Discovery of 5-(2′,4′-difluorophenyl)-salicylanilides as new inhibitors of receptor activator of NF-κ°B ligand (RANKL)-induced osteoclastogenesis

Chia Chung Lee, Fei Lan Liu, Chun Liang Chen, Tsung Chih Chen, Deh Ming Chang, Hsu Shan Huang

Research output: Contribution to journalArticle

16 Citations (Scopus)

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-κ°B 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.

Original languageEnglish
Pages (from-to)115-126
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume98
DOIs
Publication statusPublished - May 25 2015

Keywords

  • NDMC101
  • Osteoclastogenesis
  • RANKL
  • Salicylanilides
  • TRAP activity assay

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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