Combined Cardioprotective and Adipocyte Browning Effects Promoted by the Eutomer of Dual sEH/PPARγ Modulator.
Markus HartmannSofia-Iris BibliDaniel TewsXiaomin NiTheresa KircherJan S KramerWhitney KiluJan HeeringVictor Hernandez-OlmosLilia WeizelGerhard K E ScribaSulaiman KraitStefan KnappApirat ChaikuadDaniel MerkIngrid FlemingPamela Fischer-PosovszkyEwgenij ProschakPublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- insulin resistance
- high fat diet induced
- metabolic syndrome
- adipose tissue
- high fat diet
- type diabetes
- skeletal muscle
- polycystic ovary syndrome
- risk factors
- glycemic control
- end stage renal disease
- fatty acid
- blood pressure
- primary care
- ejection fraction
- human health
- newly diagnosed
- clinical trial
- chronic kidney disease
- risk assessment
- prognostic factors
- physical activity
- climate change
- cardiovascular disease
- combination therapy
- peritoneal dialysis
- weight gain
- single molecule
- sleep quality