Therapeutic Role of Cyclooxygenase-1 (COX-1) Inhibition, Challenging the Conventional View of COX-1 as Purely Constitutive

Cyclooxygenases(COXs) are the primary target of nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat a wide variety of clinical symptoms and diseases. NSAIDs inhibit both enzymes known as COX-1 and COX-2. In the early 2000s, research made enormous efforts to develop COX-2-selective inhibitors (<i>coxibs</i>) to reduce serious gastrointestinal side effects of nonselective NSAIDs caused by COX-1 inhibition. During the last few decades, several studies highlighted the contribution of COX-1-derived prostanoids in the genesis of cancer, neuroinflammation, atherosclerosis, rheumatoid arthritis, and pain. Therefore, COX-1 is now recognized as a pharmacotherapeutic target. Multistep prostanoid biosynthesis begins with the COX-catalyzed conversion of arachidonic acid into prostaglandin H₂, which in turn transformed into prostanoids by tissue-specific enzymes. Here, the physiopathological role of COX-1 is illustrated through its selective inhibitors discovered to date, its potential as a theranostic target, but also by analyzing the structural determinants for new more potent and selective COX-1 inhibitor development.