Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor γ Agonists/Soluble Epoxide Hydrolase Inhibitors.
Felix F LillichSabine WillemsXiaomin NiWhitney KiluCarmen BorkowskyMirko BrodskyJan S KramerSteffen BrunstVictor Hernandez-OlmosJan HeeringSimone SchierleRoxane-I KestnerFranziska M MayserMoritz HelmstädterTamara GöbelLilia WeizelDmitry NamgaladzeAstrid KaiserDieter SteinhilberWaltraud PfeilschifterAstrid S KahntAnna ProschakApirat ChaikuadStefan KnappDaniel MerkEwgenij ProschakPublished in: Journal of medicinal chemistry (2021)
Polypharmaceutical regimens often impair treatment of patients with metabolic syndrome (MetS), a complex disease cluster, including obesity, hypertension, heart disease, and type II diabetes. Simultaneous targeting of soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated receptor γ (PPARγ) synergistically counteracted MetS in various in vivo models, and dual sEH inhibitors/PPARγ agonists hold great potential to reduce the problems associated with polypharmacy in the context of MetS. However, full activation of PPARγ leads to fluid retention associated with edema and weight gain, while partial PPARγ agonists do not have these drawbacks. In this study, we designed a dual partial PPARγ agonist/sEH inhibitor using a structure-guided approach. Exhaustive structure-activity relationship studies lead to the successful optimization of the designed lead. Crystal structures of one representative compound with both targets revealed potential points for optimization. The optimized compounds exhibited favorable metabolic stability, toxicity, selectivity, and desirable activity in adipocytes and macrophages.
Keyphrases
- insulin resistance
- weight gain
- metabolic syndrome
- type diabetes
- adipose tissue
- high fat diet induced
- body mass index
- blood pressure
- structure activity relationship
- fatty acid
- birth weight
- weight loss
- cardiovascular disease
- skeletal muscle
- mental health
- oxidative stress
- glycemic control
- cancer therapy
- risk assessment
- uric acid
- cross sectional
- single cell
- cardiovascular risk factors
- climate change
- physical activity
- replacement therapy
- combination therapy
- smoking cessation