Inhibitors of Cytosolic Phospholipase A2α as Anti-inflammatory Drugs

Arachidonic acid derivatives, like prostaglandins and leukotrienes, as well as the alkyl-ether phospholipid platelet-activating factor (PAF) are highly active substances with diverse biological actions. Elevated levels of these lipid mediators in response to a variety of stimuli have been implicated in the pathology of many inflammatory diseases. The rate-limiting step in the generation of prostaglandins, leukotrienes and PAF, respectively, is the cleavage of the sn-2-ester of membrane phospholipids by a phospholipase A2 (PLA2). Among the superfamily of PLA2 enzymes, cytosolic PLA2α (cPLA2α, also referred to as group IVA PLA2) is thought to play the primary role in this biochemical reaction. Therefore, inhibition of cPLA2α activity is an attractive approach to the control of inflammatory disorders. In this chapter the main groups of cPLA2α inhibitors are described and the problems associated with the development of clinical active drug candidates are discussed. Furthermore, in-vivo data obtained with such compounds in pre-clinical animal models of inflammation will be presented.