Identification and optimisation of a series of tetrahydrobenzotriazoles as metabotropic glutamate receptor 5-selective positive allosteric modulators that improve performance in a preclinical model of cognition

Bioorg Med Chem Lett. 2015 Dec 15;25(24):5792-6. doi: 10.1016/j.bmcl.2015.10.050. Epub 2015 Oct 17.

Abstract

Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation.

Keywords: Cognition; Metabotropic glutamate receptor 5 (mGlu5); Positive allosteric modulator (PAM); Tetrahydrobenzotriazole.

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Antipsychotic Agents / chemistry*
  • Antipsychotic Agents / metabolism
  • Antipsychotic Agents / pharmacology
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Cognition / drug effects
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Microsomes / metabolism
  • Rats
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors*
  • Receptor, Metabotropic Glutamate 5 / metabolism
  • Structure-Activity Relationship
  • Triazoles / chemistry*
  • Triazoles / metabolism
  • Triazoles / pharmacology

Substances

  • Antipsychotic Agents
  • Receptor, Metabotropic Glutamate 5
  • Triazoles
  • benzotriazole