Synthesis of Heterocyclic Ring-Fused Bisnoralcohol Derivatives as Novel Small-Molecule Antiosteoporosis Agents.
J Med Chem
; 67(10): 8271-8295, 2024 May 23.
Article
de En
| MEDLINE
| ID: mdl-38717088
ABSTRACT
A series of heterocyclic ring-fused derivatives of bisnoralcohol (BA) were synthesized and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Most of these derivatives possessed potent antiosteoporosis activities in a dose-dependent manner. Among these compounds, 31 (SH442, IC50 = 0.052 µM) exhibited the highest potency, displaying 100% inhibition at 1.0 µM and 82.8% inhibition at an even lower concentration of 0.1 µM, which was much more potent than the lead compound BA (IC50 = 2.325 µM). Cytotoxicity tests suggested that the inhibitory effect of these compounds on RANKL-induced osteoclast differentiation did not result from their cytotoxicity. Mechanistic studies revealed that SH442 inhibited the expression of osteoclastogenesis-related marker genes and proteins, including TRAP, TRAF6, c-Fos, CTSK, and MMP9. Especially, SH442 could significantly attenuate bone loss of ovariectomy mouse in vivo. Therefore, these BA derivatives could be used as promising leads for the development of a new type of antiosteoporosis agent.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Ostéoclastes
/
Ostéoporose
Limites:
Animals
Langue:
En
Journal:
J Med Chem
/
J. med. chem
/
Journal of medicinal chemistry
Sujet du journal:
QUIMICA
Année:
2024
Type de document:
Article
Pays d'affiliation:
Chine
Pays de publication:
États-Unis d'Amérique