期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 23, 期 24, 页码 6620-6624出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.10.045
关键词
Orexin receptor antagonists; Selective orexin-2 receptor antagonists; Insomnia; Hypocretin; Rat sleep EEG
The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats. (C) 2013 Elsevier Ltd. All rights reserved.
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