Design and synthesis of (R)-1-arylsulfonylpiperidine-2-carboxamides as 11β-hydroxysteroid dehydrogenase type 1 inhibitors

ChemMedChem. 2013 Apr;8(4):577-81. doi: 10.1002/cmdc.201300022. Epub 2013 Mar 7.

Abstract

R adamantly beats S: 11β-HSD1 is a target for treating metabolic syndrome. The R isomer 5 was selected as a starting point for optimization and SAR studies. Inhibitor 8 w emerged after several rounds of optimization, showing cross-species inhibition of human and mouse 11β-HSD1. It also displays a good DMPK profile in vitro, and was advanced to PK/PD evaluations in vivo. The results confirmed its dose-dependent activity in mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Animals
  • Binding Sites
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Half-Life
  • Humans
  • Isomerism
  • Mice
  • Molecular Docking Simulation
  • Piperidines / chemistry*
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Amides
  • Enzyme Inhibitors
  • Piperidines
  • piperidine
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1