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

Blöcher, René and Lamers, Christina and Wittmann, Sandra K. and Merk, Daniel and Hartmann, Markus and Weizel, Lilia and Diehl, Olaf and Brüggerhoff, Astrid and Boß, Marcel and Kaiser, Astrid and Schader, Tim and Göbel, Tamara and Grundmann, Manuel and Angioni, Carlo and Heering, Jan and Geisslinger, Gerd and Wurglics, Mario and Kostenis, Evi and Brüne, Bernhard and Steinhilber, Dieter and Schubert-Zsilavecz, Manfred and Kahnt, Astrid S. and Proschak, Ewgenij. (2016) N-Benzylbenzamides: A Novel Merged Scaffold for Orally Available Dual Soluble Epoxide Hydrolase/Peroxisome Proliferator-Activated Receptor γ Modulators. Journal of medicinal chemistry, 59 (1). pp. 61-81.

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Official URL: https://edoc.unibas.ch/70322/

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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.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ricklin)
UniBasel Contributors:Lamers, Christina
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1520-4804
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:17 May 2020 20:42
Deposited On:17 May 2020 20:42

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