Design, Synthesis, and Biological Evaluation of Indoline and Indole Derivatives as Potent and Selective α1A-Adrenoceptor Antagonists

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• 作者：Fei Zhao ; Jing Li ; Ying Chen ; Yanxin Tian ; Chenglin Wu ; Yanan Xie ; Yu Zhou ; Jiang Wang ; Xin Xie ; Hong Liu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 28, 2016
• 年：2016
• 卷：59
• 期：8
• 页码：3826-3839
• 全文大小：564K
• 年卷期：0
• ISSN：1520-4804

文摘

A series of indoline and indole derivatives were designed, synthesized, and evaluated as selective α_1A-adrenergic receptor (α_1A-AR) antagonists for the treatment of benign prostatic hyperplasia (BPH). In this study, two highly selective and potent α_1A-AR antagonists, compounds (R)-14r (IC₅₀ = 2.7 nM, α_1B/α_1A = 640.1, α_1D/α_1A = 408.2) and (R)-23l (IC₅₀ = 1.9 nM, α_1B/α_1A = 1506, α_1D/α_1A = 249.6), which exhibited similar activities and better selectivities in cell-based calcium assays as compared with the marketed drug silodosin (IC₅₀ = 1.9 nM, α_1B/α_1A = 285.9, α_1D/α_1A = 14.4), were identified. In the functional assays with isolated rat tissues, compounds (R)-14r and (R)-23l also showed high potency and uroselectivity. Most importantly, (R)-14r and (R)-23l can significantly decrease the micturition frequency and increase the mean voided volume of the BPH rats in a dose-dependent manner, making them worthy of further investigation for the development of anti-BPH agents.