title: Identification of alpha-substituted acylamines as novel, potent, and orally active mGluR5 negative allosteric modulators.
abstract: This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure-activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia.
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Keita_Yoshikawa@nts.toray.co.jp.
authors.forename: Keita
authors.initials: K
authors.lastname: Yoshikawa
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Ohyama
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Eiki
authors.initials: E
authors.lastname: Takahashi
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Numajiri
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Konno
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Moriyama
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Takemi
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Kunita
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Hayashi
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006979:Hyperthermia, Induced; D051379:Mice; D008968:Molecular Conformation; D064529:Receptor, Metabotropic Glutamate 5 / Q000737:chemistry* / Q000378:metabolism; D012007:Rectum / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D000588:Amines; D014151:Anti-Anxiety Agents; D064529:Receptor, Metabotropic Glutamate 5
keywords: Acylamines; Metabotropic glutamate receptor; mGluR5 negative allosteric modulators