title: 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 Receptor Antagonist.
abstract: 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-activity 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.
authors.affiliation: †Medicinal Chemistry, ‡Biopharmacology, §Physical Chemistry, and ∥Drug Metabolism and Pharmacokinetics, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: †Medicinal Chemistry, ‡Biopharmacology, §Physical Chemistry, and ∥Drug Metabolism and Pharmacokinetics, 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, ‡Biopharmacology, §Physical Chemistry, and ∥Drug Metabolism and Pharmacokinetics, 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, ‡Biopharmacology, §Physical Chemistry, and ∥Drug Metabolism and Pharmacokinetics, 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: †Medicinal Chemistry, ‡Biopharmacology, §Physical Chemistry, and ∥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: Doko
authors.affiliation: †Medicinal Chemistry, ‡Biopharmacology, §Physical Chemistry, and ∥Drug Metabolism and Pharmacokinetics, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Takemura
authors.affiliation: †Medicinal Chemistry, ‡Biopharmacology, §Physical Chemistry, and ∥Drug Metabolism and Pharmacokinetics, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: †Medicinal Chemistry, ‡Biopharmacology, §Physical Chemistry, and ∥Drug Metabolism and Pharmacokinetics, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Sorimachi
authors.affiliation: †Medicinal Chemistry, ‡Biopharmacology, §Physical Chemistry, and ∥Drug Metabolism and Pharmacokinetics, 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: †Medicinal Chemistry, ‡Biopharmacology, §Physical Chemistry, and ∥Drug Metabolism and Pharmacokinetics, 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: †Medicinal Chemistry, ‡Biopharmacology, §Physical Chemistry, and ∥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, ‡Biopharmacology, §Physical Chemistry, and ∥Drug Metabolism and Pharmacokinetics, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Ozaki
authors.affiliation: †Medicinal Chemistry, ‡Biopharmacology, §Physical Chemistry, and ∥Drug Metabolism and Pharmacokinetics, 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: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry*; D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000737:chemistry*; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000601374:2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide; D000577:Amides; D000631:Aminopyridines; D003521:Cyclopropanes; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D011743:Pyrimidines; C538819:cyclopropanecarboxamide; D002118:Calcium