![]() ![]() Once a prostanoid is formed, it exits the cell and then interacts with G protein-coupled receptors, either on the parent cell or on closely neighboring cells to modulate the second messenger levels ( 6). In addition, peroxisome proliferator-activated receptors (PPAR) have been identified as novel intracellular PG receptors ( 5). These receptors are linked to the different signal transduction pathways ( 4). They act via high-affinity G protein-coupled receptors: four EP receptors for PGE2 termed EP1-EP4, IP receptor for prostacyclin, DP receptor for PGD2, FP receptor for PGF2 α. Prostaglandins (PGs) are hormone-like bioactive substances mediating autocrine and paracrine signaling over the short distances and are involved in many physiological and pathological processes. The biosynthesis of prostanoids, which include the prostaglandins (PGs) and thromboxanes, occurs in three steps: (a) the mobilization of a fatty acid substrate, typically arachidonic acid (AA), from membrane phospholipids through the action of a phospholipase A2 (b) biotransformation of AA by cyclooxygenase in a bifunctional action which leads to the generation of unstable PGG2 by the cyclooxygenase reaction, and its immediate conversion into PGH2 by the same enzyme in a peroxidase reaction (c) the conversion of PGH2 to specific prostanoids through the action of synthases and specific isomerases ( 3). The cyclooxygenase enzyme was first identified as the therapeutic target of NSAIDs by Vane in 1971, showing that these anti-inflammatory substances block the biosynthesis of prostaglandins (PGs) that contribute to a variety of physiological and pathophysiological functions ( 2). From a historical viewpoint, the first NSAID with therapeutic benefits was aspirin, which has now been used for more than 100 years as a NSAID ( 1). Through their anti-inflammatory, anti-pyretic and analgesic activities, they represent a choice treatment in various inflammatory diseases such as arthritis, rheumatisms as well as relieving the pains of everyday life. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutics. This review highlights the various structural classes of selective COX-2 inhibitors with special emphasis on their structure-activity relationships. Recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Parkinson and Alzheimer’s diseases still continues to attract investigations on the development of COX-2 inhibitors. However, the recent market removal of some COXIBs such as rofecoxib due to its adverse cardiovascular side effects clearly encourages the researchers to explore and evaluate alternative templates with COX-2 inhibitory activity. ![]() Based upon a number of selective COX-2 inhibitors (rofecoxib, celecoxib, valdecoxib etc.) were developed as safer NSAIDs with improved gastric safety profile. Thus, it was though that more selective COX-2 inhibitors would have reduced side effects. The therapeutic anti-inflammatory action of NSAIDs is produced by the inhibition of COX-2, while the undesired side effects arise from inhibition of COX-1 activity. Their use is associated with the side effects such as gastrointestinal and renal toxicity. Non-steroidal anti-inflammatory drugs (NSAIDs) are the competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the bioconversion of arachidonic acid to inflammatory prostaglandins (PGs).
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