Discovery and Biological Profile of 4-(1-aryltriazol-4-yl)-tetrahydropyridines as an Orally Active New Class of Metabotropic Glutamate Receptor 1 Antagonist

Bioorg Med Chem. 2008 Nov 15;16(22):9817-29. doi: 10.1016/j.bmc.2008.09.060. Epub 2008 Sep 30.

Abstract

We describe here the discovery and the structure-activity relationship (SAR) of a series of 4-(1-Aryltriazol-4-yl)-tetrahydropyridines as novel mGluR1 antagonists. Our extensive chemical modification of lead compound 2 successfully led to fluoropyridine analogs 7j and 1 with improved in vivo antagonistic activities. Among the evaluated compounds, chemically stable urea analog 1 showed oral antagonistic activity at dose ranges of 10-30mg/kg in an animal model.

MeSH terms

  • Administration, Oral
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Microsomes, Liver / metabolism
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacology*
  • Rats
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / metabolism
  • Structure-Activity Relationship

Substances

  • Pyridines
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1