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.

中文翻译：

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新型小分子抗骨质疏松药杂环稠合双降醇衍生物的合成


合成了一系列双降醇 (BA) 杂环稠合衍生物，并评估了它们对 RANKL 诱导的破骨细胞生成的抑制作用。大多数这些衍生物都具有剂量依赖性的有效抗骨质疏松活性。在这些化合物中，31 种 (SH442，IC ₅₀ = 0.052 μM) 表现出最高的效力，在 1.0 μM 时显示出 100% 的抑制率，在更低浓度 0.1 μM 时显示出 82.8% 的抑制率，其效力要强得多高于先导化合物 BA (IC ₅₀ = 2.325 μM)。细胞毒性测试表明，这些化合物对 RANKL 诱导的破骨细胞分化的抑制作用并不是由其细胞毒性引起的。机制研究表明，SH442 抑制破骨细胞生成相关标记基因和蛋白的表达，包括 TRAP、TRAF6、c-Fos、CTSK 和 MMP9。特别是，SH442可以显着减轻卵巢切除小鼠体内的骨丢失。因此，这些 BA 衍生物可作为开发新型抗骨质疏松药物的有前景的先导化合物。