The various phospholipase A(2) (PLA(2)) types have been implicated in diverse kinds of lipid signaling and inflammatory diseases. Rheumatoid arthritis, lung inflammation, neurological disorders, such as multiple sclerosis, cardiovascular diseases, including atherosclerosis, and cancer are included among the diseases where PLA(2) enzymes are involved. Thus, there is a great interest in developing potent and selective PLA(2) inhibitors and some of them have entered clinical trials. This review article discusses the role of each PLA(2) class in inflammatory diseases and the advances in the development of inhibitors presented in patent literature from January 2004 to May 2009. PLA(2)s cluster in four main types: secreted sPLA(2), cytosolic cPLA(2), Ca(2+)-independent iPLA(2) and lipoprotein-associated LpPLA(2). Each of those types has been implicated in diverse kinds of inflammatory diseases. Readers will rapidly gain an overview of the various PLA(2) inhibitors reported in the patent literature in the past 5 years. Furthermore, the readers will learn the difficulties related to the development of PLA(2) inhibitors as new drugs and also the different companies and research groups that are the main players in the field. Although the role of each PLA(2) is not yet distinct in different diseases, the development and future use of different PLA(2) inhibitors to treat human disease seems very promising.

The phospholipase A₂ (PLA₂) superfamily hydrolyzes phospholipids to release free fatty acids and lysophospholipids, some of which can mediate inflammation and demyelination, hallmarks of the CNS autoimmune disease multiple sclerosis. The expression of two of the intracellular PLA₂s (cPLA₂ GIVA and iPLA₂ GVIA) and two of the secreted PLA₂s (sPLA₂ GIIA and sPLA₂ GV) are increased in different stages of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We show using small molecule inhibitors, that cPLA₂ GIVA plays a role in the onset, and iPLA₂ GVIA in the onset and progression of EAE. We also show a potential role for sPLA₂ in the later remission phase. These studies demonstrate that selective inhibition of iPLA₂ can ameliorate disease progression when treatment is started before or after the onset of symptoms. The effects of these inhibitors on lesion burden, chemokine and cytokine expression as well as on the lipid profile provide insights into their potential modes of action. iPLA₂ is also expressed by macrophages and other immune cells in multiple sclerosis lesions. Our results therefore suggest that iPLA₂ might be an excellent target to block for the treatment of CNS autoimmune diseases, such as multiple sclerosis.