Discovery of benzoylisoindolines as a novel class of potent, selective and orally active GlyT1 inhibitors

Bioorg Med Chem Lett. 2010 Dec 1;20(23):6960-5. doi: 10.1016/j.bmcl.2010.09.124. Epub 2010 Oct 7.

Abstract

Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles.

MeSH terms

  • Animals
  • Cell Membrane Permeability
  • Drug Discovery
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / drug effects
  • Glycine Plasma Membrane Transport Proteins / analysis
  • Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Humans
  • Isoindoles / chemistry
  • Isoindoles / pharmacokinetics
  • Isoindoles / pharmacology
  • Mice
  • Rats
  • Solubility
  • Structure-Activity Relationship

Substances

  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Glycine Plasma Membrane Transport Proteins
  • Isoindoles
  • KCNH2 protein, human
  • Slc6a9 protein, mouse