Optimization of novel di-substituted cyclohexylbenzamide derivatives as potent 11 beta-HSD1 inhibitors

Bioorg Med Chem Lett. 2009 Mar 1;19(5):1446-50. doi: 10.1016/j.bmcl.2009.01.026. Epub 2009 Jan 15.

Abstract

Novel 4,4-disubstituted cyclohexylbenzamide inhibitors of 11beta-HSD1 were optimized to account for liabilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A representative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11beta-HSD1 in a rat pharmacodynamic model (ED(50)=10mg/kg).

Publication types

  • Comparative Study

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Animals
  • Benzamides / chemistry*
  • Benzamides / pharmacology
  • Dose-Response Relationship, Drug
  • HeLa Cells
  • Humans
  • Macaca fascicularis
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Benzamides
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1