Isozyme-Selective Heme Oxygenase Inhibitors:Design,Synthesis,and Biological Evaluation
Jason Z.VlahakisRobert T.KinobeGheorghe RomanJames F.BrienKanji NakatsuWalter A.Szarek
Departments of Chemistry Queen’s University,Kingston,Ontario,Canada K7L 3N6Pharmacology & Toxicology Queen’s University,Kingston,Ontario,Canada K7L 3N6
摘要：<正> Several imidazole-containing compounds were synthesized and evaluated as novel inhibitors of heme oxygenase （HO）. A number of these compounds showed enhanced activity for HO over other heme - dependent enzymes （such as NOS and sGC）.In addition, some of these compounds were highly selective for the inhibition of HO-1（inducible isozyme） compared with HO - 2 （constitutive isozyme）. One of the compounds.QC-13,exhibits an IC50 value of 0.8±0.2 mM for HO - 1 （rat spleen） and approximately 305 mM for HO - 2 （rat brain）. Over 100 compounds have been synthesized, and structure activity relationships amongst these analogues with respect to the inhibition of HO and other enzymes will be presented. These drugs are anticipated to become useful tools in elucidating the physiological/pathological roles of HO/carbon monoxide in mammalian and other biological systems.