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

Keita Yoshikawa; Tomofumi Ohyama; Eiki Takahashi; Yoshitaka Numajiri; Mitsuhiro Konno; Masaki Moriyama; Natsumi Takemi; Kana Kunita; Kazumi Nishimura; Ryoji Hayashi

doi:10.1016/j.bmcl.2015.06.008

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

Bioorg Med Chem Lett. 2015 Aug 15;25(16):3135-41. doi: 10.1016/j.bmcl.2015.06.008. Epub 2015 Jun 16.

Affiliations

¹ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Keita_Yoshikawa@nts.toray.co.jp.
² Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.

PMID: 26112438
DOI: 10.1016/j.bmcl.2015.06.008

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.

Keywords: Acylamines; Metabotropic glutamate receptor; mGluR5 negative allosteric modulators.

MeSH terms

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
Mice
Molecular Conformation
Receptor, Metabotropic Glutamate 5 / chemistry*
Receptor, Metabotropic Glutamate 5 / metabolism
Rectum / drug effects
Rectum / physiology
Stereoisomerism
Structure-Activity Relationship
Temperature

Substances

Amines
Anti-Anxiety Agents
Receptor, Metabotropic Glutamate 5