Design, synthesis, and structure-activity relationships of a series of novel N-aryl-2-phenylcyclopropanecarboxamide that are potent and orally active orexin receptor antagonists

作者：Yoshida Yu^*; Terauchi Taro; Naoe Yoshimitsu; Kazuta Yuji; Ozaki Fumihiro; Beuckmann Carsten T; Nakagawa Makoto; Suzuki Michiyuki; Kushida Ikuo; Takenaka Osamu; Ueno Takashi; Yonaga Masahiro

来源：Bioorganic & Medicinal Chemistry, 2014, 22(21): 6071-6088.

DOI：10.1016/j.bmc.2014.08.034

• Orexin receptor antagonist
• Hypocretin
• Insomnia
• Sleep disorder

Herein we describe the design, synthesis, and structure-activity relationships (SARs) of a novel phenylcyclopropane series represented by 7 and 33b as antagonists of orexin 1 and orexin 2 receptors. With 4 serving as the initial lead for the development of orexin antagonists, exploration of SAR resulted in improved binding affinity for orexin 1 and orexin 2 receptors. Among the synthesized compounds, 33b ((-)-N-(5-cyanopyridin-2-yl)-2-[(3,4-dimethoxyphenyl)oxymethyl]-2-phenylcyclopropanecarboxamide) exhibited potent in vitro activity and oral efficacy in animal sleep measurement experiments. The results of our study suggest that compound 33b may serve as a valuable template for the development of new orexin receptor antagonists.

• 出版日期2014-11-1