Inhibitors of Secretory Phospholipase A2 Group IIA

Abstract

Phospholipases A2 cleave membrane phospholipids to release arachidonic acid, the precursor to a large family of pro-inflammatory eicosanoids including prostaglandins and leukotrienes that have been proven to exacerbate numerous diseases that have an inflammatory component. Current therapies include NSAIDs' that inhibit cyclooxygenases (COX-1, COX-2) but have no effect on the production of leukotrienes or platelet activating factor (PAF). Inhibitors of PLA2 therefore offer the potential to block production of a more complete set of inflammatory substances through blockade at the onset of the cascade of reactions that follow arachidonic acid release. Many potent, bioavailable and selective inhibitors of human sPLA2 group IIA have been available for more than a decade and have provided compelling support for a causative role of sPLA2 group IIA in numerous studies involving animal models of inflammatory diseases. However, the true value of sPLA2 inhibitors for the treatment of human diseases has had to await phase II clinical trials which have only been completed in the last two years. This review presents the structurally diverse array of available sPLA2 group IIA inhibitors, their associated biological activity in animal models, and evaluation of therapeutic potential in phase II clinical trials in humans.

Lipid signalling in disease

“…Numerous efforts to target these enzymes have generated useful experimental inhibitors (see accompanying Poster 'Targeting lipid signalling in disease'), but no marketable drugs so far. Overall, PLA2 levels are modulated by corticosteroids 113 . Downstream of cPLA2, the cyclooxygenase (COX) activity of prostaglandin H2 synthase is a classic target of NSAIDs.…”

Integration of cytokine biology and lipid metabolism in stroke

“…Pancreatic sPLA 2 (group IB) was not expressed in ischemic brain. A large number of sPLA 2 IIA inhibitors have been developed as antiinflammatory agents (142)(143)(144) but to the best of our knowledge they have not been tested in stroke models.…”

“…This is supported by our studies demonstrating that neutralization of TNF-α or IL-1 in animal model of stroke attenuated sPLA 2 protein expression (Figure 8). It should be reminded that various sPLA 2 inhibitors have been developed but not many have been tested in stroke models (142)(143)(144).…”

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

“…Enzymes that use arachidonic acid as a substrate as well as arachidonic acid products such as 12-lipoxygenase, 5-lipoxygenase, cysteinyl leukotrienes, and thromboxane A 2 (TXA 2 ) have well-defined profibrotic properties (12,13). The precise isoform(s) responsible for arachidonate production in vivo in inflammatory conditions is still controversial, with evidence that cytosolic (c)PLA 2 and secretory (s)PLA 2 type V are more potent than sPLA 2 -IIA in phospholipid degradation (14,15). Nevertheless, the calcium-dependent human sPLA 2 -IIA enzyme is implicated in a wide range of inflammatory diseases, including rheumatoid arthritis (16,17), pancreatitis (18), and sepsis (19).…”

“…Nevertheless, the calcium-dependent human sPLA 2 -IIA enzyme is implicated in a wide range of inflammatory diseases, including rheumatoid arthritis (16,17), pancreatitis (18), and sepsis (19). Inhibitors of this enzyme have also shown therapeutic effects in many animal models of inflammatory diseases (15), providing compelling evidence for a causative role of sPLA 2 -IIA.…”