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

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

  • J Med Chem. 2016 Jan 14;59(1):61-81. doi: 10.1021/acs.jmedchem.5b01239.
René Blöcher 1,  Christina Lamers 1,  Sandra K Wittmann 1,  Daniel Merk 1,  Markus Hartmann 1,  Lilia Weizel 1,  Olaf Diehl 1,  Astrid Brüggerhoff 1,  Marcel Boß 2,  Astrid Kaiser 1,  Tim Schader 1,  Tamara Göbel 1,  Manuel Grundmann 3,  Carlo Angioni 4,  Jan Heering 5,  Gerd Geisslinger 4,  Mario Wurglics 1,  Evi Kostenis 3,  Bernhard Brüne 2,  Dieter Steinhilber 1,  Manfred Schubert-Zsilavecz 1,  Astrid S Kahnt 1,  Ewgenij Proschak 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
  • 2 Institute of Biochemistry I, Goethe-University Frankfurt , Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
  • 3 Institute of Pharmaceutical Biology, Rheinische Friedrich-Wilhelms-Universität Bonn , Nussallee 6, D-53115 Bonn, Germany.
  • 4 Institute of Clinical Pharmacology, Goethe-University Frankfurt , Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
  • 5 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.
PMID: 26595749 DOI: 10.1021/acs.jmedchem.5b01239
Abstract

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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