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
  • 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.