Eicosanoid Pathway Modulators: Prostaglandins, Prostacyclin, and Thromboxane

Abstract

Prostanoids (prostaglandins, prostacyclin, and thromboxane) are bioactive lipids, members of the eicosanoid class of compounds, derived from arachidonic acid (AA). They are involved in controlling homeostatic and pathophysiological processes. Their biosynthesis is the result of the coordinated actions of several enzymes. Cyclooxygenases (COXs) catalyze the committed step in the conversion of AA into prostanoids. There are two COX isozymes: the constitutive COX‐1 and the inducible COX‐2, both of which have different patterns of expression and biological functions. COX‐1 and COX‐2 are the targets of traditional nonsteroidal anti‐inflammatory drugs (tNSAIDs), which are used to relieve pain, fever and inflammation. Despite their clinical efficacy, tNSAIDs cause side effects, particularly in the gastrointestinal (GI) tract. NSAIDs selective for COX‐2 inhibition (coxibs) were purposefully designed to spare GI side effects, but predisposed patients to increased cardiovascular (CV) risks. The GI and CV complications from existing NSAIDs prompted interest in the downstream effectors of the COX enzymes as novel drug targets. This article describes various safety issues with tNSAIDs and coxibs, and discusses the current development of novel classes of drugs targeting the AA pathway, including nitric oxide‐releasing and hydrogen sulfide‐releasing NSAIDs, inhibitors of prostanoid synthases, dual inhibitors, and prostanoid receptor agonists and antagonists.