Pyrrolidine-pyrazole ureas as potent and selective inhibitors of 11β-hydroxysteroid-dehydrogenase type 1

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2244-51. doi: 10.1016/j.bmcl.2011.02.111. Epub 2011 Mar 23.

Abstract

A High Throughput Screening campaign allowed the identification of a novel class of ureas as 11β-HSD1 inhibitors. Rational chemical optimization provided potent and selective inhibitors of both human and murine 11β-HSD1 with an appropriate ADME profile and ex vivo activity in target tissues.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Administration, Oral
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • High-Throughput Screening Assays
  • Humans
  • Mice
  • Pyrazoles / chemistry*
  • Pyrrolidines / chemistry*
  • Urea / chemical synthesis
  • Urea / chemistry*
  • Urea / pharmacokinetics

Substances

  • Enzyme Inhibitors
  • Pyrazoles
  • Pyrrolidines
  • pyrazole
  • Urea
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • pyrrolidine