Blöcher, R.R.BlöcherLamers, C.C.LamersWittmann, S.K.S.K.WittmannMerk, D.D.MerkHartmann, M.M.HartmannWeizel, L.L.WeizelDiehl, O.O.DiehlBrüggerhoff, A.A.BrüggerhoffBoss, M.M.BossKaiser, A.A.KaiserSchader, T.T.SchaderGobel, T.T.GobelGrundmann, M.M.GrundmannAngioni, C.C.AngioniHeering, J.J.HeeringGeisslinger, G.G.GeisslingerWurglics, M.M.WurglicsKostenis, E.E.KostenisBrüne, B.B.BrüneSteinhilber, D.D.SteinhilberSchubert-Zsilavecz, M.M.Schubert-ZsilaveczKahnt, A.S.A.S.KahntProschak, E.E.Proschak2022-03-052022-03-052016https://publica.fraunhofer.de/handle/publica/24315510.1021/acs.jmedchem.5b012392-s2.0-84955121284Metabolic 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.en615journal article