Inhibitors of the heme oxygenase-carbon monoxide system: on the doorstep of the clinic?

The past decade has seen substantial developments in our understanding of the physiology, pathology, and pharmacology of heme oxygenases (HO), to the point that investigators in the field are beginning to contemplate therapies based on administration of HO agonists or HO inhibitors. A significant amount of our current knowledge is based on the judicious application of metalloporphyrin inhibitors of HO, despite their limitations of selectivity. Recently, imidazole-based compounds have been identified as potent and more selective HO inhibitors. This ‘next generation’ of HO inhibitors offers a number of desirable characteristics, including isozyme selectivity, negligible effects on HO protein expression, and physicochemical properties favourable for in vivo distribution. Some of the applications of HO inhibitors that have been suggested are treatment of hyperbilirubinemia, neurodegenerative disorders, certain types of cancer, and bacterial and fungal infections. In this review, we address various approaches to altering HO activity with a focus on the potential applications of second-generation inhibitors of HO

Recombinant truncated and microsomal heme oxygenase-1 and -2: differential sensitivity to inhibitors

Recombinant truncated forms of heme oxygenase-1 and -2 (HO-1 and HO-2) were compared with their crude microsomal counterparts from brain and spleen tissue of adult male rats with respect to their inhibition by azole-based, nonporphyrin HO inhibitors. The drugs tested were an imidazole-alcohol, an imidazole-dioxolane, and a triazole-ketone. Both the recombinant and crude forms of HO-2 were similarly inhibited by the 3 drugs. The crude microsomal spleen form of HO-1 was more susceptible to inhibition than was the truncated recombinant form. This difference is attributed to the extra amino acids in the full-length enzyme. These observations may be relevant in the design of drugs as inhibitors of HO and other membrane proteins

Creation of novel pharmacological tools in heme oxygenase research

Aims: While great strides have been made in the elucidation of the physiological and pharmacological roles of heme oxygenases (HO) in experimental animals and humans,\ud there is still an enormous potential for further research discoveries and their application in therapeutics. We have identified the need for improved pharmacological tools for\ud Heme Oxygenase research, and have conducted a program to design and test new compounds for their potential as selective inhibitors and activators of HO-1 and HO-2.\ud \ud Methods & Results: Our first undertaking exploited the "hit" compound, (2S,4S)-2-[2-(4-chlorphenyl)ethyl]-2-[(1H-imidazol- 1-yl)methyl]-4-[((4- aminophenyl)thio)methyl]-1,3-dioxolane, QC-1. New candidates were designed on the\ud basis of QC-1, and synthesized in our laboratories; they were then tested for HO inhibition using spleen and brain microsomal preparations as sources of HO-1 and HO-2,\ud respectively. Many QC-xx compounds were identified as inhibitors of both HO-1 and HO-2, while a subset were found to be selective for HO-1. X-ray crystallography has\ud revealed that these inhibitors bind to the substrate, heme, in the active site. Subsequently, we screened compound libraries and identified "hits" as candidates for new skeletons in the design of selective inhibitors and activators of HO-2. The latter compounds appear to\ud be selective for HO-2 in that we have observed up to 30-fold activation of HO-2 and no activation of HO-1.\ud \ud Conclusions: The novel compounds that have resulted from this work are being evaluated for their use as tools for the ongoing investigation of heme oxygenases, and their roles in health and disease