Exploring N-acyl-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-enes as 11β-HSD1 Inhibitors

Molecules. 2018 Feb 28;23(3):536. doi: 10.3390/molecules23030536.

Abstract

We recently found that a cyclohexanecarboxamide derived from 4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene displayed low nanomolar inhibition of 11β-HSD1. In continuation of our efforts to discover potent and selective 11β-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11β-HSD1, although with low selectivity over the isoenzyme 11β-HSD2, and poor microsomal stability.

Keywords: 11β-HSD1; SAR investigation; drug discovery; enzyme inhibitors; polycyclic hydrocarbons.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / chemistry*
  • Chemistry Techniques, Synthetic
  • Drug Design
  • Enzyme Activation
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Structure-Activity Relationship

Substances

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