N-Benzylbenzamides: A Novel Merged Scaffold for Orally Available Dual Soluble Epoxide Hydrolase/Peroxisome Proliferator-Activated Receptor γ Modulators
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- 作者：René Bl?cher ; Christina Lamers ; Sandra K. Wittmann ; Daniel Merk ; Markus Hartmann ; Lilia Weizel ; Olaf Diehl ; Astrid Brüggerhoff ; Marcel Bo? ; Astrid Kaiser ; Tim Schader ; Tamara G?bel ; Manuel Grundmann ; Carlo Angioni ; Jan Heering ; Gerd Geisslinger ; Mario Wurglics ; Evi Kostenis ; Bernhard Brüne ; Dieter Steinhilber ; Manfred Schubert-Zsilavecz ; Astrid S. Kahnt ; Ewgenij Proschak
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：January 14, 2016
- 年：2016
- 卷：59
- 期：1
- 页码：61-81
- 全文大小：881K
- ISSN：1520-4804
文摘
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.