Identification of a potent, selective, and orally active leukotriene A4 hydrolase inhibitor with anti-inflammatory activity

LTA(4)H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA(4)H stereospecifically catalyzes the transformation of the unstable epoxide LTA(4) to the diol LTB4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (1131)), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA(4)H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.