Driven by the rising occurrence of the metabolic syndrome (MetS) in western society and the related need for efficient polypharmacological approaches, we developed multi-target ligands for soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated receptors (PPAR), with <i>in vivo</i> efficacy. The MetS mainly consists of dyslipidemia, cardiovascular diseases, type 2 diabetes mellitus (T2D) and obesity, followed by neuropathy and nephropathy. Treatment of numerous diseases-factors requires a great amount of drugs, leading into the general problems of polypharmacology: unpredictable drug-drug interactions, increased side-effects, complex pharmacokinetics, rising therapy costs and medication errors. Through sEH inhibition natural epoxy-fatty acids (EFAs) are elevated, causing physiological beneficial effects. In hypertensive models EFAs act as endothelial-derived relaxation factors. In addition, EFAs show an impact on neuropathy, nephropathy and dyslipidemia, which are all enfolded in the MetS. Subtype dependent, PPAR agonists are known for their insulin-sensitizing effects or used for dyslipidemia treatment. Hence, PPAR modulation represents a suitable addition to the sEH inhibition in the dual-ligand approach. In this study, we were able to address several risk-factors of the MetS, by combining the bioactive properties of sEH inhibitors and PPAR agonists, in one molecule. In spontaneous hypertensive obese (SHROB) rats, we showed the <i>in vivo </i>efficacy of sEH/PPAR dual modulation, by decreasing blood pressure, improving glucose uptake and reducing albuminuria. Therefor we discovered an effective polypharmacological tool compound, which pathological impact now can be explored further.

Soluble epoxide hydrolase and peroxisome proliferator-activated receptors in polypharmacology: An efficient appliance for the treatment of complex diseases

251st National Meeting (2016)

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