急性毒性和hERG K+通道效应。综上所述，这些结果表明，N-甲基吡啶-氯呋喃甲酰胺类似物3 i 1可以作为一个有前途的领导新的药物治疗骨质疏松症的发展。
The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with anN-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure–activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds3cand3i1significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds3cand3vsignificantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds3c,3v, and3i1obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+channel effects of compounds3a,3c,3e,3v, and3i1were investigated. Taken together, these results indicate thatN-methylpyridine-chlorofuranformamide analog3i1could serve as a promising lead for the development of new agents for treating osteoporosis.