Imidazole-dioxolane compounds as isozyme-selective heme oxygenase inhibitors.
Several imidazole-dioxolane compounds were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds, which include (2R,4R)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-methyl-1,3-dioxolane (1) hydrochloride, are structurally distinct from metalloporphyrin HO inhibitors and lack the aminothiophenol moiety of azalanstat. They were found to be highly selective for the HO-1 isozyme (stress induced) and had substantially less inhibitory potency toward HO-2, the constitutive isozyme. These imidazole-dioxolane compounds are the first of their type known to exhibit this isozyme-selective HO inhibition.
Vlahakis
Jason Z
JZ
Department of Chemistry, Queen's University, Kingston, ON K7L 3N6, Canada.
Kinobe
Robert T
RT
Bowers
Raymond J
RJ
Brien
James F
JF
Nakatsu
Kanji
K
Szarek
Walter A
WA
D000818:Animals; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C513164:2-(2-(4-chlorophenyl)ethyl)-2-((1H-imidazol-1-yl)methyl)-4-methyl-1,3-dioxolane; D004148:Dioxolanes; D007093:Imidazoles; D007527:Isoenzymes; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2