Synthesis, structure-activity relationships and biological evaluation of 4,5,6,7-tetrahydropyrazolopyrazines as metabotropic glutamate receptor 5 negative allosteric modulators

Bioorg Med Chem Lett. 2016 Aug 15;26(16):3866-9. doi: 10.1016/j.bmcl.2016.07.019. Epub 2016 Jul 9.

Abstract

The design, synthesis and SAR studies of novel 4,5,6,7-tetrahydropyrazolopyrazines as metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) are presented in this letter. Starting from a HTS hit compound (1, IC50=477nM), optimization of various groups led to the synthesis of a potent mGluR5 NAM (32, IC50=75nM) with excellent rat PK profile and good brain penetration. This compound produced oral antidepressant-like effect in a mouse tale suspension model (MED: 30mg/kg).

Keywords: CNS drug discovery; Hit to lead studies; Negative allosteric modulator; mGluR5.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Antidepressive Agents / chemical synthesis*
  • Antidepressive Agents / metabolism
  • Antidepressive Agents / therapeutic use
  • Brain / metabolism
  • Depression / drug therapy
  • Disease Models, Animal
  • Half-Life
  • Humans
  • Mice
  • Microsomes, Liver / metabolism
  • Protein Binding
  • Pyrazines / chemical synthesis*
  • Pyrazines / chemistry
  • Pyrazines / pharmacokinetics
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacokinetics
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Rats
  • Receptor, Metabotropic Glutamate 5 / chemistry
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • Structure-Activity Relationship

Substances

  • 4,5,6,7-tetrahydropyrazolopyrazine
  • Antidepressive Agents
  • Pyrazines
  • Pyrazoles
  • Pyridines
  • Receptor, Metabotropic Glutamate 5