title: Design, synthesis, and structure-activity relationships of a series of novel N-aryl-2-phenylcyclopropanecarboxamide that are potent and orally active orexin receptor antagonists.
abstract: Herein we describe the design, synthesis, and structure-activity relationships (SARs) of a novel phenylcyclopropane series represented by 7 and 33 b 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, 33 b ((-)-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 33 b may serve as a valuable template for the development of new orexin receptor antagonists.
authors.affiliation: Medicinal Chemistry, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan. Electronic address: y11-yoshida@hhc.eisai.co.jp.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Medicinal Chemistry, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Terauchi
authors.affiliation: Medicinal Chemistry, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Naoe
authors.affiliation: Medicinal Chemistry, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kazuta
authors.affiliation: Medicinal Chemistry, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Ozaki
authors.affiliation: Biopharmacology, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Carsten T
authors.initials: CT
authors.lastname: Beuckmann
authors.affiliation: Biopharmacology, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Biopharmacology, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Michiyuki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Physical Chemistry, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kushida
authors.affiliation: Drug Metabolism and Pharmacokinetics, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takenaka
authors.affiliation: Drug Metabolism and Pharmacokinetics, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Medicinal Chemistry, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yonaga
mesh_terms: D000818:Animals; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism; D012890:Sleep / Q000187:drug effects; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors
keywords: Hypocretin; Insomnia; Orexin receptor antagonist; Sleep disorder