Current Medicinal Chemistry

Atta-ur-Rahman, FRS
Honorary Life Fellow
Kings College
University of Cambridge


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

Author(s): A. Koeberle and O. Werz

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

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


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.

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Article Details

Page: [4274 - 4296]
Pages: 23
DOI: 10.2174/092986709789578178