Proschak E

References (25)

Title : Discovery of the sEH Inhibitor Epoxykynin as a Potent Kynurenine Pathway Modulator - Dotsch_2024_J.Med.Chem__
Author(s) : Dotsch L , Davies C , Hennes E , Schonfeld J , Kumar A , Guita C , Ehrler JHM , Hiesinger K , Thavam S , Janning P , Sievers S , Knapp S , Proschak E , Ziegler S , Waldmann H
Ref : Journal of Medicinal Chemistry , : , 2024
Abstract : Disease-related phenotypic assays enable unbiased discovery of novel bioactive small molecules and may provide novel insights into physiological systems and unprecedented molecular modes of action (MMOA). Herein, we report the identification and characterization of epoxykynin, a potent inhibitor of the soluble epoxide hydrolase (sEH). Epoxykynin was discovered by means of a cellular assay monitoring modulation of kynurenine (Kyn) levels in BxPC-3 cells upon stimulation with the cytokine interferon-gamma (IFN-gamma) and subsequent target identification employing affinity-based chemical proteomics. Increased Kyn levels are associated with immune suppression in the tumor microenvironment and, thus, the Kyn pathway and its key player indoleamine 2,3-dioxygenase 1 (IDO1) are appealing targets in immuno-oncology. However, targeting IDO1 directly has led to limited success in clinical investigations, demonstrating that alternative approaches to reduce Kyn levels are in high demand. We uncover a cross-talk between sEH and the Kyn pathway that may provide new opportunities to revert cancer-induced immune tolerance.
ESTHER : Dotsch_2024_J.Med.Chem__
PubMedSearch : Dotsch_2024_J.Med.Chem__
PubMedID: 38470246
Gene_locus related to this paper: human-EPHX2

Title : Photosensitization enables Pauson-Khand-type reactions with nitrenes - Li_2024_Science_383_498
Author(s) : Li F , Zhu WF , Empel C , Datsenko O , Kumar A , Xu Y , Ehrler JHM , Atodiresei I , Knapp S , Mykhailiuk PK , Proschak E , Koenigs RM
Ref : Science , 383 :498 , 2024
Abstract : The Pauson-Khand reaction has in the past 50 years become one of the most common cycloaddition reactions in chemistry. Coupling two unsaturated bonds with carbon monoxide, the transformation remains limited to CO as a C(1) building block. Herein we report analogous cycloaddition reactions with nitrenes as an N(1) unit. The reaction of a nonconjugated diene with a nitrene precursor produces bicyclic bioisosteres of common saturated heterocycles such as piperidine, morpholine, and piperazine. Experimental and computational mechanistic studies support relaying of the diradical nature of triplet nitrene into the Pi-system. We showcase the reaction's utility in late-stage functionalization of drug compounds and discovery of soluble epoxide hydrolase inhibitors.
ESTHER : Li_2024_Science_383_498
PubMedSearch : Li_2024_Science_383_498
PubMedID: 38301027
Gene_locus related to this paper: human-EPHX2

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 : Combined Cardioprotective and Adipocyte Browning Effects Promoted by the Eutomer of Dual sEH\/PPARgamma Modulator - Hartmann_2021_J.Med.Chem_64_2815
Author(s) : Hartmann M , Bibli SI , Tews D , Ni X , Kircher T , Kramer JS , Kilu W , Heering J , Hernandez-Olmos V , Weizel L , Scriba GKE , Krait S , Knapp S , Chaikuad A , Merk D , Fleming I , Fischer-Posovszky P , Proschak E
Ref : Journal of Medicinal Chemistry , 64 :2815 , 2021
Abstract : The metabolic syndrome (MetS) is a constellation of cardiovascular and metabolic symptoms involving insulin resistance, steatohepatitis, obesity, hypertension, and heart disease, and patients suffering from MetS often require polypharmaceutical treatment. PPARgamma agonists are highly effective oral antidiabetics with great potential in MetS, which promote adipocyte browning and insulin sensitization. However, the application of PPARgamma agonists in clinics is restricted by potential cardiovascular adverse events. We have previously demonstrated that the racemic dual sEH/PPARgamma modulator RB394 (3) simultaneously improves all risk factors of MetS in vivo. In this study, we identify and characterize the eutomer of 3. We provide structural rationale for molecular recognition of the eutomer. Furthermore, we could show that the dual sEH/PPARgamma modulator is able to promote adipocyte browning and simultaneously exhibits cardioprotective activity which underlines its exciting potential in treatment of MetS.
ESTHER : Hartmann_2021_J.Med.Chem_64_2815
PubMedSearch : Hartmann_2021_J.Med.Chem_64_2815
PubMedID: 33620196

