Discovery and biological evaluation of tetrahydrothieno[2,3-c]pyridine derivatives as selective metabotropic glutamate receptor 1 antagonists for the potential treatment of neuropathic pain

Eur J Med Chem. 2015 Jun 5:97:245-58. doi: 10.1016/j.ejmech.2015.04.060. Epub 2015 Apr 30.

Abstract

Metabotropic glutamate receptor 1 (mGluR1) has been a prime target for drug discovery due to its heavy involvement in various brain disorders. Recent studies suggested that mGluR1 is associated with chronic pain and can serve as a promising target for the treatment of neuropathic pain. In an effort to develop a novel mGluR1 antagonist, we designed and synthesized a library of compounds with tetrahydrothieno[2,3-c]pyridine scaffold. Among these compounds, compound 9b and 10b showed excellent antagonistic activity in vitro and demonstrated pain-suppressing activity in animal models of pain. Both compounds were orally active, and compound 9b exhibited a favorable pharmacokinetic profile in rats. We believe that these compounds can provide a promising lead compound that is suitable for the potential treatment of neuropathic pain.

Keywords: Metabotropic glutamate receptor; Neuropathic pain; Thiophene derivatives; mGluR1 antagonist.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Analgesics / administration & dosage
  • Analgesics / chemistry*
  • Analgesics / pharmacokinetics
  • Analgesics / pharmacology*
  • Animals
  • Cells, Cultured
  • Disease Models, Animal*
  • Drug Discovery*
  • HEK293 Cells
  • Humans
  • Male
  • Microsomes, Liver / drug effects
  • Neuralgia / drug therapy*
  • Nitriles / administration & dosage
  • Nitriles / chemistry*
  • Nitriles / pharmacokinetics
  • Nitriles / pharmacology*
  • Pyridines / administration & dosage
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / metabolism
  • Structure-Activity Relationship
  • Tissue Distribution

Substances

  • 2-(benzylamino)-6-(3-methyl-1H-pyrazole-5-carbonyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine-3-carbonitrile
  • 2-(benzylamino)-6-(4-fluorobenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine-3-carbonitrile
  • Analgesics
  • Nitriles
  • Pyridines
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • pyridine