Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs)
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- 作者：Swati P. Mercer ; Anthony J. Roecker ; Susan Garson ; Duane R. Reiss ; C. Meacham Harrell ; Kathy L. Murphy ; Joseph G. Bruno ; Rodney A. Bednar ; Wei Lemaire ; Donghui Cui ; Tamara D. Cabalu ; Cuyue Tang ; Thomayant Prueksaritanont ; George D. Hartman ; Steven D. Young ; Christopher J. Winrow ; John J. Renger ; Paul J. Coleman
- 关键词：Orexin receptor antagonists ; Selective orexin-2 receptor antagonists ; Insomnia ; Hypocretin ; Rat sleep EEG
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：15 December, 2013
- 年：2013
- 卷：23
- 期：24
- 页码：6620-6624
- 全文大小：2106 K
文摘
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.