title: N-Benzylbenzamides: A Novel Merged Scaffold for Orally Available Dual Soluble Epoxide Hydrolase/Peroxisome Proliferator-Activated Receptor γ Modulators.
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.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Blöcher
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Lamers
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Wittmann
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Merk
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hartmann
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Lilia
authors.initials: L
authors.lastname: Weizel
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Diehl
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Brüggerhoff
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt , Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Boß
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kaiser
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Schader
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Göbel
authors.affiliation: Institute of Pharmaceutical Biology, Rheinische Friedrich-Wilhelms-Universität Bonn , Nussallee 6, D-53115 Bonn, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Grundmann
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University Frankfurt , Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Heering
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University Frankfurt , Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Wurglics
authors.affiliation: Institute of Pharmaceutical Biology, Rheinische Friedrich-Wilhelms-Universität Bonn , Nussallee 6, D-53115 Bonn, Germany.
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt , Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Astrid S
authors.initials: AS
authors.lastname: Kahnt
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
mesh_terms: D016475:3T3 Cells; D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D066298:In Vitro Techniques; D024821:Metabolic Syndrome / Q000188:drug therapy*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D047495:PPAR gamma / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D047495:PPAR gamma; D004851:Epoxide Hydrolases