Bicyclo[2.2.2]octyltriazole inhibitors of 11β-hydoxysteroid dehydrogenase type 1. Pharmacological agents for the treatment of metabolic syndrome

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2568-72. doi: 10.1016/j.bmcl.2011.01.018. Epub 2011 Jan 11.

Abstract

Following the discovery of a metabolic 'soft-spot' on a bicyclo[2.2.2]octyltriazole lead, an extensive effort was undertaken to block the oxidative metabolism and improve PK of this potent HSD1 lead. In this communication, SAR survey focusing on various alkyl chain replacements will be detailed. This effort culminated in the discovery of a potent ethyl sulfone inhibitor with an improved PK profile across species and improved physical properties.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / antagonists & inhibitors
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism
  • Animals
  • Bridged Bicyclo Compounds / chemistry*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Metabolic Syndrome / drug therapy*
  • Mice
  • Structure-Activity Relationship
  • Triazoles / chemistry*
  • Triazoles / pharmacokinetics
  • Triazoles / therapeutic use

Substances

  • Bridged Bicyclo Compounds
  • Enzyme Inhibitors
  • Triazoles
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2