Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin R
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- 作者：Yu Yoshida ; Yoshimitsu Naoe ; Taro Terauchi ; Fumihiro Ozaki ; Takashi Doko ; Ayumi Takemura ; Toshiaki Tanaka ; Keiichi Sorimachi ; Carsten T. Beuckmann ; Michiyuki Suzuki ; Takashi Ueno ; Shunsuke Ozaki ; Masahiro Yonaga
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：June 11, 2015
- 年：2015
- 卷：58
- 期：11
- 页码：4648-4664
- 全文大小：609K
- ISSN：1520-4804
文摘
The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure鈥揳ctivity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements.