Inhibitors of phospholipase A₂ and their therapeutic potential: an update on patents (2012-2016)

ABSTRACT

Introduction: The regulation of the catalytic activity of the various phospholipase A₂ enzymes is of high importance because these enzymes are involved in various pathological conditions such as arthritis, cardiovascular diseases, neurological diseases, and cancer. Thus, a great effort has been devoted in developing synthetic inhibitors as new agents to treat inflammatory diseases. Some of them have reached clinical trials.

Areas covered: This review article discusses the phospholipase A₂ inhibitors presented in patent literature from October 2012 to June 2016, their activities in vitro and in vivo as well as the results of clinical trials using synthetic PLA₂ inhibitors.

Expert opinion: None of the inhibitors studied in clinical trials have reached the market yet. The failure of lipoprotein-associated PLA₂ inhibitor darapladib to reduce the risk of major coronary events suggests that this enzyme may be a biomarker of vascular inflammation rather than a causal pathway of cardiovascular diseases. These findings, together with the failure of secreted PLA₂ inhibitor varespladib for the treatment of cardiovascular disease, indicate that deeper knowledge on these enzymes is needed. Inhibitors of cytosolic PLA₂ are in clinical trials against psoriasis and atopic dermatitis.

KEYWORDS:

• Arthritis
• atherosclerosis
• autoimmune diseases
• cancer
• inflammation
• inhibitors
• phospholipase A₂

Article highlights

• Phospholipase A₂ enzymes act as the most upstream regulators of eicosanoid biosynthesis and regulate the eicosanoid response during different phases of an inflammatory response.

• Organic chemistry together with biophysical methods and in vitro assays allow to understand the enzyme-inhibitor interactions and to design more potent inhibitors.

• The failure of lipoprotein-associated phospholipase A₂ inhibitor darapladib to reduce the risk of coronary events suggests that this enzyme may be a biomarker of vascular inflammation rather than a casual pathway of cardiovascular diseases.

• Inhibitors of cytosolic phospholipase A₂ are currently in clinical trials against psoriasis and atopic dermatitis.

• Calcium-independent phospholipase A₂ is a relatively unexplored medicinal target and its inhibitors may become new agents for the treatment of autoimmune diseases.

This box summarizes key points contained in the article.

Acknowledgments

D Limnios would like to thanks IKY for a postdoctoral fellowship.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper has been funded by the General Secretariat for Research and Technology (11∑YN-1-1258). This research has been co-financed by the European Union (European Regional Development Fund ERDF) and Greek national funds through the Operational Program ‘Competitiveness and Entrepreneurship’ of the National Strategic Reference Framework (NSRF) Research Funding Program ‘Phospholipases A₂ Inhibitors: Developing a Drug Pipeline for the Treatment of Inflammatory Neurological Disorders’. D Limnios received funding for his postdoctoral fellowship from the National Scholarships Foundation (IKY) Grant ID – DL.