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Bruce D. Hammock - One of the best experts on this subject based on the ideXlab platform.
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discovery of soluble Epoxide Hydrolase inhibitors from chemical synthesis and natural products
Journal of Medicinal Chemistry, 2021Co-Authors: Chengpeng Sun, Sunghee Hwang, Christophe Morisseau, Xinyue Zhang, Zhanjun Zhang, Bruce D. HammockAbstract:Soluble Epoxide Hydrolase (sEH) is an α/β Hydrolase fold protein and widely distributed in numerous organs including the liver, kidney, and brain. The inhibition of sEH can effectively maintain endogenous epoxyeicosatrienoic acids (EETs) levels and reduce dihydroxyeicosatrienoic acids (DHETs) levels, resulting in therapeutic potentials for cardiovascular, central nervous system, and metabolic diseases. Therefore, since the beginning of this century, the development of sEH inhibitors is a hot research topic. A variety of potent sEH inhibitors have been developed by chemical synthesis or isolated from natural sources. In this review, we mainly summarized the interconnected aspects of sEH with cardiovascular, central nervous system, and metabolic diseases and then focus on representative inhibitors, which would provide some useful guidance for the future development of potential sEH inhibitors.
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soluble Epoxide Hydrolase inhibitor mediated analgesia lacks tolerance in rat models
Brain Research, 2020Co-Authors: Karen Wagner, Jogen Atone, Bruce D. HammockAbstract:Effectively treating chronic pain remains a therapeutic challenge in the clinic. Recent evidence has shown the inhibition of the soluble Epoxide Hydrolase (sEH) to be an effective strategy to limit chronic pain in preclinical models, horses and companion animals. Determining the safety of sEH inhibition in addition to this demonstrated efficacy is a critical step to the further development of sEH inhibitors (sEHI) as analgesics. Here we describe a comparison of the sEHI TPPU with other first in class analgesics for human chronic pain. We assess the development of tolerance to the analgesia mediated by TPPU with extended use. We also assess for CNS effects by measuring changes in motor control and functioning. The sEHI are multimodal analgesics that have demonstrated potent efficacy against chronic pain. They have previously been tested and show no reward potential using operant methods. The results of the current experiments show that they lack motor function effects and also lack the development of tolerance with extended dosing.
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exploring the size of the lipophilic unit of the soluble Epoxide Hydrolase inhibitors
Bioorganic & Medicinal Chemistry, 2019Co-Authors: Sandra Codony, Bruce D. Hammock, Christophe Morisseau, Elena Valverde, Rosana Leiva, Jose Brea, Isabel M Loza, Santiago VazquezAbstract:Abstract Soluble Epoxide Hydrolase (sEH) inhibitors are potential drugs for several diseases. Adamantyl ureas are excellent sEH inhibitors but have limited metabolic stability. Herein, we report the effect of replacing the adamantane group by alternative polycyclic hydrocarbons on sEH inhibition, solubility, permeability and metabolic stability. Compounds bearing smaller or larger polycyclic hydrocarbons than adamantane yielded all good inhibition potency of the human sEH (0.4 ≤ IC50 ≤ 21.7 nM), indicating that sEH is able to accommodate inhibitors of very different size. Human liver microsomal stability of diamantane containing inhibitors is lower than that of their corresponding adamantane counterparts.
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fluoroaromatic fragments on 1 3 disubstituted ureas enhance soluble Epoxide Hydrolase inhibition
Journal of Fluorine Chemistry, 2019Co-Authors: V. V. Burmistrov, Christophe Morisseau, Gennady M. Butov, Vladimir S Dyachenko, V B Rybakov, Bruce D. HammockAbstract:A series of soluble Epoxide Hydrolase (sEH) inhibitors containing 2-fluorophenyl fragment was developed. Inhibition potency of the described compounds ranges from 0.7 to 630.9 nM. 1-(Adamantan-1-ylmethyl)-3-(2-fluorophenyl) urea (3b, IC50 = 0.7 nM) and 1-(adamantan-2-yl)-3-(2-fluorophenyl) urea (3i, IC50 =1.0 nM) were found to be the most potent sEH inhibitors within the described series. Crystal results suggest that potency is probably enhanced by extra hydrogen bond between the fluorine atom and catalytic tyrosine residues.