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 : Multi-Target Approaches in Metabolic Syndrome - Lillich_2020_Front.Pharmacol_11_554961
Author(s) : Lillich FF , Imig JD , Proschak E
Ref : Front Pharmacol , 11 :554961 , 2020
Abstract : Metabolic syndrome (MetS) is a highly prevalent disease cluster worldwide. It requires polypharmacological treatment of the single conditions including type II diabetes, hypertension, and dyslipidemia, as well as the associated comorbidities. The complex treatment regimens with various drugs lead to drug-drug interactions and inadequate patient adherence, resulting in poor management of the disease. Multi-target approaches aim at reducing the polypharmacology and improving the efficacy. This review summarizes the medicinal chemistry efforts to develop multi-target ligands for MetS. Different combinations of pharmacological targets in context of in vivo efficacy and future perspective for multi-target drugs in MetS are discussed.
ESTHER : Lillich_2020_Front.Pharmacol_11_554961
PubMedSearch : Lillich_2020_Front.Pharmacol_11_554961
PubMedID: 33776749

Title : Computer-Aided Fragment Growing Strategies to Design Dual Inhibitors of Soluble Epoxide Hydrolase and LTA4 Hydrolase - Hefke_2020_ACS.Med.Chem.Lett_11_1244
Author(s) : Hefke L , Hiesinger K , Zhu WF , Kramer JS , Proschak E
Ref : ACS Med Chem Lett , 11 :1244 , 2020
Abstract : Multitarget ligands are interesting candidates for drug discovery and development due to improved safety and efficacy. However, rational design and optimization of multitarget ligands is tedious because affinity optimization for two or more targets has to be performed simultaneously. In this study, we demonstrate that, given a molecular fragment, which binds to two targets of interest, computer-aided fragment growing can be applied to optimize compound potency, relying on either ligand- or structure-derived information. This methodology is applied to the design of dual inhibitors of soluble epoxide hydrolase and leukotriene A4 hydrolase.
ESTHER : Hefke_2020_ACS.Med.Chem.Lett_11_1244
PubMedSearch : Hefke_2020_ACS.Med.Chem.Lett_11_1244
PubMedID: 32551007

Title : Dual Soluble Epoxide Hydrolase Inhibitor\/PPAR-gamma Agonist Attenuates Renal Fibrosis - Stavniichuk_2020_Prostaglandins.Other.Lipid.Mediat__106472
Author(s) : Stavniichuk A , Hye Khan MA , Yeboah MM , Chesnik MA , Jankiewicz WK , Hartmann M , Blocher R , Kircher T , Savchuk O , Proschak E , Imig JD
Ref : Prostaglandins Other Lipid Mediat , :106472 , 2020
Abstract : Renal fibrosis is a contributor to chronic kidney disease and an important predictor of long-term prognosis. We developed a dual soluble epoxide hydrolase inhibitor-PPAR-gamma agonist (sEHi/PPAR-gamma), RB394, and investigated its ability to attenuate renal fibrosis in a mouse unilateral ureteral obstruction (UUO) model. RB394 efficacy was compared to an sEH inhibitor (sEHi), a PPAR-gamma agonist rosiglitazone (Rosi), or their combination (sEHi + Rosi). All interventional treatments were administrated in drinking water 3 days after UUO induction surgery and continued for 7 days. UUO mice developed renal fibrosis with higher collagen formation and RB394 significantly attenuated fibrosis (P < 0.05). Renal expression of alpha-smooth muscle actin (alpha-SMA) was elevated in UUO mice and all treatments except sEHi significantly attenuated renal alpha-SMA expression. Renal mRNA expression fibrotic and fibrosis regulators were higher in UUO mice and RB394 and sEHi + Rosi treatments attenuated their expression. Renal inflammation was evident in UUO mice with increased infiltration of CD45 and F4/80 positive cells. RB394 and sEHi + Rosi treatments attenuated renal inflammation in UUO mice. UUO mice had renal tubular and vascular injury. Renal tubular and vascular injuries were attenuated to a greater extent by RB394 and sEHi + Rosi than sEHi or Rosi treatment alone. Renal mRNA expression of oxidative stress markers were significantly higher in UUO mice (P < 0.05). RB394 and sEHi + Rosi attenuated expression of oxidative stress markers to a greater extent than other interventional treatments (P < 0.05). These findings demonstrate that RB394 can attenuate renal fibrosis by reducing renal inflammation, oxidative stress, tubular injury, and vascular injury. In conclusion, RB394 demonstrates exciting potential as a therapeutic for renal fibrosis and chronic kidney disease.
ESTHER : Stavniichuk_2020_Prostaglandins.Other.Lipid.Mediat__106472
PubMedSearch : Stavniichuk_2020_Prostaglandins.Other.Lipid.Mediat__106472
PubMedID: 32569747

