Synthesis and biological analysis of benzazol-2-yl piperazine sulfonamides as 11β-hydroxysteroid dehydrogenase 1 inhibitors

Bioorg Med Chem Lett. 2013 Oct 1;23(19):5397-400. doi: 10.1016/j.bmcl.2013.07.047. Epub 2013 Jul 31.

Abstract

In the last decade the inhibition of the enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) emerged as a promising new strategy to treat diabetes and several metabolic syndrome phenotypes. Using a molecular modeling approach and classical bioisosteric studies, we discovered a new class of 11β-HSD1 inhibitors bearing an arylsulfonylpiperazine scaffold. Optimization of the initial lead resulted in compound 11 that selectively inhibits 11β-HSD1 (IC50=0.7 μM).

Keywords: 11β-Hydroxysteroid dehydrogenase; 2-Benzazolylpiperazine; Metabolic diseases; Molecular modeling; Structure–activity relationships (SAR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • Animals
  • Azoles / chemistry*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Piperazine
  • Piperazines / chemical synthesis
  • Piperazines / chemistry*
  • Piperazines / pharmacology
  • Structure-Activity Relationship
  • Sulfonamides* / chemical synthesis
  • Sulfonamides* / chemistry
  • Sulfonamides* / pharmacology

Substances

  • Azoles
  • Enzyme Inhibitors
  • Piperazines
  • Sulfonamides
  • Piperazine
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1