Discovery of Tamsulosin Derivatives with Shifted Selectivity from the α<sub>1</sub>-Adrenergic Receptor to ANO1 as Potent Antiosteoporotic Agents
ANO1, a calcium-activated chloride channel, is a newly reported therapeutic target for osteoporosis. Tamsulosin (<b>Tam</b>), an approved α<sub>1</sub>-AR antagonist, was previously discovered to be a novel ANO1 allosteric inhibitor. Here, a series of <b>Tam</b> derivatives were designed and synthesized with the aim of developing selective ANO1 inhibitors for osteoporosis treatment. Among them, compound <b>10</b> exhibited the best overall activities. The potency of compound <b>10</b> against ANO1 was comparable to that of <b>Tam</b> (IC<sub>50</sub>: 4.57 vs 7.22 μM), but its selectivity over α<sub>1</sub>-AR was significantly improved. Compared with <b>Tam</b>, the potency of compound <b>10</b> against α<sub>1A</sub>-, α<sub>1B</sub>-, and α<sub>1D</sub>-AR decreased by 118-fold, 642-fold, and 10,000-fold, respectively. In addition, compound <b>10</b> exhibited significant inhibitory effects on osteoclast differentiation and function. In the OVX (ovariectomy) mice, compound <b>10</b> effectively prevented OVX-induced bone loss. Collectively, these findings highlighted the therapeutic potential of <b>10</b> as a novel lead compound for antiosteoporosis by targeting ANO1.
Authors
- Tao Yu (ORCID: https://orcid.org/0000-0003-4809-8169)
- Wenyi Mei
- Chaoquan Tian
- Shuang Li (ORCID: https://orcid.org/0009-0006-4938-262X)
- Jiaqi He (ORCID: https://orcid.org/0009-0006-0296-4497)
- Zhenjiang Zhao (ORCID: https://orcid.org/0000-0002-1060-5316)
- Yuheng Li (ORCID: https://orcid.org/0000-0002-0648-4136)
- Honglin Li (ORCID: https://orcid.org/0000-0003-2270-1900)
- Yanyan Diao (ORCID: https://orcid.org/0000-0002-4210-4399)
- Shuai Guo (ORCID: https://orcid.org/0000-0002-5342-9666)
- Lili Zhu (ORCID: https://orcid.org/0000-0003-1957-973X)
- Yiqing Zhang (ORCID: https://orcid.org/0000-0003-4434-6890)
- Weijia Sun (ORCID: https://orcid.org/0000-0003-3604-6919)
- Yingxian Li (ORCID: https://orcid.org/0000-0002-5440-3281)
- L. Eduardo Wu
- Meng-Lin Yu (ORCID: https://orcid.org/0009-0002-3773-4756)
Institutions
- Beijing Institute of Technology (CN)
- East China University of Science and Technology (CN)
- Fudan University (CN)
- China National Space Administration (CN)
- Huadong Hospital (CN)
- National Space Science Center (CN)
- Drug Discovery Laboratory (Norway) (NO)
- China Astronaut Research and Training Center (CN)
- Hebei University (CN)
- East China Normal University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01408
- Primary Topic
- Ion channel regulation and function
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Shanghai Rising-Star Program
- National Key Research and Development Program of China