Current status of leukotriene A₄ hydrolase inhibitors

Abstract

Background: Leukotriene A₄ hydrolase (LTA₄H) is a ubiquitously distributed 69-kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA₄H stereospecifically catalyzes the transformation of the unstable epoxide LTA₄ to the diol leukotriene B₄ (LTB₄), a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, T cells, dendritic cells, smooth muscle cells and keratinocytes. Inhibiting the formation of LTB₄ is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease, asthma and atherosclerosis. Objective: The focus of this review will be on patent applications/patents containing LTA₄H inhibitors that were published between 1996 and March 2008 from four different companies. The documents reviewed are presented in a tabular manner. Method: The first part of this review focuses on the primary literature supporting LTA₄H as a potential target. The second part covers the patent literature organized by applicant identified during the prescribed period. Conclusion: Activity towards identifying small molecule inhibitors of LTA4H has escalated in the last few years in line with important scientific and clinical developments involving the leukotriene pathway. One inhibitor from deCODE, DG-051, is reported to be in clinical trials for myocardial infarction and future reports of clinical efficacy will undoubtedly stimulate further work in the field by others.

Keywords::

• arachidonic acid
• eicosanoid
• immune-mediated inflammatory disease
• inflammation
• leukotriene A₄ hydrolase
• leukotriene B₄ synthesis inhibitor