Heme oxygenase inhibition by 2-oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbutanes: effect of halogen substitution in the phenyl ring.
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.
Roman
Gheorghe
G
Department of Chemistry, Queen's University, Kingston, Ont., Canada.
Riley
John G
JG
Vlahakis
Jason Z
JZ
Kinobe
Robert T
RT
Brien
James F
JF
Nakatsu
Kanji
K
Szarek
Walter A
WA
D000818:Animals; D001921:Brain / Q000201:enzymology; D002073:Butanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006219:Halogens / Q000737:chemistry*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000201:enzymology; D013329:Structure-Activity Relationship
D002073:Butanes; D004791:Enzyme Inhibitors; D006219:Halogens; D007093:Imidazoles; D006419:Heme Oxygenase (Decyclizing)