The development of COX2 inhibitors

Key Points Prostaglandins are bioactive lipids that have potent actions in both pathological (inflammation, fever and pain) and physiological (protection of gastric mucosa, platelet agrregation) events. Prostaglandins are formed enzymatically by the cyclooxygenase (COX1) enzyme from unesterified fatty acids, especially arachidonic acid. The synthesis of prostaglandins is blocked by the aspirin-like drugs (NSAIDs) and this explains the therapeutic (anti-inflammatory, analgesic and antipyretic) actions of these drugs as well as their principal side effects (gastric damage and inhibition of platelet aggregation). Early hints in the literature suggested that there may be more than one form of the enzyme and this was eventually confirmed when a second isoform (COX2) was discovered in increased amounts in inflammatory tissues. It was suggested that the constitutive COX1 is the isozyme responsible for the physiological effects of prostaglandins in the stomach and in platelets, whereas the inducible COX2 was proposed as the main isoform responsible for inflammation. Most of the pre-existing NSAIDs inhibited both isoforms, perhaps explaining why these drugs had both therapeutic and side effects. An intensive search was begun to find a selective COX2 inhibitor. This culminated in the introduction of a new class of anti-inflammatories — the COX2 selective inhibitors — with improved tolerance. There may be other forms of COX that could account for some of the remaining discrepancies in action amongst NSAIDs. Aspirin, arguably the world's favourite drug, has been around since the late nineteenth century, but it wasn't until the late 1970s that its ability to inhibit prostaglandin production by the cyclooxygenase enzyme was identified as the basis of its therapeutic action. Early hints of a second form of the cyclooxygenase that was differentially sensitive to other aspirin-like drugs ultimately ushered in an exciting era of drug discovery, culminating in the introduction of an entirely new generation of anti-inflammatories. This article reviews the story of this discovery and looks at the future of cyclooxygenase pharmacology.