title: Discovery and in vitro and in vivo profiles of N-ethyl-N-[2-[3-(5-fluoro-2-pyridinyl)-1H-pyrazol-1-yl]ethyl]-2-(2H-1,2,3-triazol-2-yl)-benzamide as a novel class of dual orexin receptor antagonist.
abstract: Orexins play an important role in sleep/wake regulation, and orexin receptor antagonists are a focus of novel therapy for the treatment of insomnia. We identified 27e (TASP0428980) as a potent dual orexin receptor antagonist through the systematic modification of our original designed lead A. We demonstrated the potent sleep-promoting effects of 27e at ip dose of 3mg/kg in a rat polysomnogram study. 27e exhibited relatively short half-life profiles in rats and dogs. Furthermore, accumulating evidence regarding ADME profiles indicates that the predicted human half-life of 27e should be 1.2-1.4h. These data indicated that 27e has a short-acting hypnotic property, suggesting that 27e might be useful for treating primary insomnia while exhibiting a low risk of next-day residual somnolence. Thus, 27e and its related compounds should be further evaluated to enable advancement to clinical trials.
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Nozawa
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Futamura
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Nishikawa-Shimono
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Abe
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohta
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Araki
authors.affiliation: Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Daiji
authors.initials: D
authors.lastname: Kambe
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Ohmichi
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Seiken
authors.initials: S
authors.lastname: Tokura
authors.affiliation: Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Ohtake
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan. Electronic address: h-kawamoto@so.taisho.co.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008297:Male; D015394:Molecular Structure; D000068796:Orexin Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001549:Benzamides; C000602708:N-ethyl-N-(2-(3-(5-fluoro-2-pyridinyl)-1H-pyrazol-1-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide; D000068796:Orexin Receptor Antagonists; D014230:Triazoles
keywords: Dual orexin receptor antagonist; Insomnia; Short half-life