Over the last two decades polypharmacology has emerged as a new paradigm in drug discovery, even though developing drugs with high potency and selectivity toward a single biological target is still a major strategy. Often, targeting only a single enzyme or receptor shows lack of efficacy. High levels of inhibitor of a single target also can lead to adverse side effects. A second target may offer additive or synergistic effects to affecting the first target thereby reducing on- and off-target side effects. Therefore, drugs that inhibit multiple targets may offer a great potential for increased efficacy and reduced the adverse effects. In this review we summarize recent findings of rationally designed multitarget compounds that are aimed to improve efficacy and safety profiles compared to those that target a single enzyme or receptor. We focus on dual inhibitors/modulators that target the soluble epoxide hydrolase (sEH) as a common part of their design to take advantage of the beneficial effects of sEH inhibition.

Selective optimization of side activities is a valuable source of novel lead structures in drug discovery. In this study, a computer-aided approach was used to deorphanize the pleiotropic cholesterol-lowering effects of the beta-blocker talinolol, which result from the inhibition of the enzyme soluble epoxide hydrolase (sEH). X-ray structure analysis of the sEH in complex with talinolol enables a straightforward optimization of inhibitory potency. The resulting lead structure exhibited in vivo activity in a rat model of diabetic neuropatic pain.

The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure-activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid (22b, SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo.