Inhibitors of sEH and FAAH

sEH ENZYME: Soluble epoxide hydrolase (sEH) is an enzyme that has been detected in various tissues from plants to mammals. In humans it is mostly located in liver, lungs and vascular tissues. This enzyme is selective for aliphatic epoxides of fatty acids, and the best known substrate is epoxyeicosatrienoic acid (EET).

EETs are one of the metabolic derivatives of Arachidonic acid. Under normal circumstances, Arachidonic Acid (AA) is not available for metabolism and is conjugated to the cellular membrane. EETs exhibit vasodilatory effects in various arteries and have also been shown to possess anti-inflammatory properties.

AA is metabolized through three enzymatic pathways, namely, cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) pathways. Whereas the COX and LOX pathways have been studied in detail in the treatment of inflammatory diseases, the third pathway remains unexplored mechanistically and underused clinically.

sEH mediates the addition of water to EETs, leading to the corresponding diols (DHET), which show abolished or diminished or changed biological activity.

Therefore, it has been postulated that sEH inhibition may lead to elevated levels of EETs, which could then have beneficial therapeutic effects on blood pressure, inflammation and other related diseases.

FAAH ENZYME: Endocannabinoids are endogenous lipid ligands that activate the cannabinoid GPCRs CB1 and CB2. These receptors are also activated by THC. It has been known that exogenous CB1 agonists possess properties including pain relief. However, these compounds produce also undesirable side effects including impairments in cognition and motor control, which limit their utility as therapeutic agents. The observation that endocannabinoid synthesis is selectively up-regulated in active neural pathways also suggests that this strategy may have a greater selectivity and lower side effect profile than global activation of cannabinoid receptors via exogenous agonists.

Two endocannabinoids have been identified in mammals: Anandamide (AEA) and 2-arachidonoylglycerol (2-AG). One approach to retain the beneficial effects of cannabinoid activation is to inhibit enzyme that is hydrolyzing endocannabinoids.

FAAH represents an attractive therapeutic target for treatment of pain, inflammation and other CNS disorders. 

It is still a major challenge to identify the first inhibitor of FAAH suitable for clinical exploitation that satisfies the requirements of potency, selectivity versus proteins related to anandamide activity as well as other potential off-targets, reversibility versus irreversibility, and efficacy toward rat versus human FAAH.