| Title : Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor gamma Agonists\/Soluble Epoxide Hydrolase Inhibitors - Lillich_2021_J.Med.Chem_64_17259 |
| Author(s) : Lillich FF , Willems S , Ni X , Kilu W , Borkowsky C , Brodsky M , Kramer JS , Brunst S , Hernandez-Olmos V , Heering J , Schierle S , Kestner RI , Mayser FM , Helmstadter M , Gobel T , Weizel L , Namgaladze D , Kaiser A , Steinhilber D , Pfeilschifter W , Kahnt AS , Proschak A , Chaikuad A , Knapp S , Merk D , Proschak E |
| Ref : Journal of Medicinal Chemistry , : , 2021 |
| Abstract : 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 gamma (PPARgamma) synergistically counteracted MetS in various in vivo models, and dual sEH inhibitors/PPARgamma agonists hold great potential to reduce the problems associated with polypharmacy in the context of MetS. However, full activation of PPARgamma leads to fluid retention associated with edema and weight gain, while partial PPARgamma agonists do not have these drawbacks. In this study, we designed a dual partial PPARgamma 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. |
| ESTHER : Lillich_2021_J.Med.Chem_64_17259 |
| PubMedSearch : Lillich_2021_J.Med.Chem_64_17259 |
| PubMedID: 34818007 |
| Gene_locus related to this paper: human-EPHX2 |
| Gene_locus related to this paper: human-EPHX2 |
Lillich FF, Willems S, Ni X, Kilu W, Borkowsky C, Brodsky M, Kramer JS, Brunst S, Hernandez-Olmos V, Heering J, Schierle S, Kestner RI, Mayser FM, Helmstadter M, Gobel T, Weizel L, Namgaladze D, Kaiser A, Steinhilber D, Pfeilschifter W, Kahnt AS, Proschak A, Chaikuad A, Knapp S, Merk D, Proschak E (2021)
Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor gamma Agonists\/Soluble Epoxide Hydrolase Inhibitors
Journal of Medicinal Chemistry
:
Lillich FF, Willems S, Ni X, Kilu W, Borkowsky C, Brodsky M, Kramer JS, Brunst S, Hernandez-Olmos V, Heering J, Schierle S, Kestner RI, Mayser FM, Helmstadter M, Gobel T, Weizel L, Namgaladze D, Kaiser A, Steinhilber D, Pfeilschifter W, Kahnt AS, Proschak A, Chaikuad A, Knapp S, Merk D, Proschak E (2021)
Journal of Medicinal Chemistry
: