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.
Keita Yoshikawa  1 ,  Tomofumi Ohyama  2 ,  Eiki Takahashi  2 ,  Yoshitaka Numajiri  2 ,  Mitsuhiro Konno  2 ,  Masaki Moriyama  2 ,  Natsumi Takemi  2 ,  Kana Kunita  2 ,  Kazumi Nishimura  2 ,  Ryoji Hayashi  2
Affiliations
  • 1. Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: [email protected].
  • 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.