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

Journal of medicinal chemistry 2021 Mar 11

filter terms:

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.

Citation

Markus Hartmann, Sofia-Iris Bibli, Daniel Tews, Xiaomin Ni, Theresa Kircher, Jan S Kramer, Whitney Kilu, Jan Heering, Victor Hernandez-Olmos, Lilia Weizel, Gerhard K E Scriba, Sulaiman Krait, Stefan Knapp, Apirat Chaikuad, Daniel Merk, Ingrid Fleming, Pamela Fischer-Posovszky, Ewgenij Proschak. Combined Cardioprotective and Adipocyte Browning Effects Promoted by the Eutomer of Dual sEH/PPARγ Modulator. Journal of medicinal chemistry. 2021 Mar 11;64(5):2815-2828