Selective inhibition of heme oxygenase-2 activity by analogs of 1-(4-chlorobenzyl)-2-(pyrrolidin-1-ylmethyl)-1H-benzimidazole (clemizole): Exploration of the effects of substituents at the N-1 position

Bioorg Med Chem. 2013 Nov 1;21(21):6788-95. doi: 10.1016/j.bmc.2013.07.050. Epub 2013 Aug 8.

Abstract

Several analogs based on the lead structure of 1-(4-chlorobenzyl)-2-(pyrrolidin-1-ylmethyl)-1H-benzimidazole (clemizole) were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). Many of the compounds were found to be potent and highly selective for the HO-2 isozyme (constitutive), and had substantially less inhibitory activity on the HO-1 isozyme (inducible). The compounds represent the first report of highly potent and selective inhibitors of HO-2 activity, and complement our suite of selective HO-1 inhibitors. The study has revealed many candidates based on the inhibition of heme oxygenases for potentially useful pharmacological and therapeutic applications.

Keywords: Carbon monoxide; Clemizole analogs; Heme; Heme oxygenase; Selective inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry*
  • Benzimidazoles / metabolism
  • Brain / enzymology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Heme Oxygenase (Decyclizing) / antagonists & inhibitors*
  • Heme Oxygenase (Decyclizing) / metabolism
  • Heme Oxygenase-1 / antagonists & inhibitors
  • Heme Oxygenase-1 / metabolism
  • Protein Binding
  • Rats
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Enzyme Inhibitors
  • benzimidazole
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • heme oxygenase-2
  • clemizole