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Adamantyl thioureas as soluble Epoxide Hydrolase inhibitors
Bioorganic & medicinal chemistry letters, 2018Co-Authors: V. V. Burmistrov, Christophe Morisseau, Gennady M. Butov, Dmitry Pitushkin, Dmitry S. Karlov, Robert R. Fayzullin, Bruce D. HammockAbstract:Abstract A series of inhibitors of the soluble Epoxide Hydrolase (sEH) containing one or two thiourea groups has been developed. Inhibition potency of the described compounds ranges from 50 μM to 7.2 nM. 1,7-(Heptamethylene)bis[(adamant-1-yl)thiourea] (6f) was found to be the most potent sEH inhibitor, among the thioureas tested. The inhibitory activity of the thioureas against the human sEH is closer to the value of activity against rat sEH rather than murine sEH. While being less active, thioureas are up to 7-fold more soluble than ureas, which makes them more bioavailable and thus promising as sEH inhibitors.
Christophe Morisseau - One of the best experts on this subject based on the ideXlab platform.
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discovery of soluble Epoxide Hydrolase inhibitors from chemical synthesis and natural products
Journal of Medicinal Chemistry, 2021Co-Authors: Chengpeng Sun, Sunghee Hwang, Christophe Morisseau, Xinyue Zhang, Zhanjun Zhang, Bruce D. HammockAbstract:Soluble Epoxide Hydrolase (sEH) is an α/β Hydrolase fold protein and widely distributed in numerous organs including the liver, kidney, and brain. The inhibition of sEH can effectively maintain endogenous epoxyeicosatrienoic acids (EETs) levels and reduce dihydroxyeicosatrienoic acids (DHETs) levels, resulting in therapeutic potentials for cardiovascular, central nervous system, and metabolic diseases. Therefore, since the beginning of this century, the development of sEH inhibitors is a hot research topic. A variety of potent sEH inhibitors have been developed by chemical synthesis or isolated from natural sources. In this review, we mainly summarized the interconnected aspects of sEH with cardiovascular, central nervous system, and metabolic diseases and then focus on representative inhibitors, which would provide some useful guidance for the future development of potential sEH inhibitors.
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development of potent inhibitors of the human microsomal Epoxide Hydrolase
European Journal of Medicinal Chemistry, 2020Co-Authors: Bogdan Barnych, Nalin Singh, Sophie Negrel, Yue Zhang, Damien Magis, Capucine Roux, Xiude Hua, Zhewen Ding, Christophe MorisseauAbstract:Abstract Microsomal Epoxide Hydrolase (mEH) hydrolyzes a wide range of Epoxide containing molecules. Although involved in the metabolism of xenobiotics, recent studies associate mEH with the onset and development of certain disease conditions. This phenomenon is partially attributed to the significant role mEH plays in hydrolyzing endogenous lipid mediators, suggesting more complex and extensive physiological functions. In order to obtain pharmacological tools to further study the biology and therapeutic potential of this enzyme target, we describe the development of highly potent 2-alkylthio acetamide inhibitors of the human mEH with IC50 values in the low nanomolar range. These are around 2 orders of magnitude more potent than previously obtained primary amine, amide and urea-based mEH inhibitors. Experimental assay results and rationalization of binding through docking calculations of inhibitors to a mEH homology model indicate that an amide connected to an alkyl side chain and a benzyl-thio function as key pharmacophore units.
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exploring the size of the lipophilic unit of the soluble Epoxide Hydrolase inhibitors
Bioorganic & Medicinal Chemistry, 2019Co-Authors: Sandra Codony, Bruce D. Hammock, Christophe Morisseau, Elena Valverde, Rosana Leiva, Jose Brea, Isabel M Loza, Santiago VazquezAbstract:Abstract Soluble Epoxide Hydrolase (sEH) inhibitors are potential drugs for several diseases. Adamantyl ureas are excellent sEH inhibitors but have limited metabolic stability. Herein, we report the effect of replacing the adamantane group by alternative polycyclic hydrocarbons on sEH inhibition, solubility, permeability and metabolic stability. Compounds bearing smaller or larger polycyclic hydrocarbons than adamantane yielded all good inhibition potency of the human sEH (0.4 ≤ IC50 ≤ 21.7 nM), indicating that sEH is able to accommodate inhibitors of very different size. Human liver microsomal stability of diamantane containing inhibitors is lower than that of their corresponding adamantane counterparts.
