Overview of recent drug discovery approaches for new generation leukotriene A4 hydrolase inhibitors

Introduction: LTA(4)H is a bifunctional enzyme with hydrolase and aminopeptidase activities. The hydrolase function of this enzyme specifically catalyzes the rate-limiting step in the conversion of LTA(4) to LTB4, one of the most potent chemoattractant and activator of neutrophils. The wealth of in vitro and in vivo data favors in support of LTA(4)H as an appealing target for the discovery and development of anti-inflammatory drugs. Areas covered: The authors provide an overview of the recent advances on LTA(4)H inhibitors since 2000. The review details the medicinal chemistry efforts leading to the generation of novel inhibitor chemotypes with desirable drug-like properties as well as the advantages and disadvantages of LTA(4)H as a desirable therapeutic target. Expert opinion: Most of the LTA(4)H inhibitors block pro-inflammatory LTB4 biosynthesis by concomitant inhibition of both the hydrolase and aminopeptidase activities of LTA(4)H. However, the degradation of another endogenous chemoattractant substrate (PGP) by aminopeptidase function of LTA(4)H was shown, introducing a new anti-inflammatory mission for this pro-inflammatory enzyme. LTA(4)H inhibitors were also shown to maintain anti-inflammatory lipoxin formation. Hence, the data on new LTA(4)H inhibitors should be cautiously interpreted with regard to potential repercussions of preventing PGP degradation as well as for the clinical benefits of concomitant lipoxin formation.