Paul R. Johnson

Novel Synthesis of Potent Site-Specific Phospholipase A2 Inhibitors

Phospholipase A2 (PLA2) is an esterase responsible for the liberation of phospholipid-bound arachidonic acid, a biosynthetic precursor of putative inflammatory mediators. Arachidonic acid is metabolized by cyclooxygenase and lipoxygenase to the corresponding prostaglandins and leukotrienes (Fig. 1). Traditional antiinflammatory therapy has relied on cyclooxygenase and more recently on lipoxygenase blockade (Shen, 1981), but direct control of arachidonic acid pools has remained relatively unexplored. Recent evidence (Hirata et al., 1980; Blackwell et al., 1980; Rothhut et al., 1983) demonstrates that antiinflammatory steroids control polyunsaturated fatty acid release at both cyclooxygense and lipoxygenase pathways by enhancing the production of PLA2 inhibitory proteins (lipomodulin, macrocortin, renocortin). Direct phospholipase A2 site-specific inhibition, therefore, offers new opportunities in antiinflammatory treatment.