Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors

Bioorg Med Chem Lett. 2012 Jun 1;22(11):3786-90. doi: 10.1016/j.bmcl.2012.04.005. Epub 2012 Apr 9.

Abstract

A novel series of benzenesulfonanilide derivatives of 11β-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11β-HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively).

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / genetics
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / pharmacology
  • Anilides / chemical synthesis
  • Anilides / chemistry*
  • Aniline Compounds / chemical synthesis
  • Aniline Compounds / chemistry*
  • Aniline Compounds / pharmacology
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • HEK293 Cells
  • Humans
  • Molecular Conformation
  • Piperazine
  • Piperazines / chemical synthesis
  • Piperazines / chemistry*
  • Piperazines / pharmacology
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology
  • Transfection

Substances

  • Anilides
  • Aniline Compounds
  • Enzyme Inhibitors
  • Piperazines
  • Sulfonamides
  • Piperazine
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1