Inhibitors of phospholipase A₂and their therapeutic potential: an update on patents (2012-2016)

Abstract

The regulation of the catalytic activity of the various phospholipase A 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 A 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 PLA inhibitors. Expert opinion: None of the inhibitors studied in clinical trials have reached the market yet. The failure of lipoprotein-associated PLA 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 PLA inhibitor varespladib for the treatment of cardiovascular disease, indicate that deeper knowledge on these enzymes is needed. Inhibitors of cytosolic PLA are in clinical trials against psoriasis and atopic dermatitis.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…In a recent review article, Ramanadham et al discuss in detail how increased or decreased expression of iPLA 2 s may affect the metabolic state, CNS function, cardiovascular performance and cell survival [58]. Since dysregulation of iPLA 2 s may play a critical role in the development of many diseases, such as diabetes, Barth syndrome, ovarian cancer, ischemia, multiple sclerosis, research for the discovery of potent small-molecule inhibitors is therefore considered crucial [4,7,8,13].…”

“…However, four types of human PLA 2 s have been targeted for the development of synthetic inhibitors as new medicinal agents: GIVA cPLA 2 , sPLA 2 , cytosolic GVIA iPLA 2 and lipoprotein-associated PLA 2 (LpPLA 2 or GVII PLA 2 ). The various classes of small-molecule synthetic PLA 2 inhibitors are summarized in two recent review articles [7,8]. Apart from their importance as new potential therapeutics to treat inflammatory diseases, small-molecule PLA 2 inhibitors are excellent tools to unveil the role that each PLA 2 type plays in cells and in vivo.…”

Highly Potent 2-Oxoester Inhibitors of Cytosolic Phospholipase A2 (GIVA cPLA2)

“…1 Two recent review articles discuss the classes of PLA 2 inhibitors and highlight the in vitro activities and selectivity and the in vivo studies in animal models. 5,6 …”

Phospholipases during membrane dynamics in malaria parasites

“…The link between PLA 2 and cancer makes these enzymes potential anti-cancer targets (reviewed in Cummings, 2007;Marks et al, 2000;Wang and Dubois,2006). Although a broad range of PLA 2 inhibitors exist (reviewed in Farooqui et al, 1999;Kokotou et al, 2017;Meyer et al, 2005), current knowledge about the mode of action or toxicity in humans or animal models is limited and their effectiveness as pharmacological agents has yet to be addressed (reviewed in Cummings, 2007;Laye and Gill, 2003). A main drawback in targeting PLA 2 with chemotherapeutics is the wide range of individual PLA 2 isoforms, as well as their physiological roles in healthy cell homeostasis (reviewed in Balsinde et al, 1999;Cummings, 2007).…”