Prostaglandin endoperoxide H synthase, colloquially is known as cyclooxygenase or COX enzyme the molecular target of NSAIDs. In the early 1990s, a second isoform (COX-2) was discovered, distinct from the first one, then renamed COX-1. While both enzymes carry out essentially the same catalytic reaction, they differ in expression, function and structure. COX-1 is constitutively expressed in most tissues and is involved in the regulation of physiological functions such as platelet aggregation and homeostasis of the GI tract and the kidney. The second isoform, COX-2, though almost undetectable in healthy man, its expression is rapidly induced in inflammatory cells in response to pro-inflammatory stimuli such as cytokines, growth factors, tumor-promoting agents, bacterial endotoxin, etc. The prostaglandins (PGs) produced by COX-2 play a major role in inflammatory reactions and are responsible for the characteristic inflammatory and pathological processes such as various cancer types, Alzheimer and Parkinson’s diseases. Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammatory diseases, such as arthritis is impaired by their adverse effects, especially in the GI tract and the kidney. Selective COX-2 inhibitors have been developed in order to reduce NSAIDs-induced side effects associated with COX-1 inhibition. However, recent findings have highlighted an important role for COX-2 in several physiological processes, as well as a key role in inflammation and pain perception for COX-1. Moreover, COX inhibition leads to an up-regulation of the 5-LOX (5-lipoxygenase) pathway, yielding various adverse effects. As a result, a new strategy involving dual inhibition of 5-LOX and COX enzymes has been considered. Various structural families of dual inhibitors have been designed and several compounds are currently undergoing preclinical or clinical development. By preventing the biosynthesis of both prostanoids and LTs, they are potent anti-inflammatory agents who might represent a valuable therapeutic alternative to classical NSAIDs and to some extent, to selective COX-2 inhibitors, notably because of their almost complete lack of GI toxicity. As COX-2 and 5-LOX are also up-regulated in various cancers, development of drugs targeting both enzymes would be a boon in modern therapeutics. The most promising COX/5-LOX inhibitor, ML3000 ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid), is now under advance stage of clinical trials.

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WO2008135767A1 NEW TRIAZOLE COMPOUNDS USEFUL IN THE TREATMENT OF INFLAMMATION