Discovery of Novel Antiosteoporosis Leads with Bone Resorption Inhibition and Anabolic Promotion through a Chemotype-Assembly Approach,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery of Novel Antiosteoporosis Leads with Bone Resorption Inhibition and Anabolic Promotion through a Chemotype-Assembly Approach
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-21 , DOI: 10.1021/acs.jmedchem.4c00909
Dane Huang ₁ , Chao Zhao _{2,

3} , Ruyue Li ₄ , Nan Yao ₁ , Jun Xu ₂ , Qiong Gu ₂

Affiliation

Developing a dual-efficiency agent with antiresorptive and anabolic applications is a promising strategy for treating osteoporosis. This study reports the discovery of dual antiosteoporosis agents via a chemotype-assembly approach. Chemotype analysis identified 12 antiresorptive and 12 anabolic chemotypes and 7 dual-function chemotype-assembly rules. Based on these assembly rules, a dual-functional compound S24 was discovered. S24 exhibits osteoclastogenesis inhibition with an IC₅₀ value of 10.28 μM and osteoblast differentiation stimulation at 10 μM. S24 derivatives were designed and synthesized based on the activity relationship of the chemotypes. This yielded a more active compound, S24–14, with an osteoclastogenesis inhibition IC₅₀ value of 0.40 μM and osteoblast differentiation stimulation at 1.0 μM; compound S24–14 also suppressed bone loss in vivo. These results prove that S24–14 can be a potential lead for antiosteoporosis drug development.

中文翻译：

通过化学型组装方法发现具有骨吸收抑制和合成代谢促进作用的新型抗骨质疏松先导化合物

开发具有抗吸收和合成代谢应用的双效药物是治疗骨质疏松症的一种有前途的策略。这项研究报告了通过化学型组装方法发现的双重抗骨质疏松药物。化学型分析确定了 12 种抗吸收化学型和 12 种合成代谢化学型以及 7 种双功能化学型组装规则。基于这些组装规则，发现了双功能化合物S24 。 S24表现出破骨细胞生成抑制作用，IC ₅₀值为 10.28 μM，并在 10 μM 时刺激成骨细胞分化。根据化学型的活性关系设计并合成了S24衍生物。由此产生了活性更强的化合物S24–14 ，其破骨细胞生成抑制 IC ₅₀值为 0.40 μM，并在 1.0 μM 时刺激成骨细胞分化；化合物S24-14也能抑制体内骨质流失。这些结果证明S24-14可以成为抗骨质疏松药物开发的潜在先导。

更新日期：2024-08-21

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南