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Drug DiscoveryArachidonic Acid Cascades-EH InhibitorSelected Publications

 

Arachidonic Acid Cascade

The breakdown of arachidonic acid, an omega-6 fatty acid, gives rise to a large group of biologically important 20-carbon substances known as eicosanoids (from the Greek eicosa for twenty), which play a key role in many diseases including inflammation. Arachidonic acid can be broken down by three enzyme families: cyclooxygenases (COX), lipoxygenases (LOX) and cytochrome P450 epoxygenases (EOX). These enzymes act along three major pathways to produce eicosanoids including prostaglandins, thromboxanes, lipoxins, leukotrienes and epoxyeicosatrienoic acids (EETs).


 

The metabolism of arachidonic acid into prostaglandins and leukotrienes has been well described, and has formed the basis of several anti-inflammatory drugs (i.e. Celebrex®, Singulair®). Recently, a third pathway has been discovered demonstrating that arachidonic acid can be broken down by epoxygenases into epoxyeicosatrienoic acids (EETs). EETs are particularly prevalent in the kidney, endothelium (cells that cover the inner surface of all vascular beds in the body) and lungs. EETs are known to be potent vasodilators and have a variety of anti-inflammatory properties, but they are rapidly broken down into a less active form (DHETs) by an enzyme called soluble epoxide hydrolase (s-EH).

Inhibiting s-EH, the enzyme which breaks down EETs, therefore has the potential to treat a variety of disorders including hypertension, metabolic syndrome and inflammatory diseases.

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