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

[ Vol. 16 , Issue. 32 ]


A. Koeberle and O. Werz   Pages 4274 - 4296 ( 23 )


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.


Microsomal prostaglandin E2 synthase-1,5-lipoxygenase,cyclooxygenase,prostaglandins,leukotrienes,enzyme inhibitors,knockout,inflammation


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

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