Vicinally disubstituted pyridazinones act as potent and selective COX-2 inhibitors. Compound, ABT-963, (2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one) has an excellent selectivity (ratio of 276, COX-2/COX-1), improved aqueous solubility compared with celecoxib and rofecoxib, high oral anti-inflammatory potency and gastric safety in the ani...

Design of selective cyclooxygenase-2 (COX-2) inhibitors is still a challenging task because of active site similarities between COX isoenzymes. To help with this issue, we tried to generate a 3D-QSAR (3 dimensional quantitative structure activity relationships) model that might reflect the essential features of COX-2 active sites. Compounds in a series of resveratrol derivatives inhibitors with...

A small set of substituted 1,5-diarylpyrrole-3-acetic and -glyoxylic acid derivatives have been synthesized, and their cyclooxygenase (COX-1 and COX-2) inhibiting properties have been evaluated. Some compounds proved to be highly selective COX-2 inhibitors, and their affinity data have been rationalized through docking simulations in terms of interactions with a crystallographic model of the CO...

In mammalian cells, eicosanoid biosynthesis is usually initiated by the activation of phospholipase A(2) and the release of arachidonic acid from membrane phospholipids in response to the interaction of a stimulus with a receptor on the cell surface. Arachidonic acid is subsequently transformed by the enzyme cyclooxygenase (COX) to prostaglandins (PGs) and thromboxane (TX). The COX pathway is o...

Treatment with non-steroidal anti-inflammatory drugs, either non-selective or selective cyclooxygenase-2 (COX-2) inhibitors, consistently impairs ovulation, indicating the essential role of COX-2/prostaglandins in the ovulatory process. Indomethacin, a potent inhibitor of both COX-1 and COX-2, induced several ovulatory alterations, consisting of a decrease in the number of oocytes effectively o...

Prostaglandins (PG) are synthesized by the sequential action of phosholipases, cyclooxygenases (COX)-1 and COX-2, and specific terminal synthases, and exert their diverse biological effects through several membrane receptors. In particular, PGE2 is involved in many normal and pathological pathways that are mediated by four different E prostanoid receptors (EP1-4). Selective COX-2 inhibitors (Co...

NS-398 [N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide], a selective inhibitor of cyclooxygenase-2 (COX-2), inhibited proliferation induced by platelet-derived growth factor (PDGF) in Swiss 3T3 fibroblasts. The effect of NS-398 was found to be concentration-dependent. The half-maximal effect occurred at approximately 0.1 microM. NS-398 decreased mitogenesis at subsaturating PDGF concentrat...

Selective cyclooxygenase (COX)-2 inhibitors are expected to cause fewer gastric side effects because of sparing of COX-1-dependent prostaglandin (PG) synthesis in the gastric mucosa. However, the possible contribution of COX-2 to overall gastric PG biosynthesis is not known. This study demonstrates constitutive expression of COX-2 mRNA and protein in apparently healthy human and rabbit gastric ...

Treatment of pain in rheumatoid arthritis must take into account the gastrointestinal and cardiovascular risk of individual patients. Adequate results are not yet available, and until they are, treatment recommendations must take into account, not only the more favourable gastrointestinal risk profile of selective COX-2 inhibitors, but also the potential atherothrombotic risk of any NSAID or se...

Recent data have suggested that regular consumption of nonsteroid anti-inflammatory drugs (NSAIDs), particularly selective inhibitors of cyclo-oxygenase-2 (COX-2), is associated with an increased risk of thrombotic events. It has been suggested that this is due to NSAIDs reducing the release from the endothelium of the antithrombotic mediator prostaglandin I2 as a result of inhibition of endoth...