Drug discovery strategies for novel leukotriene A4 hydrolase inhibitors

ABSTRACT

Introduction

Leukotriene A4 hydrolase (LTA4H) is the final and rate limiting enzyme regulating the biosynthesis of leukotriene B4 (LTB4), a pro-inflammatory lipid mediator implicated in a large number of inflammatory pathologies. Inhibition of LTA4H not only prevents LTB4 biosynthesis but also induces a lipid mediator class-switch within the 5-lipoxygenase pathway, elevating biosynthesis of the anti-inflammatory lipid mediator Lipoxin A4. Ample preclinical evidence advocates LTA4H as attractive drug target for the treatment of chronic inflammatory diseases.

Areas covered

This review covers details about the biochemistry of LTA4H and describes its role in regulating pro- and anti-inflammatory mediator generation. It summarizes recent efforts in medicinal chemistry toward novel LTA4H inhibitors, recent clinical trials testing LTA4H inhibitors in pulmonary inflammatory diseases, and potential reasons for the discontinuation of former development programs.

Expert opinion

Given the prominent role of LTB4 in initiating and perpetuating inflammation, LTA4H remains an appealing drug target. The reason former attempts targeting this enzyme have not met with success in the clinic can be attributed to compound-specific liabilities of first-generation inhibitors and/or choice of target indications to test this mode of action. A new generation of highly potent and selective LTA4H inhibitors is currently undergoing clinical testing in indications with a strong link to LTB4 biology.

KEYWORDS:

• Leukotrienes
• LTA4H
• anti-inflammatory
• drug discovery
• lipid mediators

Article highlights

• LTA4H is a cytosolic zinc metallopeptidase with two distinct but overlapping catalytic sites that exert two functions, an epoxide hydrolase and an aminopeptidase function.

• Inhibition of LTA4H differentiates from inhibition of upstream enzymes cPLA2/5-LO/FLAP or downstream receptor BLT1/BLT2 receptor antagonists as it results in a modulation of immune modulatory lipid mediators, most notably it suppresses pro-inflammatory LTB4 and elevates anti-inflammatory LXA4 and to some extend CysLT biosynthesis.

• Inhibition of LTA4H shows strong anti-inflammatory activity pre-clinically and recent clinical trials in pulmonary inflammatory conditions also demonstrated its capacity to suppress neutrophilic inflammation and inflammatory exacerbation, clinically, but failed to impact lung function.

• While drug discovery efforts in recent years have mostly focused on the identification of epoxide hydrolase selective LTA4H inhibitors, these efforts have not resulted in potent, drug-like and selective compounds. In addition, the physiological relevance of sparing the aminopeptidase function of LTA4H remains unclear.

• Novel highly potent and selective LTA4H inhibitors have very recently entered phase II clinical studies in non-pulmonary neutrophil-driven inflammatory conditions and results will soon show, if inhibition of LTA4H can recapitulate its profound anti-inflammatory effect also clinically in selected indications.

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Declaration of interest

The authors declare that they are employees of and hold stocks or stock options with Novartis Pharma AG. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are funded by Novartis Institutes for Biomedical Research.