UC San Diego

Cytosolic phospholipase A₂ (GIVA cPLA₂) is the only PLA₂ that exhibits a marked preference for hydrolysis of arachidonic acid containing phospholipid substrates releasing free arachidonic acid and lysophospholipids and giving rise to the generation of diverse lipid mediators involved in inflammatory conditions. Thus, the development of potent and selective GIVA cPLA₂ inhibitors is of great importance. We have developed a novel class of such inhibitors based on the 2-oxoester functionality. This functionality in combination with a long aliphatic chain or a chain carrying an appropriate aromatic system, such as the biphenyl system, and a free carboxyl group leads to highly potent and selective GIVA cPLA₂ inhibitors (X _I(50) values 0.00007-0.00008) and docking studies aid in understanding this selectivity. A methyl 2-oxoester, with a short chain carrying a naphthalene ring, was found to preferentially inhibit the other major intracellular PLA₂, the calcium-independent PLA₂. In RAW264.7 macrophages, treatment with the most potent 2-oxoester GIVA cPLA₂ inhibitor resulted in over 50% decrease in KLA-elicited prostaglandin D₂ production. The novel, highly potent and selective GIVA cPLA₂ inhibitors provide excellent tools for the study of the role of the enzyme and could contribute to the development of novel therapeutic agents for the treatment of inflammatory diseases.