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[摘要]：A review. The use of NSAIDs (nonselective inhibitors of COX-1 and COX-2) and coxibs (selective inhibitors of COX-2) is a mainstay of anti-inflammatory and analgesic therapy. Since coxibs and NSAIDs intervene in the prostaglandin (PG) pathway at the level of PGH2 synthesis, the question that arises is whether similar or greater. anti-inflammatory and analgesic efficacy might be obtained by selective inhibition of one of the downstream PG synthesizing enzymes. Present thinking is that COX-2 derived PGE2, acting on one or more of its cellular receptors EPI through EP4 is the major mediator of inflammatory pain. However, the suggestion that PGI2 is also a significant contributor in the inflammatory process is supported by preclin. studies using PGI2 receptor (IP) deficient mice and selective IP antagonists. The availability of a pharmacol. active mol. capable of selective inhibition of PGE2 synthesis may provide the answer to the question of whether this therapeutic approach would exhibit anti- inflammatory and analgesic efficacy equal to that of selective COX-2 inhibitors or NSAIDs. The first PGE2 synthase was identified in 1999 and termed microsomal PGE synthase- I (mPGES- 1). Two other PGE2 synthases have been cloned: cytosolic PGES (cPGES) and membrane PGES-2 (mPGES-2). Both cPGES and mPGES-2 are constitutively expressed enzymes with cPGES coupling through COX-1 and with mPGES-2 coupling through both COX-I and COX-2. A no. of excellent reviews have summarized the biol. and pharmacol. of mPGES-I and provide a firm rationale for targeting this enzyme in drug development. Therefore, the following sections will only briefly outline the rationale behind the advocacy of this particular enzyme as the key player in these therapeutic areas, and the focus of this review will be on summarizing the progress to date in the development of selective mPGES-I inhibitors and their efficacy in preclin. animal models of inflammation. |
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