Journal of Medicinal Chemistry p. 61 - 81 (2016)
Update date:2022-08-15
Topics:
Bl?cher, René
Lamers, Christina
Wittmann, Sandra K.
Merk, Daniel
Hartmann, Markus
Weizel, Lilia
Diehl, Olaf
Brüggerhoff, Astrid
Bo?, Marcel
Kaiser, Astrid
Schader, Tim
G?bel, Tamara
Grundmann, Manuel
Angioni, Carlo
Heering, Jan
Geisslinger, Gerd
Wurglics, Mario
Kostenis, Evi
Brüne, Bernhard
Steinhilber, Dieter
Schubert-Zsilavecz, Manfred
Kahnt, Astrid S.
Proschak, Ewgenij
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.
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