Design, Synthesis, and Biological Evaluation of Indoline and Indole Derivatives as Potent and Selective α1A-Adrenoceptor Antagonists.
J Med Chem
; 59(8): 3826-39, 2016 04 28.
Article
em En
| MEDLINE
| ID: mdl-27031406
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antagonistas de Receptores Adrenérgicos alfa 1
/
Indóis
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
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Male
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2016
Tipo de documento:
Article