2. Academic Validation
  3. Discovery of Tamsulosin Derivatives with Shifted Selectivity from the α1-Adrenergic Receptor to ANO1 as Potent Antiosteoporotic Agents

Discovery of Tamsulosin Derivatives with Shifted Selectivity from the α1-Adrenergic Receptor to ANO1 as Potent Antiosteoporotic Agents

  • J Med Chem. 2025 Aug 28;68(16):17705-17722. doi: 10.1021/acs.jmedchem.5c01408.
Chaoquan Tian 1,  Weijia Sun 2 3,  Tao Yu 4,  Shuai Guo 5,  Yiqing Zhang 1,  Shuang Li 1,  Jiaqi He 1,  Mingqi Yu 2,  Lingkang Wu 1,  Wenyi Mei 1,  Yuheng Li 2,  Zhenjiang Zhao 1,  Lili Zhu 1,  Yanyan Diao 4,  Honglin Li 1 4,  Yingxian Li 2,  Shiliang Li 4 6
Affiliations

Affiliations

  • 1 School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 2 National Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China.
  • 3 School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China.
  • 4 Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai 200062, China.
  • 5 School of Life Science, Hebei University, Baoding, Hebei 071000, China.
  • 6 Department of Pain Management, HuaDong Hospital affiliated to Fudan University, Shanghai 200040, China.
PMID: 40794435 DOI: 10.1021/acs.jmedchem.5c01408
Abstract

ANO1, a calcium-activated Chloride Channel, is a newly reported therapeutic target for osteoporosis. Tamsulosin (Tam), an approved α1-AR antagonist, was previously discovered to be a novel ANO1 allosteric inhibitor. Here, a series of Tam derivatives were designed and synthesized with the aim of developing selective ANO1 inhibitors for osteoporosis treatment. Among them, compound 10 exhibited the best overall activities. The potency of compound 10 against ANO1 was comparable to that of Tam (IC50: 4.57 vs 7.22 μM), but its selectivity over α1-AR was significantly improved. Compared with Tam, the potency of compound 10 against α1A-, α1B-, and α1D-AR decreased by 118-fold, 642-fold, and 10,000-fold, respectively. In addition, compound 10 exhibited significant inhibitory effects on osteoclast differentiation and function. In the OVX (ovariectomy) mice, compound 10 effectively prevented OVX-induced bone loss. Collectively, these findings highlighted the therapeutic potential of 10 as a novel lead compound for antiosteoporosis by targeting ANO1.

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