There is an increasing demand to develop agents that concurrently modulate multiple targets, aiming for enhancement of efficacy and improvement of safety compared to drugs that target only a single target. Cyclooxygenase-2 selective inhibitors or coxibs are a class of drugs that are effective for treating inflammation, pain, and cancers. However, their mechanism-based adverse effects limit their chronic use. Meanwhile soluble epoxide hydrolase is involved in the metabolism of endogenously derived fatty acid epoxides by cytochrome P450 (CYP) in the arachidonic cascade. These CYP metabolites of arachidonic acid are known modulators of blood pressure, inflammation, and pain. Therefore, co-inhibition of both enzymes showed synergistic effect in several animal studies. Interestingly the synergism was maximized by combining both actions into a single molecule, which was more active than higher combined doses of a coxib and a sEH inhibitor. However, bioavailability of these compounds is limited. Therefore, studies have been conducted to improve their water solubility and metabolic stability, while retaining potencies for both sEH and COX-2, and thus improving the oral bioavailability.  Here, structure-activity relationships and lead optimization of these novel COX-2/sEH dual inhibitors and their <i>in vivo</i> efficacy in several disease models will be presented.<br/>

Novel multi-target agents: COX-2/sEH dual inhibitors

251st National Meeting (2016)

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