Progress in the development of selective heme oxygenase-1 inhibitors and their potential therapeutic application

Heme oxygenases (HOs) are a family of enzymes involved in the selective catabolism of free circulating heme. While HO-2 is constitutively expressed, HO-1 is strongly overexpressed under stressful stimuli (e.g., oxidative stress). Under these conditions, HO-1 exerts its strong cytoprotective activities and plays a crucial role in stimulating cell survival by removing the pro-oxidant heme and by producing carbon monoxide and biliverdin (promptly reduced to bilirubin). Unfortunately, the broad spectrum of HO-1 cytoprotective effects has been well experimentally documented both in normal and tumor cells, where the enzyme can be overexpressed, making it an exciting target in the management of some type of tumors. Development of non-competitive HO-1 inhibitors dates back in 2002 with the discovery of Azalanstat. Since then, many efforts have been devoted to the identification of selective HO-1 and HO-2 inhibitors and to unravel the molecular determinants responsible for selectivity. Molecular modeling studies supported the identification of chemical features involved in the recognition and inhibition of these enzymes. Herein, medicinal chemistry aspects and in silico studies related to the development of HO inhibitors will be discussed. The purpose of this review is to highlight recent advances in the development of new selective HO-1 and HO-2 inhibitors and covers the last six years (2013-2018).