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N-Benzylbenzamides: A novel merged scaffold for orally available dual soluble epoxide hydrolase/peroxisome proliferator-activated receptor gamma modulators

: Blöcher, R.; Lamers, C.; Wittmann, S.K.; Merk, D.; Hartmann, M.; Weizel, L.; Diehl, O.; Brüggerhoff, A.; Boss, M.; Kaiser, A.; Schader, T.; Gobel, T.; Grundmann, M.; Angioni, C.; Heering, J.; Geisslinger, G.; Wurglics, M.; Kostenis, E.; Brüne, B.; Steinhilber, D.; Schubert-Zsilavecz, M.; Kahnt, A.S.; Proschak, E.


Journal of medicinal chemistry 59 (2016), No.1, pp.61-81
ISSN: 0022-2623
ISSN: 1520-4804
Deutsche Forschungsgemeinschaft DFG
SFB 1039; PR1405/1-2
Journal Article
Fraunhofer IME ()

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 gamma (PPAR gamma). Simultaneous modulation of sEH and PPAR gamma can improve diabetic conditions and hypertension at once. N-Benzylbenzamide derivatives were determined to fit a merged sEH/PPAR gamma pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 mu M/PPAR gamma EC50 = 0.3 mu M) 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.