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 : 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 : Development of multitarget agents possessing soluble epoxide hydrolase inhibitory activity - Hiesinger_2019_Prostaglandins.Other.Lipid.Mediat_140_31
Author(s) : Hiesinger K , Wagner KM , Hammock BD , Proschak E , Hwang SH
Ref : Prostaglandins Other Lipid Mediat , 140 :31 , 2019
Abstract : Over the last two decades polypharmacology has emerged as a new paradigm in drug discovery, even though developing drugs with high potency and selectivity toward a single biological target is still a major strategy. Often, targeting only a single enzyme or receptor shows lack of efficacy. High levels of inhibitor of a single target also can lead to adverse side effects. A second target may offer additive or synergistic effects to affecting the first target thereby reducing on- and off-target side effects. Therefore, drugs that inhibit multiple targets may offer a great potential for increased efficacy and reduced the adverse effects. In this review we summarize recent findings of rationally designed multitarget compounds that are aimed to improve efficacy and safety profiles compared to those that target a single enzyme or receptor. We focus on dual inhibitors/modulators that target the soluble epoxide hydrolase (sEH) as a common part of their design to take advantage of the beneficial effects of sEH inhibition.
ESTHER : Hiesinger_2019_Prostaglandins.Other.Lipid.Mediat_140_31
PubMedSearch : Hiesinger_2019_Prostaglandins.Other.Lipid.Mediat_140_31
PubMedID: 30593866

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 : Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase - Lukin_2018_Bioorg.Chem_80_655
Author(s) : Lukin A , Kramer J , Hartmann M , Weizel L , Hernandez-Olmos V , Falahati K , Burghardt I , Kalinchenkova N , Bagnyukova D , Zhurilo N , Rautio J , Forsberg M , Ihalainen J , Auriola S , Leppanen J , Konstantinov I , Pogoryelov D , Proschak E , Dar'in D , Krasavin M
Ref : Bioorg Chem , 80 :655 , 2018
Abstract : Spirocyclic 1-oxa-9-azaspiro[5.5]undecan-4-amine scaffold was explored as a basis for the design of potential inhibitors of soluble epoxide hydrolase (sEH). Synthesis and testing of the initial SAR-probing library followed by biochemical testing against sEH allowed nominating a racemic lead compound (+/-)-22. The latter showed remarkable (> 0.5mM) solubility in aqueous phosphate buffer solution, unusually low (for sEH inhibitors) lipophilicity as confirmed by experimentally determined logD7.4 of 0.99, and an excellent oral bioavailability in mice (as well as other pharmacokinetic characteristics). Individual enantiomer profiling revealed that the inhibitory potency primarily resided with the dextrorotatory eutomer (+)-22 (IC50 4.99+/-0.18nM). For the latter, a crystal structure of its complex with a C-terminal domain of sEH was obtained and resolved. These data fully validate (+)-22 as a new non-racemic advanced lead compound for further development as a potential therapeutic agent for use in such areas as cardiovascular disease, inflammation and pain.
ESTHER : Lukin_2018_Bioorg.Chem_80_655
PubMedSearch : Lukin_2018_Bioorg.Chem_80_655
PubMedID: 30059891
Gene_locus related to this paper: human-EPHX2

