Bacterial Expression and HTS Assessment of Soluble Epoxide Hydrolase Phosphatase

Klingler, Franca‐Maria; Wolf, Markus; Wittmann, Sandra K.; Gribbon, Philip; Proschak, Ewgenij

doi:10.1177/1087057116637609

Cited by 11 publications

(13 citation statements)

References 28 publications

(44 reference statements)

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“…18 Benzaldehydes 13a−m were treated with trimethylsilyl cyanide (TMSCN,14) in the presence of a catalytic amount of triethylamine under neat conditions to yield silylprotected cyanohydrins 15a−m. As described by Stork et al, 17 O-protected cyanohydrins are easily deprotonated at the αposition by LDA in THF to obtain stable nucleophiles at low temperatures, which can react with an electrophile, in this case benzyl bromide (16). The desired deoxybenzoins 17a−m were subsequently obtained by cleaving the remaining silyl ether group of the intermediate with tetrabutylammonium fluoride (TBAF) solution.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain

et al. 2019

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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.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain

et al. 2019

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“…The sEH inhibitory potency of the compounds was determined in a fluorescence-based 96-well sEH activity assay using recombinant human enzyme. , Nonfluorescent PHOME (3-phenylcyano-(6-methoxy-2-naphthalenyl)methyl ester 2-oxiraneacetic acid; Cayman Chemicals) which can be hydrolyzed by the sEH to fluorescent 6-methoxynaphthaldehyde served as substrate. Recombinant human sEH (in Bis-Tris buffer, pH 7, with 0.1 mg/mL BSA containing a final concentration of 0.01% Triton-X 100) was preincubated with test compounds (in DMSO, final DMSO concentration of 1%) for 30 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

A Dual Modulator of Farnesoid X Receptor and Soluble Epoxide Hydrolase To Counter Nonalcoholic Steatohepatitis

et al. 2017

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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.

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“… [a] sEH inhibition was determined on recombinant human sEH protein using (3‐phenyloxiranyl)acetic acid cyano‐(6‐methoxynaphthalen‐2‐yl)methyl ester (PHOME) as fluorogenic substrate [31] . Data are the mean±S.E.M., n=3.…”

Section: Resultsmentioning

confidence: 99%

Development and in vitro Profiling of Dual FXR/LTA4H Modulators

et al. 2021

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Designed polypharmacology presents as an attractive strategy to increase therapeutic efficacy in multi‐factorial diseases by a directed modulation of multiple involved targets with a single molecule. Such an approach appears particularly suitable in non‐alcoholic steatohepatitis (NASH) which involves hepatic steatosis, inflammation and fibrosis as pathological hallmarks. Among various potential pharmacodynamic mechanisms, activation of the farnesoid X receptor (FXRa) and inhibition of leukotriene A4 hydrolase (LTA4Hi) hold promise to counteract NASH according to preclinical and clinical observations. We have developed dual FXR/LTA4H modulators as pharmacological tools, enabling evaluation of this polypharmacology concept to treat NASH and related pathologies. The optimized FXRa/LTA4Hi exhibits well‐balanced dual activity on the intended targets with sub‐micromolar potency and is highly selective over related nuclear receptors and enzymes rendering it suitable as tool to probe synergies of dual FXR/LTA4H targeting.

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Bacterial Expression and HTS Assessment of Soluble Epoxide Hydrolase Phosphatase

Cited by 11 publications

References 28 publications

Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain

Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain

A Dual Modulator of Farnesoid X Receptor and Soluble Epoxide Hydrolase To Counter Nonalcoholic Steatohepatitis

Development and in vitro Profiling of Dual FXR/LTA4H Modulators

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