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ID: ALA3763124
Journal: J Med Chem
Title: N-Benzylbenzamides: A Novel Merged Scaffold for Orally Available Dual Soluble Epoxide Hydrolase/Peroxisome Proliferator-Activated Receptor γ Modulators.
Authors: Blöcher R, Lamers C, Wittmann SK, Merk D, Hartmann M, Weizel L, Diehl O, Brüggerhoff A, Boß M, Kaiser A, Schader T, Göbel T, Grundmann M, Angioni C, Heering J, Geisslinger G, Wurglics M, Kostenis E, Brüne B, Steinhilber D, Schubert-Zsilavecz M, Kahnt AS, Proschak E.
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.
CiteXplore: 26595749