In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor

Podolin, Patricia L.; Bolognese, Brian; Foley, Joseph; Long, Edward R.; Peck, Brian; Umbrecht, Sandra; Zhang, Xiaojun; Zhu, Peijuan; Schwartz, Benjamin; Xie, Wensheng; Quinn, Chad; Qi, Hongwei; Sweitzer, Sharon; Chen, Stephanie; Galop, Marc; Ding, Yun; Belyanskaya, Svetlana; Israel, David I.; Morgan, Barry A.; Behm, David J.; Marino, Joseph P.; Kurali, Edit; Barnette, Mary S.; Mayer, Ruth; Booth-Genthe, Catherine; Callahan, James F.

doi:10.1016/j.prostaglandins.2013.02.001

Cited by 102 publications

(69 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, here we demonstrate a complete profile analysis of omega-3 and 6 fatty acid metabolites in regard to tobacco smoke exposure, lung inflammation and soluble epoxide hydrolase inhibition. In accordance to a recent study published by Podolin et al [40], shown that inhibition of EETs to DHETs conversion also result in down-regulation of the inflammatory response induced by repetitive exposure to cigarette smoke. While the mechanism of action is not reported, supporting evidences from previous studies show that the anti-inflammatory effects of sEHI are believed to occur primarily as a result of the attenuation of the metabolism of EETs to DHETs [40].…”

Section: Discussionsupporting

confidence: 92%

Bioactive lipid profiling reveals drug target engagement of a soluble epoxide hydrolase inhibitor in a murine model of tobacco smoke exposure

et al. 2015

View full text Add to dashboard Cite

The inflammatory process underlying chronic obstructive pulmonary disease (COPD) may be caused by tobacco smoke (TS) exposure. Previous studies show that epoxyeicosatrienoic acids (EETs) possess promising anti-inflammatory properties, therefore stabilization of EETs and other fatty acid epoxides through inhibition of soluble epoxide hydrolase (sEH) was investigated in mouse models of acute and sub-chronic inflammation caused by TS exposure. During the entire TS exposure, the potent sEH inhibitor 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS) was given via drinking water. To assess drug target engagement of TUPS, a tandem mass spectrometry method was used for bioactive lipid profiling of a broad range of fatty acid metabolites, including EETs, and their corresponding diols (DHETs) derived from arachidonic acid, as well as epoxides and diols derived from other fatty acids. Several, but not all, plasma epoxide/diol ratios increased in mice treated with sEH inhibitor, compared to non-treated mice suggesting a wider role for sEH involving more fatty acid precursors besides arachidonic acid. This study supports qualitative use of epoxide/diol ratios explored by bioactive lipid profiling to indicate drug target engagement in mouse models of TS exposure relevant to COPD, which may have ramifications for future therapeutic interventions of sEH.

show abstract

Section: Discussionsupporting

confidence: 92%

Bioactive lipid profiling reveals drug target engagement of a soluble epoxide hydrolase inhibitor in a murine model of tobacco smoke exposure

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Chronic obstructive pulmonary disorder is common among chronic smokers and was estimated to affect 5.1% of the population in 2009 (Akinbami and Liu, 2011), making it a good indication for potential entry into the market for sEH inhibitors. GSK2256294 demonstrates picomolar activity toward sEH, effectively increases in vivo EET/DHET and epoxyoctadecenoic acid/dihydroxyoctadecenoic acid ratios, and reduces cell counts of macrophages, neutrophils, and keratinocyte chemoattractant cells of smoke-exposed rodents (Podolin et al, 2013). These observations are consistent with several studies demonstrating the efficacy of sEH inhibitors at reducing inflammation and general lung injury from smoke exposure (Smith et al, 2005;Wang et al, 2012) and asthma (Yang et al, 2015).…”

Section: Developing a Path To The Clinicsupporting

confidence: 85%

“…IND and development candidates among sEH inhibitors. GSK2256294 is a potent inhibitor that has demonstrated efficacy in vivo and is in the clinic (Podolin et al, 2013). Triclocarban is a commonly used antimicrobial that also inhibits the human sEH and has proved successful as a topical analgesic when used with diclofenac in a double-blind clinical trial for diabetic neuropathic pain.…”

Section: Discovering Physiologic Roles For Epfasmentioning

confidence: 99%

The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

Kodani¹,

Hammock²

2015

Drug Metab Dispos

View full text Add to dashboard Cite

Dr. Bernard Brodie's legacy is built on fundamental discoveries in pharmacology and drug metabolism that were then translated to the clinic to improve patient care. Similarly, the development of a novel class of therapeutics termed the soluble epoxide hydrolase (sEH) inhibitors was originally spurred by fundamental research exploring the biochemistry and physiology of the sEH. Here, we present an overview of the history and current state of research on epoxide hydrolases, specifically focusing on sEHs. In doing so, we start with the translational project studying the metabolism of the insect juvenile hormone mimic R-20458 [(E)-6,7-epoxy-1-(4-ethylphenoxy)-3,7-dimethyl-2-octene], which led to the identification of the mammalian sEH. Further investigation of this enzyme and its substrates, including the epoxyeicosatrienoic acids, led to insight into mechanisms of inflammation, chronic and neuropathic pain, angiogenesis, and other physiologic processes. This basic knowledge in turn led to the development of potent inhibitors of the sEH that are promising therapeutics for pain, hypertension, chronic obstructive pulmonary disorder, arthritis, and other disorders.

show abstract

“…Our fi ndings offer important insight into the potential therapeutic utility of increasing EETs in obstructive CAD patients predisposed to low EET levels. Importantly, agents that promote the effects of EETs are in early development for a variety of therapeutic indications (47)(48)(49). In parallel, technology for the high-throughput by guest, on May 7, 2018 www.jlr.org Downloaded from .html http://www.jlr.org/content/suppl/2015/11/10/jlr.M061697.DC1 Supplemental Material can be found at:…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study

Oni‐Orisan

Edin

Lee

et al. 2016

Journal of Lipid Research

View full text Add to dashboard Cite

In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor

Cited by 102 publications

References 20 publications

Bioactive lipid profiling reveals drug target engagement of a soluble epoxide hydrolase inhibitor in a murine model of tobacco smoke exposure

Bioactive lipid profiling reveals drug target engagement of a soluble epoxide hydrolase inhibitor in a murine model of tobacco smoke exposure

The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study

Contact Info

Product

Resources

About