Spirocyclic ureas: orally bioavailable 11 beta-HSD1 inhibitors identified by computer-aided drug design

Bioorg Med Chem Lett. 2010 Feb 1;20(3):881-6. doi: 10.1016/j.bmcl.2009.12.082. Epub 2010 Jan 4.

Abstract

Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11beta-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.

Publication types

  • Comparative Study

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Administration, Oral
  • Animals
  • Binding Sites / physiology
  • Biological Availability
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Drug Design*
  • Humans
  • Macaca fascicularis
  • Mice
  • Rats
  • Structure-Activity Relationship
  • Urea / administration & dosage*
  • Urea / analogs & derivatives
  • Urea / pharmacokinetics*

Substances

  • Urea
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1