Heme oxygenase inhibition by 2-oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbutanes: effect of halogen substitution in the phenyl ring

Bioorg Med Chem. 2007 May 1;15(9):3225-34. doi: 10.1016/j.bmc.2007.02.034. Epub 2007 Feb 22.

Abstract

A series of 2-oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbutanes comprising imidazole-ketones, imidazole-dioxolanes, and imidazole-alcohols substituted with halogens in the phenyl ring were synthesized and evaluated as novel inhibitors of heme oxygenase which are structurally distinct from metalloporphyrins. The entire library of compounds was found to be highly active, with the bromine- and iodine-substituted derivatives being the most potent. The imidazole-dioxolanes were all selective for the HO-1 isozyme (inducible) and exhibited substantially lower activity toward the HO-2 isozyme (constitutive). The corresponding imidazole-ketones and imidazole-alcohols showed selectivity toward HO-1 to a lesser degree than the similarly substituted imidazole-dioxolanes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / enzymology
  • Butanes / chemical synthesis
  • Butanes / chemistry
  • Butanes / pharmacology*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Halogens / chemistry*
  • Heme Oxygenase (Decyclizing) / antagonists & inhibitors*
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Molecular Structure
  • Rats
  • Rats, Sprague-Dawley
  • Spleen / enzymology
  • Structure-Activity Relationship

Substances

  • Butanes
  • Enzyme Inhibitors
  • Halogens
  • Imidazoles
  • Heme Oxygenase (Decyclizing)