Steinhilber D

References (12)

Title : Repurposing of 8-Hydroxyquinoline-based Butyrylcholinesterase and Cathepsin B Ligands as Potent Non-peptidic Deoxyribonuclease I Inhibitors - Gajic_2022_ChemMedChem__
Author(s) : Gajic M , Knez D , Sosic I , Mravljak J , Meden A , Kosak U , Leitzbach L , George S , Hofmann B , Zivkovic A , Steinhilber D , Stark H , Gobec S , Smelcerovic A , Anderluh M
Ref : ChemMedChem , : , 2022
Abstract : A library of 31 butyrylcholinesterase (BChE) and cathepsin B (CatB) inhibitors, was screened in vitro for inhibition of deoxyribonuclease I (DNase I). Compounds 22, 8 and 7 are among the most potent synthetic non-peptide DNase I inhibitors reported up to date. Three 8-hydroxyquinoline analogues inhibited both DNase I and BChE with IC50 values below 35 microM and 50 nM, respectively, while 2 nitroxoline derivatives inhibited DNase I and Cat B endopeptidase activity with IC50 values below 60 microM and 20 microM, respectively. Selected derivatives were screened for various co-target binding affinities at dopamine D2 and D3, histamine H3 and H4 receptors and inhibition of 5-lipoxygenase. Compound 8 bound to the H3 receptor and is highlighted as the most promising multifunctional ligand with a favorable pharmacokinetic profile and one of the most potent non-peptide DNase I inhibitors. The present study demonstrates that 8-hydroxyquinoline is a structural fragment critical for DNase I inhibition in the presented series of compounds.
ESTHER : Gajic_2022_ChemMedChem__
PubMedSearch : Gajic_2022_ChemMedChem__
PubMedID: 34994078

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 : Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA4 Hydrolase - Hiesinger_2020_ACS.Med.Chem.Lett_11_298
Author(s) : Hiesinger K , Schott A , Kramer JS , Blocher R , Witt F , Wittmann SK , Steinhilber D , Pogoryelov D , Gerstmeier J , Werz O , Proschak E
Ref : ACS Med Chem Lett , 11 :298 , 2020
Abstract : Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA4 hydrolase (LTA4H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure-activity relationship studies were performed to identify optimal substitution patterns. X-ray structure analysis of a promising dual inhibitor in complex with sEH, as well as molecular docking with LTA4H provided a rationale for further optimization. Hereby, scaffold extension was successfully applied to yield potent dual sEH/LTA4H inhibitors. The spectrum of pro- and anti-inflammatory lipid mediators was evaluated in M1 and M2 macrophages, stimulated with LPS, and incubated with the most promising compound 14. The effect of 14 on the inflammatory lipid mediator profile characterizes dual sEH/LTA4H inhibitors as an interesting option for future anti-inflammatory agent investigations.
ESTHER : Hiesinger_2020_ACS.Med.Chem.Lett_11_298
PubMedSearch : Hiesinger_2020_ACS.Med.Chem.Lett_11_298
PubMedID: 32184960
Gene_locus related to this paper: human-EPHX2

Title : Computer-Aided Selective Optimization of Side Activities of Talinolol - Hiesinger_2019_ACS.Med.Chem.Lett_10_899
Author(s) : Hiesinger K , Kramer JS , Achenbach J , Moser D , Weber J , Wittmann SK , Morisseau C , Angioni C , Geisslinger G , Kahnt AS , Kaiser A , Proschak A , Steinhilber D , Pogoryelov D , Wagner K , Hammock BD , Proschak E
Ref : ACS Med Chem Lett , 10 :899 , 2019
Abstract : Selective optimization of side activities is a valuable source of novel lead structures in drug discovery. In this study, a computer-aided approach was used to deorphanize the pleiotropic cholesterol-lowering effects of the beta-blocker talinolol, which result from the inhibition of the enzyme soluble epoxide hydrolase (sEH). X-ray structure analysis of the sEH in complex with talinolol enables a straightforward optimization of inhibitory potency. The resulting lead structure exhibited in vivo activity in a rat model of diabetic neuropatic pain.
ESTHER : Hiesinger_2019_ACS.Med.Chem.Lett_10_899
PubMedSearch : Hiesinger_2019_ACS.Med.Chem.Lett_10_899
PubMedID: 31223445
Gene_locus related to this paper: human-EPHX2

