Prostaglandin E₂ synthase inhibition as a therapeutic target

Abstract

Background: Most NSAIDs function by inhibiting biosynthesis of PGE₂ by inhibition of COX-1 and/or COX-2. Since COX-1 has a protective function in the gastro-intestinal tract (GIT), non-selective inhibition of both cycloxy genases leads to moderate to severe gastro-intestinal intolerance. Attempts to identify selective inhibitors of COX-2, led to the identification of celecoxib and rofecoxib. However, long-term use of these drugs has serious adverse effects of sudden myocardial infarction and thrombosis. Drug-mediated imbalance in the levels of prostaglandin I₂ (PGI₂) and thromboxane A₂ (TXA₂) with a bias towards TXA₂ may be the primary reason for these events. This resulted in the drugs being withdrawn from the market, leaving a need for an effective and safe anti-inflammatory drug. Methods: Recently, the focus of research has shifted to enzymes downstream of COX in the prosta glandin biosynthetic pathway such as prostaglandin E₂ synthases. Microsomal prostaglandin E₂ synthase-1 (mPGES-1) specifically isomerizes PGH₂ to PGE₂, under inflammatory conditions. In this review, we examine the biology of mPGES-1 and its role in disease. Progress in designing molecules that can selectively inhibit mPGES-1 is reviewed. Conclusion: mPGES-1 has the potential to be a target for anti-inflammatory therapy, devoid of adverse GIT and cardiac effects and warrants further investigation.

Keywords::

• COX-2
• inflammation
• mPGES-1
• neoplasia
• PGE2

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