1. Combined Cardioprotective and Adipocyte Browning Effects Promoted by the Eutomer of Dual sEH/PPARγ Modulator.
- Author
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Hartmann M, Bibli SI, Tews D, Ni X, Kircher T, Kramer JS, Kilu W, Heering J, Hernandez-Olmos V, Weizel L, Scriba GKE, Krait S, Knapp S, Chaikuad A, Merk D, Fleming I, Fischer-Posovszky P, and Proschak E
- Subjects
- Animals, Benzamides chemical synthesis, Butyrates chemical synthesis, Cardiotonic Agents chemical synthesis, Cell Differentiation drug effects, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, HEK293 Cells, Humans, Mice, Inbred C57BL, Stereoisomerism, Mice, Adipocytes drug effects, Benzamides pharmacology, Butyrates pharmacology, Cardiotonic Agents pharmacology, Epoxide Hydrolases metabolism, PPAR gamma agonists
- Abstract
The metabolic syndrome (MetS) is a constellation of cardiovascular and metabolic symptoms involving insulin resistance, steatohepatitis, obesity, hypertension, and heart disease, and patients suffering from MetS often require polypharmaceutical treatment. PPARγ agonists are highly effective oral antidiabetics with great potential in MetS, which promote adipocyte browning and insulin sensitization. However, the application of PPARγ agonists in clinics is restricted by potential cardiovascular adverse events. We have previously demonstrated that the racemic dual sEH/PPARγ modulator RB394 ( 3 ) simultaneously improves all risk factors of MetS in vivo. In this study, we identify and characterize the eutomer of 3 . We provide structural rationale for molecular recognition of the eutomer. Furthermore, we could show that the dual sEH/PPARγ modulator is able to promote adipocyte browning and simultaneously exhibits cardioprotective activity which underlines its exciting potential in treatment of MetS.
- Published
- 2021
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