Inhibitors of Secretory Phospholipase A2 Group IIA

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.