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Discovery of 5-(2′,4′-difluorophenyl)-salicylanilides as new inhibitors of receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis.
- Source :
-
European Journal of Medicinal Chemistry . Jun2015, Vol. 98, p115-126. 12p. - Publication Year :
- 2015
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 98
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 103159933
- Full Text :
- https://doi.org/10.1016/j.ejmech.2015.05.015