1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as potent GR antagonists with reduced hERG inhibition and an improved pharmacokinetic profile

Bioorg Med Chem Lett. 2015 Dec 15;25(24):5720-5. doi: 10.1016/j.bmcl.2015.10.097. Epub 2015 Oct 31.

Abstract

We report the further optimization of our series 1H-pyrazolo[3,4-g]hexahydro-isoquinoline sulfonamides as GR antagonists. By incorporating a heteroaryl ketone group at the ring junction, we have obtained compounds with excellent functional GR antagonism. Optimization of the sulfonamide substituent has provided compounds with a very desirable overall profile, including minimal hERG activity, good bioavailability and in vivo efficacy.

Keywords: 1H-Pyrazolo[3,4-g]hexahydro-isoquinolines; Glucocorticoid receptor antagonists; Insulin resistance; hERG inhibition.

MeSH terms

  • Animals
  • Binding Sites
  • Catalytic Domain
  • Cell Line
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Hep G2 Cells
  • Humans
  • Isoquinolines / chemistry*
  • Isoquinolines / metabolism
  • Molecular Docking Simulation
  • Protein Binding
  • Pyrazoles / chemistry
  • Rats
  • Receptors, Glucocorticoid / antagonists & inhibitors*
  • Receptors, Glucocorticoid / metabolism
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism

Substances

  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Isoquinolines
  • KCNH2 protein, human
  • Pyrazoles
  • Receptors, Glucocorticoid
  • Sulfonamides
  • isoquinoline