title: Discovery of 5-(2',4'-difluorophenyl)-salicylanilides as new inhibitors of receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis.
abstract: To improve the inhibitory potency of lead compound NDMC101 on RANKL-induced osteoclastogenesis, a series of new 5-(2',4'-difluorophenyl)-salicylanilide derivatives were synthesized and evaluated for osteoclast inhibition by using TRAP-staining assay. Among them, both of compounds 6d and 6i showed three-fold increase in osteoclast-inhibitory activities compared to NDMC101 at half-inhibitory concentration. Further, the mechanistic study showed that 6d and 6i could suppress RANKL-induced osteoclastogenesis-related genes, such as NFATc1, c-fos, TRAP, and cathepsin K. Their inhibitory activities were further confirmed by including specific inhibition of NF-κB and NFATc1 expression levels in nucleus. In addition, 6d and 6i also could significantly attenuate bone-resorbing activity of osteoclasts by performing pit formation assay. Thus, a new class of 5-(2',4'-difluorophenyl)-salicylanilide derivatives may be considered as essential lead structures for the further development of anti-resorptive agents.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan.
authors.forename: Chia-Chung
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Rheumatology/Immunology/Allergy, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors.forename: Fei-Lan
authors.initials: FL
authors.lastname: Liu
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Tsung-Chih
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Rheumatology/Immunology/Allergy, Taipei Veterans General Hospital, Taipei 112, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan. Electronic address: ming0503@ms3.hinet.net.
authors.forename: Deh-Ming
authors.initials: DM
authors.lastname: Chang
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan. Electronic address: huanghs99@tmu.edu.tw.
authors.forename: Hsu-Shan
authors.initials: HS
authors.lastname: Huang
mesh_terms: D000818:Animals; D002460:Cell Line; D055808:Drug Discovery; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects*; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000502:physiology; D012458:Salicylanilides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D053245:RANK Ligand; D012458:Salicylanilides; C505689:Tnfsf11 protein, mouse
keywords: NDMC101; Osteoclastogenesis; RANKL; Salicylanilides; TRAP activity assay