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

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.