Hernandez-Olmos V

References (6)

Title : Synthesis and structure-activity relationships for some novel diflapolin derivatives with benzimidazole subunit - Vieider_2022_J.Enzyme.Inhib.Med.Chem_37_1752
Author(s) : Vieider L , Zoeller E , Romp E , Schoenthaler M , Hernandez-Olmos V , Temml V , Hasenoehrl T , Schuster D , Werz O , Garscha U , Matuszczak B
Ref : J Enzyme Inhib Med Chem , 37 :1752 , 2022
Abstract : A series of derivatives of the potent dual soluble epoxide hydrolase (sEH)/5-lipoxygenase-activating protein (FLAP) inhibitor diflapolin was designed, synthesised, and characterised. These novel compounds, which contain a benzimidazole subunit were evaluated for their inhibitory activity against sEH and FLAP. Molecular modelling tools were applied to analyse structure-activity relationships (SAR) on both targets and to predict solubility and gastrointestinal (GI) absorption. The most promising dual inhibitors of these series are 5a, 6b, and 6c.
ESTHER : Vieider_2022_J.Enzyme.Inhib.Med.Chem_37_1752
PubMedSearch : Vieider_2022_J.Enzyme.Inhib.Med.Chem_37_1752
PubMedID: 36124840

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 : 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 : Synthesis, Biological Evaluation and Structure-Activity Relationships of Diflapolin Analogues as Dual sEH\/FLAP Inhibitors - Vieider_2019_ACS.Med.Chem.Lett_10_62
Author(s) : Vieider L , Romp E , Temml V , Fischer J , Kretzer C , Schoenthaler M , Taha A , Hernandez-Olmos V , Sturm S , Schuster D , Werz O , Garscha U , Matuszczak B
Ref : ACS Med Chem Lett , 10 :62 , 2019
Abstract : A series of derivatives of the potent dual soluble epoxide hydrolase (sEH)/5-lipoxygenase-activating protein (FLAP) inhibitor diflapolin was designed, synthesized, and characterized by (1)H NMR, (13)C NMR, and elemental analysis. These novel compounds were biologically evaluated for their inhibitory activity against sEH and FLAP. Molecular modeling tools were applied to analyze structure-activity relationships (SAR) on both targets. Results show that even small modifications on the lead compound diflapolin markedly influence the inhibitory potential, especially on FLAP, suggesting very narrow SAR.
ESTHER : Vieider_2019_ACS.Med.Chem.Lett_10_62
PubMedSearch : Vieider_2019_ACS.Med.Chem.Lett_10_62
PubMedID: 30655948

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