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Inhibitors of the Microsomal Prostaglandin E2 Synthase-1 as Alternative to Non Steroidal Anti-Inflammatory Drugs (NSAIDs) - A Critical Review

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Pharmacological suppression of cyclooxygenase (COX)-1 and -2-mediated prostanoid biosynthesis by non steroidal anti-inflammatory drugs (NSAIDs) is used in the therapy of inflammation, fever, and pain. However, long-term application of these drugs is associated with severe side effects, mainly gastrointestinal injury and renal irritations, apparently due to impaired biosynthesis of physiologically relevant prostanoids. Although COX-2 selective drugs (coxibs) show reduced gastrointestinal complications, recent clinical trials indicated a significantly increased cardiovascular risk. In order to minimize these side-effects, selective suppression of microsomal prostaglandin E2 synthase (mPGES)-1 derived prostaglandin (PG)E2 formation has been considered as alternative to general inhibition of prostanoid biosynthesis. mPGES-1 is functionally coupled to COX-2 being responsible for excessive PGE2 generation connected to pathologies and current knowledge suggests key roles of mPGES-1 in inflammation, pain, fever, atherosclerosis, and tumorigenesis. However, mPGES-1 as promising therapeutic target was questioned because blockade of mPGES-1 allows redirection of the substrate PGH2 to other PG synthases, and the consequences are still elusive. This review summarizes current knowledge about synthetic and natural mPGES-1 inhibitors focusing on structural and mechanistic investigations. Further, the therapeutic efficiency and safety is critically discussed on the basis of cellular and animal studies in which mPGES-1 activity was pharmacologically or genetically (knockout, knockdown) modulated.

Keywords: 5-lipoxygenase; Microsomal prostaglandin E2 synthase-1; cyclooxygenase; enzyme inhibitors; inflammation; knockout; leukotrienes; prostaglandins

Document Type: Research Article


Affiliations: Department of Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany.

Publication date: November 1, 2009

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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