Synthesis and Biological Evaluation of Cyclopentaquinoline Derivatives as Nonsteroidal Glucocorticoid Receptor Antagonists

The steroidal glucocorticoid antagonist mifepristone has been reported to improve the symptoms of depression. We report the discovery of 6-(3,5-dimethylisoxazol-4-yl)-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one 3d (QCA-1093) as a novel nonsteroidal glucocorticoid recep...

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Veröffentlicht in:	Journal of medicinal chemistry 2015-06, Vol.58 (12), p.4918-4926
Hauptverfasser:	Eda, Masahiro, Kuroda, Tomoko, Kaneko, Satoshi, Aoki, Yoshiyuki, Yamashita, Masami, Okumura, Chieko, Ikeda, Yoshitaka, Ohbora, Tomoko, Sakaue, Masaki, Koyama, Natsumi, Aritomo, Keiichi
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antidepressive Agents - chemical synthesis Antidepressive Agents - chemistry Antidepressive Agents - pharmacology Antidepressive Agents - therapeutic use Cell Line Depression - drug therapy Humans Male Molecular Docking Simulation Quinolines - chemical synthesis Quinolines - chemistry Quinolines - pharmacology Quinolines - therapeutic use Rats Rats, Wistar Receptors, Glucocorticoid - antagonists & inhibitors Receptors, Glucocorticoid - metabolism Structure-Activity Relationship
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Zusammenfassung:	The steroidal glucocorticoid antagonist mifepristone has been reported to improve the symptoms of depression. We report the discovery of 6-(3,5-dimethylisoxazol-4-yl)-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one 3d (QCA-1093) as a novel nonsteroidal glucocorticoid receptor antagonist. The compound displayed potent in vitro activity, high selectivity over other steroid hormone receptors, and significant antidepressant-like activity in vivo.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm501758q