Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4)

Bioorg Med Chem Lett. 2016 Jul 1;26(13):2984-2987. doi: 10.1016/j.bmcl.2016.05.029. Epub 2016 May 11.

Abstract

Herein we report the synthesis and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as novel positive allosteric modulators of mGlu4. We detail our work towards finding phenyl replacements for the core scaffold of previously reported phenyl sulfonamides and phenyl sulfone compounds. Our efforts culminated in the identification of N-(1-((3,4-dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide as a potent PAM of mGlu4.

Keywords: Metabotropic glutamate receptor 4; PK; Phenyl replacement; Positive allosteric modulator (PAM); Pyrrole sulfonamide.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Microsomes, Liver / metabolism
  • Picolinic Acids / chemical synthesis
  • Picolinic Acids / pharmacokinetics
  • Picolinic Acids / pharmacology*
  • Pyrroles / chemical synthesis
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology*
  • Rats
  • Receptors, Metabotropic Glutamate / metabolism*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*
  • Triazoles / pharmacology

Substances

  • N-(1-((3,4-dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide
  • Picolinic Acids
  • Pyrroles
  • Receptors, Metabotropic Glutamate
  • Sulfonamides
  • Triazoles
  • 1-aminobenzotriazole
  • metabotropic glutamate receptor 4