Title : Orally Available Soluble Epoxide Hydrolase\/Phosphodiesterase 4 Dual Inhibitor Treats Inflammatory Pain - Blocher_2018_J.Med.Chem_61_3541
Author(s) : Blocher R , Wagner KM , Gopireddy RR , Harris TR , Wu H , Barnych B , Hwang SH , Xiang YK , Proschak E , Morisseau C , Hammock BD
Ref : Journal of Medicinal Chemistry , 61 :3541 , 2018
Abstract : Inspired by previously discovered enhanced analgesic efficacy between soluble epoxide hydrolase (sEH) and phosphodiesterase 4 (PDE4) inhibitors, we designed, synthesized and characterized 21 novel sEH/PDE4 dual inhibitors. The best of these displayed good efficacy in in vitro assays. Further pharmacokinetic studies of a subset of four selected compounds led to the identification of a bioavailable dual inhibitor N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA). In a lipopolysaccharide induced inflammatory pain rat model, MPPA rapidly increased in the blood ( Tmax = 30 min; Cmax = 460 nM) after oral administration of 3 mg/kg and reduced inflammatory pain with rapid onset of action correlating with blood levels over a time course of 4 h. Additionally, MPPA does not alter self-motivated exploration of rats with inflammatory pain or the withdrawal latency in control rats.
ESTHER : Blocher_2018_J.Med.Chem_61_3541
PubMedSearch : Blocher_2018_J.Med.Chem_61_3541
PubMedID: 29614224

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 : Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3 R Antagonism for Neurodegenerative Diseases - Bautista-Aguilera_2017_Angew.Chem.Int.Ed.Engl_56_12765
Author(s) : Bautista-Aguilera OM , Hagenow S , Palomino-Antolin A , Farre-Alins V , Ismaili L , Joffrin PL , Jimeno ML , Soukup O , Janockova J , Kalinowsky L , Proschak E , Iriepa I , Moraleda I , Schwed JS , Romero Martinez A , Lopez-Munoz F , Chioua M , Egea J , Ramsay RR , Marco-Contelles J , Stark H
Ref : Angew Chem Int Ed Engl , 56 :12765 , 2017
Abstract : The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg(-1) i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.
ESTHER : Bautista-Aguilera_2017_Angew.Chem.Int.Ed.Engl_56_12765
PubMedSearch : Bautista-Aguilera_2017_Angew.Chem.Int.Ed.Engl_56_12765
PubMedID: 28861918

Title : Phosphatase activity of soluble epoxide hydrolase - Kramer_2017_Prostaglandins.Other.Lipid.Mediat_133_88
Author(s) : Kramer J , Proschak E
Ref : Prostaglandins Other Lipid Mediat , 133 :88 , 2017
Abstract : Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that exhibits lipid epoxide hydrolase (sEH-H) and lipid phosphatase activity (sEH-P), with each being located in its own distinct domain. While the epoxide hydrolase activity is well-investigated, the role of the phosphatase domain remains unclear. This article briefly summarizes the evolution, structure and SNPs of the human sEH, with a special focus on the function and postulated role of the N-terminal domain of sEH. Furthermore, the article provides an overview of tools to study sEH-P.
ESTHER : Kramer_2017_Prostaglandins.Other.Lipid.Mediat_133_88
PubMedSearch : Kramer_2017_Prostaglandins.Other.Lipid.Mediat_133_88
PubMedID: 28729091

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

Title : Evaluation of structure-derived pharmacophore of soluble epoxide hydrolase inhibitors by virtual screening - Moser_2012_Bioorg.Med.Chem.Lett_22_6762
Author(s) : Moser D , Achenbach J , Klingler FM , Estel la B , Hahn S , Proschak E
Ref : Bioorganic & Medicinal Chemistry Lett , 22 :6762 , 2012
Abstract : The soluble epoxide hydrolase (sEH) is an enzyme located downstream of the CYP 450 branch of the arachidonic acid cascade and can be linked to a number of indications, including cardiovascular disorders, diabetes and inflammatory processes. Numerous inhibitors (sEHI) have been reported, mostly based on urea or amide scaffolds. The search for valid bioisosteric replacements is an ongoing challenge in the discovery of sEHI. We developed a receptor-based pharmacophore model on the basis of 13 crystal structures of the sEH and performed a virtual screening for novel compounds. The virtual screening hits were verified in vitro proving the basic applicability of the model and leading to novel non-urea sEHI.
ESTHER : Moser_2012_Bioorg.Med.Chem.Lett_22_6762
PubMedSearch : Moser_2012_Bioorg.Med.Chem.Lett_22_6762
PubMedID: 23017883