Modulation of inflammatory disease by inhibitors of leukotriene A4 hydrolase

Leukotriene A4 hydrolase (LTA4H) is a ubiquitously expressed enzyme that catalyzes the final step in the synthesis of leukotriene B4 (LTB4), a potent proinflammatory lipid mediator derived from arachidonic acid. Although LTB4 was identified 30 years ago, several recent findings have refocused attention on this mediator as a target for inflammatory and autoimmune diseases. While LTB4 was once thought to be a chemoattractant and activator only of leukocytes mediating acute, innate inflammatory responses, LTB4 receptors have since been discovered on multiple cell types, including T-lymphocytes and antigen-presenting dendritic cells. Thus, the inhibition of LTB4 synthesis demonstrates potential for targeting chronic, autoimmune-driven inflammation. In addition to genetic data in animals and humans linking the LTB4 pathway to cardiovascular disease, variants in the LTA4H gene have been linked with susceptibility to asthma. Several companies have initiated drug discovery efforts to identify potent, selective LTA4H inhibitors. Selected molecules have demonstrated oral efficacy in preclinical models of asthma, inflammatory bowel disease and arthritis, suggesting therapeutic potential for multiple indications. This review focuses on developments with therapeutic relevance for inhibitors of LTA4H as anti-inflammatory drugs, and particularly in the treatment of respiratory disease.