{Reference Type}: Journal Article
{Title}: Synthesis of Heterocyclic Ring-Fused Bisnoralcohol Derivatives as Novel Small-Molecule Antiosteoporosis Agents.
{Author}: Zhang DJ;Chen R;Zhang YX;Li CC;Ning RN;Jiang M;Qiu WW;
{Journal}: J Med Chem
{Volume}: 67
{Issue}: 10
{Year}: 2024 May 23
{Factor}: 8.039
{DOI}: 10.1021/acs.jmedchem.4c00349
{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.