Prostaglandin E(2) synthase inhibition as a therapeutic target.
BACKGROUND
Most NSAIDs function by inhibiting biosynthesis of PGE(2) 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 I(2) (PGI(2)) and thromboxane A(2) (TXA(2)) with a bias towards TXA(2) 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 This resulted in the drugs being withdrawn from the market, leaving a need for an effective and safe anti-inflammatory drug.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 E(2) synthases. Microsomal prostaglandin E(2) synthase-1 (mPGES-1) specifically isomerizes PGH(2) to PGE(2), 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.


CONCLUSIONS
mPGES-1 has the potential to be a target for anti-inflammatory therapy, devoid of adverse GIT and cardiac effects and warrants further investigation.
Iyer
Jitesh P
JP
Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, Plot No-20, Sector-18, Udyog Vihar, Gurgaon, Haryana, India-122015.
Srivastava
Punit K
PK
Dev
Rishabh
R
Dastidar
Sunanda G
SG
Ray
Abhijit
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071876:Prostaglandin-E Synthases
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases