The discovery of the existence of two cyclooxygenases greatly refines the understanding of how the therapeutic and toxic effect of NSAIDs relate to inhibition of PG synthesis. As was reported, NSAIDs inhibit both COX-1 and COX-2 to different extents. This accounts for their anti-inflammatory and analgesic activities and also their unwanted GI side effect. Current evidence indicates that selective COX-2 inhibitors have important adverse cardiovascular effects that include increased risk for myocardial infarction, stroke, heart failure and hypertension. Thus, the development of selective COX-2 inhibitors could be a big step ahead in the therapeutic treatment of anti-inflammatory diseases with fewer risks and side effects. The selective COX-2 diaryl heterocyclic, Coxib group; is characterized by having different 1,2-diaryl five-membered or six-membered heterocycles that are considered as pharmacophore templates, such as, Celcoxib, Refecoxib, Valdecoxib and Etoricoxib. Moreover, the SAR studies have shown that the substituted sulfonyl group present in the structure of Coxibs, is considered one of the pharmacophoric moieties responsible for the selective recognition with the key amino acid residues at COX-2 active site pocket. Also, it has been reported that compounds having aryl methylsufone or aryl sulfonamide moieties display a propensity for COX-2 selectivity. Furthermore, taking in consideration the main difference between the two COX active sites which is the replacement of Ile523 in COX-1 by the less bulky Val523 in COX-2 active site, results in opening a polar side pocket that enlarges the volume of COX-2 active site and is considered a prerequisite for COX-2 drug selectivity.