Efficacy, Mechanism, and Structure–Activity Relationship of 6-Methoxy Benzofuran Derivatives as a Useful Tool for Senile Osteoporosis,Journal of Medicinal Chemistry

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Efficacy, Mechanism, and Structure–Activity Relationship of 6-Methoxy Benzofuran Derivatives as a Useful Tool for Senile Osteoporosis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-01-20 , DOI: 10.1021/acs.jmedchem.2c01377
Zi-Ying Zhou ₁ , Lian-Qi Sun ₁ , Xiao-Yang Han ₁ , Yong-Jian Wang ₁ , Zhuo-Song Xie ₁ , Si-Tu Xue ₁ , Zhuo-Rong Li ₁

Affiliation

Most patients with senile osteoporosis (SOP) are severely deficient in bone mass, and treatments using bone resorption inhibitors, such as bisphosphonates, have shown limited efficacy. Small-molecule osteogenesis-promoting drugs are required to improve the treatment for this disease. Previously, we demonstrated that a compound with a benzofuran-like structure promoted bone formation by upregulating BMP-2, and it exhibited a therapeutic effect in SAMP-6 mice, glucocorticoid-induced osteoporosis rats, and ovariectomized rats. In this study, aged C57 and SAMP-6 mice models were used to investigate the therapeutic and preventive effects of compound 125 on SOP. scRNA-seq analysis showed that BMP-2 upregulation is the mechanism through which 125 accelerates bone turnover and increases the proportion of osteoblasts. We evaluated the structure–activity relationship of the candidate drugs and found that the derivative I-9 showed significantly higher efficacy than 125 and teriparatide in the zebrafish osteoporosis model. This study provides a foundation for the development of SOP drugs.

中文翻译：

6-甲氧基苯并呋喃衍生物作为治疗老年性骨质疏松症有用工具的功效、机制和构效关系

大多数老年性骨质疏松症 (SOP) 患者的骨量严重不足，使用骨吸收抑制剂（例如双膦酸盐）进行的治疗效果有限。需要小分子促骨药物来改善这种疾病的治疗。之前，我们证明了一种具有苯并呋喃样结构的化合物通过上调 BMP-2 促进骨形成，并且它在 SAMP-6 小鼠、糖皮质激素诱导的骨质疏松症大鼠和卵巢切除大鼠中表现出治疗作用。在这项研究中，使用老年 C57 和 SAMP-6 小鼠模型来研究化合物125对 SOP 的治疗和预防作用。scRNA-seq 分析表明 BMP-2 上调是125加速骨转换，增加成骨细胞的比例。我们评估了候选药物的构效关系，发现衍生物I-9在斑马鱼骨质疏松症模型中的疗效显着高于125和特立帕肽。该研究为SOP药物的开发提供了基础。

更新日期：2023-01-20

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