Polypharmaceutical regimens often impair treatment of patients with metabolic syndrome (MetS), a complex disease cluster, including obesity, hypertension, heart disease, and type II diabetes. Simultaneous targeting of soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated receptor gamma (PPARgamma) synergistically counteracted MetS in various in vivo models, and dual sEH inhibitors/PPARgamma agonists hold great potential to reduce the problems associated with polypharmacy in the context of MetS. However, full activation of PPARgamma leads to fluid retention associated with edema and weight gain, while partial PPARgamma agonists do not have these drawbacks. In this study, we designed a dual partial PPARgamma agonist/sEH inhibitor using a structure-guided approach. Exhaustive structure-activity relationship studies lead to the successful optimization of the designed lead. Crystal structures of one representative compound with both targets revealed potential points for optimization. The optimized compounds exhibited favorable metabolic stability, toxicity, selectivity, and desirable activity in adipocytes and macrophages.
Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 muM, respectively. In contrast, only montelukast and zafirlukast activated PPARgamma in the reporter gene assay with EC50 values of 1.17 muM (21.9% max. activation) and 2.49 muM (148% max. activation), respectively. PPARalpha and delta were not affected by any of the compounds. The activation of PPARgamma was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARgamma phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARgamma target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARgamma cofactor CBP upon ligand binding suggesting that both compounds act as PPARgamma modulators. In addition, zafirlukast impaired the TNFalpha triggered phosphorylation of PPARgamma2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARgamma modulator representing an excellent starting point for the further development of this compound class.
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.
Metabolic syndrome (MetS) is a multifactorial disease cluster that consists of dyslipidemia, cardiovascular disease, type 2 diabetes mellitus, and obesity. MetS patients are strongly exposed to polypharmacy; however, the number of pharmacological compounds required for MetS treatment can be reduced by the application of multitarget compounds. This study describes the design of dual-target ligands that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated receptor type gamma (PPARgamma). Simultaneous modulation of sEH and PPARgamma can improve diabetic conditions and hypertension at once. N-Benzylbenzamide derivatives were determined to fit a merged sEH/PPARgamma pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 muM/PPARgamma EC50 = 0.3 muM) modulator 14c. In vitro and in vivo evaluations revealed good ADME properties qualifying 14c as a pharmacological tool compound for long-term animal models of MetS.
