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

Abstract

Introduction: LTA₄H 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 LTA₄ 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 LTA₄H 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 LTA₄H 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 LTA₄H as a desirable therapeutic target.

Expert opinion: Most of the LTA₄H inhibitors block pro-inflammatory LTB₄ biosynthesis by concomitant inhibition of both the hydrolase and aminopeptidase activities of LTA₄H. However, the degradation of another endogenous chemoattractant substrate (PGP) by aminopeptidase function of LTA₄H was shown, introducing a new anti-inflammatory mission for this pro-inflammatory enzyme. LTA₄H inhibitors were also shown to maintain anti-inflammatory lipoxin formation. Hence, the data on new LTA₄H 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.

Keywords::

• aminopeptidase
• hydrolase
• inflammation
• leukotriene A4
• leukotriene B4
• PGP

Notes

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