Synthesis of N-methylpyridine-chlorofuranformamide analogs as novel OPG up-regulators and inhibitors of RANKL-induced osteoclastogenesis

• Published in: Bioorganic chemistry Vol. 116; pp. 105361 - 105373
• Main Authors: Liu, Chao, Li, Yining, Sheng, Ren, Han, Xiaowan, Bao, Li, Wang, Chenyin, Wang, Weizhi, Jiang, Xinhai, Han, Jiangxue, Lei, Lijuan, Li, Ni, Zhang, Jing, Chen, Minghua, Li, Yan, Wu, Yexiang, Li, Shunwang, Ren, Yu, Xu, Yanni, Si, Shuyi
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.11.2021; Elsevier
• Subjects: 3T3 Cells; Animals; Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Dose-Response Relationship, Drug; Formamides - chemistry; Formamides - pharmacology; Furans - chemistry; Furans - pharmacology; Life Sciences & Biomedicine; Mice; Molecular Structure; OPG; Osteoblast; Osteoclast; Osteogenesis - drug effects; Osteoporosis; Osteoprotegerin - metabolism; Physical Sciences; Pyridines - chemistry; Pyridines - pharmacology; RANK Ligand - antagonists & inhibitors; RANK Ligand - metabolism; RANKL; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Science & Technology; Structure-Activity Relationship; RANKL; α-MEM; DMSO; JNK; OPG; HRP; SPF; RANK; TRAP; TNF; AUC; Osteoporosis; NF-κB; CHCl3; FBS; CCK-8; CDCl3; MAPKs; PBS; BCA; MS; PVDF; IκBα; SDS-PAGE; CMC-Na; Tmax; Me; SEM; GAPDH; MMP-9; ELISA; ERK; ARS; RT; SAR; HTS; Osteoclast; NFATc1; TLC; WB; MRT; RIPA; OVX; DMEM; Osteoblast; ESI; SOCl2; DMF; CH2Cl2; Et3N, TEA; Cmax; hERG; F12; ECL; LC-MS; PK; TMS; Cpds; DIFFERENTIATION
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105361

[Display omitted] •A series of pyridine-furanformamide analogs as OPG up-regulators were synthesized.•Most analogs inhibited RANKL-induced osteoclastogenesis in RAW264.7 cells.•Compounds 3c and 3i1 reduced osteoclasts through inhibiting NF-κB and MAPKs pathways.•Compounds 3c and 3i1 had acceptable pharmacokinetic profiles and safety.•Compound 3i1 could serve as a new promising lead for treating osteoporosis. The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-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, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis.