Combined Cardioprotective and Adipocyte Browning Effects Promoted by the Eutomer of Dual sEH/PPARγ Modulator

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 ant...

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Published in:Journal of medicinal chemistry 2021-03, Vol.64 (5), p.2815-2828
Main Authors: Hartmann, Markus, Bibli, Sofia-Iris, Tews, Daniel, Ni, Xiaomin, Kircher, Theresa, Kramer, Jan S, Kilu, Whitney, Heering, Jan, Hernandez-Olmos, Victor, Weizel, Lilia, Scriba, Gerhard K. E, Krait, Sulaiman, Knapp, Stefan, Chaikuad, Apirat, Merk, Daniel, Fleming, Ingrid, Fischer-Posovszky, Pamela, Proschak, Ewgenij
Format: Article
Language:English
Subjects:
Adipocytes - drug effects
Animals
Benzamides - chemical synthesis
Benzamides - pharmacology
Butyrates - chemical synthesis
Butyrates - pharmacology
Cardiotonic Agents - chemical synthesis
Cardiotonic Agents - pharmacology
Cell Differentiation - drug effects
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Epoxide Hydrolases - metabolism
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
PPAR gamma - agonists
Stereoisomerism
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c02063