Discovery of SAR184841, a potent and long-lasting inhibitor of 11β-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D

Bioorg Med Chem Lett. 2013 Apr 15;23(8):2414-21. doi: 10.1016/j.bmcl.2013.02.018. Epub 2013 Feb 22.


Starting from 11β-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11β-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Adamantane / chemistry
  • Adamantane / pharmacokinetics
  • Adamantane / pharmacology*
  • Animals
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Transgenic
  • Structure-Activity Relationship


  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • Adamantane