Identification of alpha-substituted acylamines as novel, potent, and orally active mGluR5 negative allosteric modulators

[Display omitted] 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 activi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2015-08, Vol.25 (16), p.3135-3141
Main Authors: Yoshikawa, Keita, Ohyama, Tomofumi, Takahashi, Eiki, Numajiri, Yoshitaka, Konno, Mitsuhiro, Moriyama, Masaki, Takemi, Natsumi, Kunita, Kana, Nishimura, Kazumi, Hayashi, Ryoji
Format: Article
Language:English
Subjects:
Acylamines
Administration, Oral
Allosteric Regulation
Amines - chemical synthesis
Amines - chemistry
Amines - pharmacology
Animals
Anti-Anxiety Agents - chemical synthesis
Anti-Anxiety Agents - chemistry
Anti-Anxiety Agents - pharmacology
Crystallography, X-Ray
Disease Models, Animal
Hyperthermia, Induced
Metabotropic glutamate receptor
mGluR5 negative allosteric modulators
Mice
Molecular Conformation
Receptor, Metabotropic Glutamate 5 - chemistry
Receptor, Metabotropic Glutamate 5 - metabolism
Rectum - drug effects
Rectum - physiology
Stereoisomerism
Structure-Activity Relationship
Temperature
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Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.06.008