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

Title : Zafirlukast Is a Dual Modulator of Human Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptor gamma - Gobel_2019_Front.Pharmacol_10_263
Author(s) : Gobel T , Diehl O , Heering J , Merk D , Angioni C , Wittmann SK , Buscato E , Kottke R , Weizel L , Schader T , Maier TJ , Geisslinger G , Schubert-Zsilavecz M , Steinhilber D , Proschak E , Kahnt AS
Ref : Front Pharmacol , 10 :263 , 2019
Abstract : Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 muM, respectively. In contrast, only montelukast and zafirlukast activated PPARgamma in the reporter gene assay with EC50 values of 1.17 muM (21.9% max. activation) and 2.49 muM (148% max. activation), respectively. PPARalpha and delta were not affected by any of the compounds. The activation of PPARgamma was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARgamma phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARgamma target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARgamma cofactor CBP upon ligand binding suggesting that both compounds act as PPARgamma modulators. In addition, zafirlukast impaired the TNFalpha triggered phosphorylation of PPARgamma2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARgamma modulator representing an excellent starting point for the further development of this compound class.
ESTHER : Gobel_2019_Front.Pharmacol_10_263
PubMedSearch : Gobel_2019_Front.Pharmacol_10_263
PubMedID: 30949053

Title : A Dual Modulator of Farnesoid X Receptor and Soluble Epoxide Hydrolase To Counter Nonalcoholic Steatohepatitis - Schmidt_2017_J.Med.Chem_60_7703
Author(s) : Schmidt J , Rotter M , Weiser T , Wittmann S , Weizel L , Kaiser A , Heering J , Goebel T , Angioni C , Wurglics M , Paulke A , Geisslinger G , Kahnt A , Steinhilber D , Proschak E , Merk D
Ref : Journal of Medicinal Chemistry , 60 :7703 , 2017
Abstract : Nonalcoholic steatohepatitis arising from Western diet and lifestyle is characterized by accumulation of fat in liver causing inflammation and fibrosis. It evolves as serious health burden with alarming incidence, but there is no satisfying pharmacological therapy to date. Considering the disease's multifactorial nature, modulation of multiple targets might provide superior therapeutic efficacy. In particular, farnesoid X receptor (FXR) activation that revealed antisteatotic and antifibrotic effects in clinical trials combined with inhibition of soluble epoxide hydrolase (sEH) as anti-inflammatory strategy promises synergies. To exploit this dual concept, we developed agents exerting partial FXR agonism and sEH inhibitory activity. Merging known pharmacophores and systematic exploration of the structure-activity relationship on both targets produced dual modulators with low nanomolar potency. Extensive in vitro characterization confirmed high dual efficacy in cellular context combined with low toxicity, and pilot in vivo data revealed favorable pharmacokinetics as well as engagement on both targets in vivo.
ESTHER : Schmidt_2017_J.Med.Chem_60_7703
PubMedSearch : Schmidt_2017_J.Med.Chem_60_7703
PubMedID: 28845983

Title : Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase - Meirer_2016_Molecules_22_
Author(s) : Meirer K , Glatzel D , Kretschmer S , Wittmann SK , Hartmann M , Blocher R , Angioni C , Geisslinger G , Steinhilber D , Hofmann B , Furst R , Proschak E
Ref : Molecules , 22 : , 2016
Abstract : The arachidonic acid cascade is a key player in inflammation, and numerous well-established drugs interfere with this pathway. Previous studies have suggested that simultaneous inhibition of 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH) results in synergistic anti-inflammatory effects. In this study, a novel prototype of a dual 5-LO/sEH inhibitor KM55 was rationally designed and synthesized. KM55 was evaluated in enzyme activity assays with recombinant enzymes. Furthermore, activity of KM55 in human whole blood and endothelial cells was investigated. KM55 potently inhibited both enzymes in vitro and attenuated the formation of leukotrienes in human whole blood. KM55 was also tested in a cell function-based assay. The compound significantly inhibited the LPS-induced adhesion of leukocytes to endothelial cells by blocking leukocyte activation.
ESTHER : Meirer_2016_Molecules_22_
PubMedSearch : Meirer_2016_Molecules_22_
PubMedID: 28036068

