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J Med Chem. 2016 Apr 28;59(8):3826-39. doi: 10.1021/acs.jmedchem.5b02023. Epub 2016 Apr 13.

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

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Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University , 168 Hua Guan Road, Chengdu 610052, People's Republic of China.
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, People's Republic of China.


A series of indoline and indole derivatives were designed, synthesized, and evaluated as selective α1A-adrenergic receptor (α1A-AR) antagonists for the treatment of benign prostatic hyperplasia (BPH). In this study, two highly selective and potent α1A-AR antagonists, compounds (R)-14r (IC50 = 2.7 nM, α1B/α1A = 640.1, α1D/α1A = 408.2) and (R)-23l (IC50 = 1.9 nM, α1B/α1A = 1506, α1D/α1A = 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, α1B/α1A = 285.9, α1D/α1A = 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.

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