Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor g Agonists/Soluble Epoxide Hydrolase Inhibitors
| Autor: | Whitney Kilu, Ewgenij Proschak, Victor Hernandez-Olmos, Carmen Borkowsky, Astrid Kaiser, Roxane-I Kestner, Jan S. Kramer, Tamara Göbel, Sabine Willems, Stefan Knapp, Steffen Brunst, Jan Heering, Moritz Helmstädter, Dmitry Namgaladze, Xiaomin Ni, Waltraud Pfeilschifter, Mirko Brodsky, Anna Proschak, Dieter Steinhilber, Felix F Lillich, Franziska Mayser, Apirat Chaikuad, Lilia Weizel, Astrid S. Kahnt, Simone Schierle, Daniel Merk |
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| Přispěvatelé: | Publica |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Epoxide hydrolase 2
Peroxisome proliferator-activated receptor Context (language use) Pharmacology Crystallography X-Ray Mice Structure-Activity Relationship In vivo Drug Discovery medicine Animals Humans Enzyme Inhibitors Receptor Epoxide Hydrolases chemistry.chemical_classification Peroxisome medicine.disease Rats PPAR gamma HEK293 Cells chemistry Drug Design Toxicity Microsomes Liver Polypharmacy Molecular Medicine Metabolic syndrome |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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