Discovery of bicyclic pyrazoles as class III histone deacetylase SIRT1 and SIRT2 inhibitors

Bioorg Med Chem Lett. 2015 Jun 15;25(12):2514-8. doi: 10.1016/j.bmcl.2015.04.068. Epub 2015 Apr 28.

Abstract

A series of bicyclic pyrazole carboxamides was synthesized and tested for inhibitory activity against the class III deacetylase sirtuin enzymes. Moderate to low micromolar inhibitory activities were obtained against SIRT1 and SIRT2. These bicyclic pyrazole compounds represent a new class of sirtuin inhibitors with a preference for SIRT1 over SIRT2.

Keywords: Docking; Inhibitor; Pyrazole; SIRT; Sirtuin.

MeSH terms

  • Binding Sites
  • Bridged Bicyclo Compounds / chemistry*
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Molecular Dynamics Simulation
  • Protein Binding
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism
  • Sirtuin 1 / antagonists & inhibitors*
  • Sirtuin 1 / metabolism
  • Sirtuin 2 / antagonists & inhibitors*
  • Sirtuin 2 / metabolism
  • Structure-Activity Relationship

Substances

  • Bridged Bicyclo Compounds
  • Pyrazoles
  • Sirtuin 1
  • Sirtuin 2