Discovery of novel 7-membered cyclic amide derivatives that inhibit 11beta-hydroxysteroid dehydrogenase type 1

Bioorg Med Chem Lett. 2013 Mar 15;23(6):1617-21. doi: 10.1016/j.bmcl.2013.01.090. Epub 2013 Jan 29.

Abstract

A series of novel 5-trans-hydroxyadamantan-2-yl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-ones that inhibit 11beta-hydroxysteroid dehydrogenase type 1 are described. We discovered these 7-membered cyclic amide derivatives by introducing a distinctive linker through pharmacophore analysis of known ligands included in X-ray co-crystal structures. Further optimization using docking studies led to highly potent inhibitors 15b and 27, which furthermore showed the potent efficacy in in vivo studies.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / metabolism
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Mice
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

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