Title : N-Benzylbenzamides: A Novel Merged Scaffold for Orally Available Dual Soluble Epoxide Hydrolase\/Peroxisome Proliferator-Activated Receptor gamma Modulators - Blocher_2016_J.Med.Chem_59_61
Author(s) : Blocher R , Lamers C , Wittmann SK , Merk D , Hartmann M , Weizel L , Diehl O , Bruggerhoff A , Boss M , Kaiser A , Schader T , Gobel T , Grundmann M , Angioni C , Heering J , Geisslinger G , Wurglics M , Kostenis E , Brune B , Steinhilber D , Schubert-Zsilavecz M , Kahnt AS , Proschak E
Ref : Journal of Medicinal Chemistry , 59 :61 , 2016
Abstract : Metabolic syndrome (MetS) is a multifactorial disease cluster that consists of dyslipidemia, cardiovascular disease, type 2 diabetes mellitus, and obesity. MetS patients are strongly exposed to polypharmacy; however, the number of pharmacological compounds required for MetS treatment can be reduced by the application of multitarget compounds. This study describes the design of dual-target ligands that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated receptor type gamma (PPARgamma). Simultaneous modulation of sEH and PPARgamma can improve diabetic conditions and hypertension at once. N-Benzylbenzamide derivatives were determined to fit a merged sEH/PPARgamma pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 muM/PPARgamma EC50 = 0.3 muM) modulator 14c. In vitro and in vivo evaluations revealed good ADME properties qualifying 14c as a pharmacological tool compound for long-term animal models of MetS.
ESTHER : Blocher_2016_J.Med.Chem_59_61
PubMedSearch : Blocher_2016_J.Med.Chem_59_61
PubMedID: 26595749

Title : Exploring the chemical space of multitarget ligands using aligned self-organizing maps - Achenbach_2013_ACS.Med.Chem.Lett_4_1169
Author(s) : Achenbach J , Klingler FM , Blocher R , Moser D , Hafner AK , Rodl CB , Kretschmer S , Kruger B , Lohr F , Stark H , Hofmann B , Steinhilber D , Proschak E
Ref : ACS Med Chem Lett , 4 :1169 , 2013
Abstract : Design of multitarget drugs and polypharmacological compounds has become popular during the past decade. However, the main approach to design such compounds is to link two selective ligands via a flexible linker. Although such chimeric ligands often have reasonable potency in vitro, the in vivo efficacy is low due to high molecular weight, low ligand efficiency, and poor pharmacokinetic profile. We developed an unprecedented in silico approach for fragment-based design of multitarget ligands. It relies on superposition of the chemical spaces related to the affinity on single targets represented by self-organizing maps. We used this approach for screening of molecular fragments, which bind to the enzymes 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH). Using STD-NMR and activity-based assays, we were able to identify fragments binding to both targets. Furthermore, we were able to expand one of the fragments to a potent dual inhibitor bearing a reasonable molecular weight (MW = 446) and high affinity to both targets (IC50 of 0.03 muM toward 5-LO and 0.17 muM toward sEH).
ESTHER : Achenbach_2013_ACS.Med.Chem.Lett_4_1169
PubMedSearch : Achenbach_2013_ACS.Med.Chem.Lett_4_1169
PubMedID: 24900624

Title : Synthesis and structure-activity relationship studies of novel dual inhibitors of soluble epoxide hydrolase and 5-lipoxygenase - Meirer_2013_J.Med.Chem_56_1777
Author(s) : Meirer K , Rodl CB , Wisniewska JM , George S , Hafner AK , Buscato EL , Klingler FM , Hahn S , Berressem D , Wittmann SK , Steinhilber D , Hofmann B , Proschak E
Ref : Journal of Medicinal Chemistry , 56 :1777 , 2013
Abstract : Current research leads to the assumption that drugs affecting more than one target could result in a more efficient treatment of diseases and fewer safety concerns. Administration of drugs inhibiting only one branch of the arachidonic acid cascade is usually accompanied by side effects. We therefore designed and synthesized a library of hybrid molecules incorporating an imidazo[1,2-a]pyridine and an urea moiety as novel soluble epoxide hydrolase (sEH)/5-lipoxygenase (5-LO) dual inhibitors. Evaluation of the compounds was accomplished by in vitro testing using recombinant enzyme assays.
ESTHER : Meirer_2013_J.Med.Chem_56_1777
PubMedSearch : Meirer_2013_J.Med.Chem_56_1777
PubMedID: 23356879