2. Academic Validation
  3. Discovery of 5-(2',4'-difluorophenyl)-salicylanilides as new inhibitors of receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis

Discovery of 5-(2',4'-difluorophenyl)-salicylanilides as new inhibitors of receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis

  • Eur J Med Chem. 2015 Jun 15:98:115-26. doi: 10.1016/j.ejmech.2015.05.015.
Chia-Chung Lee 1,  Fei-Lan Liu 2,  Chun-Liang Chen 3,  Tsung-Chih Chen 3,  Deh-Ming Chang 4,  Hsu-Shan Huang 5
Affiliations

Affiliations

  • 1 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.
  • 2 Rheumatology/Immunology/Allergy, Taipei Veterans General Hospital, Taipei 112, Taiwan.
  • 3 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
  • 4 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.
  • 5 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.
PMID: 26005025 DOI: 10.1016/j.ejmech.2015.05.015
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.

Keywords

NDMC101; Osteoclastogenesis; RANKL; Salicylanilides; TRAP activity assay.

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