Synthesis of Heterocyclic Ring-Fused Bisnoralcohol Derivatives as Novel Small-Molecule Antiosteoporosis Agents

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.