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J Med Chem. 2016 Jan 14;59(1):61-81. doi: 10.1021/acs.jmedchem.5b01239. Epub 2015 Dec 25.

N-Benzylbenzamides: A Novel Merged Scaffold for Orally Available Dual Soluble Epoxide Hydrolase/Peroxisome Proliferator-Activated Receptor γ Modulators.

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Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
Institute of Biochemistry I, Goethe-University Frankfurt , Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Institute of Pharmaceutical Biology, Rheinische Friedrich-Wilhelms-Universität Bonn , Nussallee 6, D-53115 Bonn, Germany.
Institute of Clinical Pharmacology, Goethe-University Frankfurt , Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.


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 γ (PPARγ). Simultaneous modulation of sEH and PPARγ can improve diabetic conditions and hypertension at once. N-Benzylbenzamide derivatives were determined to fit a merged sEH/PPARγ pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 μM/PPARγ EC50 = 0.3 μM) 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.

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