Brunst S

References (5)

Title : Designing a Small Fluorescent Inhibitor to Investigate Soluble Epoxide Hydrolase Engagement in Living Cells - Brunst_2022_ACS.Med.Chem.Lett_13_1062
Author(s) : Brunst S , Schonfeld J , Breunig P , Burgers LD , DeMeglio M , Ehrler JHM , Lillich FF , Weizel L , Hefendehl JK , Furst R , Proschak E , Hiesinger K
Ref : ACS Med Chem Lett , 13 :1062 , 2022
Abstract : Soluble epoxide hydrolase (sEH) is a promising target for a number of inflammation-related diseases. In addition, inhibition of sEH has been shown to reduce neuroinflammation, which plays a critical role in the development of central nervous system (CNS) diseases such as Alzheimer's disease. In this study, we present the rational design of a small fluorescent sEH inhibitor. Starting from the clinical candidate GSK2256294A, we replaced the triazine moiety with the 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) fluorophore. The resulting fluorescent sEH inhibitor displayed excellent potency in an in vitro enzyme activity assay (IC(50) < 2 nM). The developed inhibitor is applicable in a NanoBRET-based assay system suitable for studying sEH target engagement in living cells. Furthermore, the inhibitor can be used to visualize sEH in sEH-transfected HEK293 cells and in primary mouse astrocytes by fluorescence microscopy.
ESTHER : Brunst_2022_ACS.Med.Chem.Lett_13_1062
PubMedSearch : Brunst_2022_ACS.Med.Chem.Lett_13_1062
PubMedID: 35859883

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

Title : Design, Synthesis, and Structure-Activity Relationship Studies of Dual Inhibitors of Soluble Epoxide Hydrolase and 5-Lipoxygenase - Hiesinger_2020_J.Med.Chem_63_11498
Author(s) : Hiesinger K , Kramer JS , Beyer S , Eckes T , Brunst S , Flauaus C , Wittmann SK , Weizel L , Kaiser A , Kretschmer SBM , George S , Angioni C , Heering J , Geisslinger G , Schubert-Zsilavecz M , Schmidtko A , Pogoryelov D , Pfeilschifter J , Hofmann B , Steinhilber D , Schwalm S , Proschak E
Ref : Journal of Medicinal Chemistry , 63 :11498 , 2020
Abstract : Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The optimized lead structure displayed cellular activity in human polymorphonuclear leukocytes, oral bioavailability, and target engagement in vivo and demonstrated profound anti-inflammatory and anti-fibrotic efficiency in a kidney injury model caused by unilateral ureteral obstruction in mice. These results pave the way for investigating the therapeutic potential of dual 5-LOX/sEH inhibitors in other inflammation- and fibrosis-related disease models.
ESTHER : Hiesinger_2020_J.Med.Chem_63_11498
PubMedSearch : Hiesinger_2020_J.Med.Chem_63_11498
PubMedID: 33044073
Gene_locus related to this paper: human-EPHX2

Title : Soluble epoxide hydrolase inhibitors with carboranes as non-natural 3-D pharmacophores - Scholz_2020_Eur.J.Med.Chem_185_111766
Author(s) : Scholz MS , Wingen LM , Brunst S , Wittmann SK , Cardoso ILA , Weizel L , Proschak E
Ref : Eur Journal of Medicinal Chemistry , 185 :111766 , 2020
Abstract : In the present article we describe the creation of a small carboranylcarboxamide compound library followed by a screening campaign at the soluble epoxide hydrolase (sEH). We identified meta-carboranyl alkylamides, -anilides, and -benzylamides as potent sEH inhibitors. Furthermore, we optimized the scaffolds and we derived structure-activity relationships. The most potent benzylamide 33 (MS1) was similar to a previously reported adamantane derivative and gave an IC50 value of 0.07muM for meta- and 0.08muM for para-carborane at isolated sEH. The ortho-derivative suffered deboronation. The results underline the potential of carboranes as non-natural 3-D pharmacophores to extend the chemical space in drug discovery.
ESTHER : Scholz_2020_Eur.J.Med.Chem_185_111766
PubMedSearch : Scholz_2020_Eur.J.Med.Chem_185_111766
PubMedID: 31677445

Title : Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain - Kramer_2019_J.Med.Chem_62_8443
Author(s) : Kramer JS , Woltersdorf S , Duflot T , Hiesinger K , Lillich FF , Knoll F , Wittmann SK , Klingler FM , Brunst S , Chaikuad A , Morisseau C , Hammock BD , Buccellati C , Sala A , Rovati GE , Leuillier M , Fraineau S , Rondeaux J , Hernandez-Olmos V , Heering J , Merk D , Pogoryelov D , Steinhilber D , Knapp S , Bellien J , Proschak E
Ref : Journal of Medicinal Chemistry , 62 :8443 , 2019
Abstract : The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure-activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid (22b, SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo.
ESTHER : Kramer_2019_J.Med.Chem_62_8443
PubMedSearch : Kramer_2019_J.Med.Chem_62_8443
PubMedID: 31436984