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fluoroaromatic fragments on 1 3 disubstituted ureas enhance soluble Epoxide Hydrolase inhibition
Journal of Fluorine Chemistry, 2019Co-Authors: V. V. Burmistrov, Christophe Morisseau, Gennady M. Butov, Vladimir S Dyachenko, V B Rybakov, Bruce D. HammockAbstract:A series of soluble Epoxide Hydrolase (sEH) inhibitors containing 2-fluorophenyl fragment was developed. Inhibition potency of the described compounds ranges from 0.7 to 630.9 nM. 1-(Adamantan-1-ylmethyl)-3-(2-fluorophenyl) urea (3b, IC50 = 0.7 nM) and 1-(adamantan-2-yl)-3-(2-fluorophenyl) urea (3i, IC50 =1.0 nM) were found to be the most potent sEH inhibitors within the described series. Crystal results suggest that potency is probably enhanced by extra hydrogen bond between the fluorine atom and catalytic tyrosine residues.
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Adamantyl thioureas as soluble Epoxide Hydrolase inhibitors
Bioorganic & medicinal chemistry letters, 2018Co-Authors: V. V. Burmistrov, Christophe Morisseau, Gennady M. Butov, Dmitry Pitushkin, Dmitry S. Karlov, Robert R. Fayzullin, Bruce D. HammockAbstract:Abstract A series of inhibitors of the soluble Epoxide Hydrolase (sEH) containing one or two thiourea groups has been developed. Inhibition potency of the described compounds ranges from 50 μM to 7.2 nM. 1,7-(Heptamethylene)bis[(adamant-1-yl)thiourea] (6f) was found to be the most potent sEH inhibitor, among the thioureas tested. The inhibitory activity of the thioureas against the human sEH is closer to the value of activity against rat sEH rather than murine sEH. While being less active, thioureas are up to 7-fold more soluble than ureas, which makes them more bioavailable and thus promising as sEH inhibitors.
John D Imig - One of the best experts on this subject based on the ideXlab platform.
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Epoxides and soluble Epoxide Hydrolase in cardiovascular physiology
Physical Review, 2012Co-Authors: John D ImigAbstract:Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites that importantly contribute to vascular and cardiac physiology. The contribution of EETs to vascular and cardiac function is further influenced by soluble Epoxide Hydrolase (sEH) that degrades EETs to diols. Vascular actions of EETs include dilation and angiogenesis. EETs also decrease inflammation and platelet aggregation and in general act to maintain vascular homeostasis. Myocyte contraction and increased coronary blood flow are the two primary EET actions in the heart. EET cell signaling mechanisms are tissue and organ specific and provide significant evidence for the existence of EET receptors. Additionally, pharmacological and genetic manipulations of EETs and sEH have demonstrated a contribution for this metabolic pathway to cardiovascular diseases. Given the impact of EETs to cardiovascular physiology, there is emerging evidence that development of EET-based therapeutics will be beneficial for cardiovascular diseases.
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soluble Epoxide Hydrolase inhibition exhibits antihypertensive actions independently of nitric oxide in mice with renovascular hypertension
Kidney & Blood Pressure Research, 2012Co-Authors: Libor Kopkan, Sunghee Hwang, Bruce D. Hammock, John D Imig, Hsing Ju Tsai, Zuzana Huskova, Alexandra Sporkova, Sarka Varcabova, Zuzana Honetschlagerova, Herbert J KramerAbstract:Objective: The present study was performed to examine whether the blood pressure (BP)-lowering effects of soluble Epoxide Hydrolase (sEH) inhibition in two-kidney
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soluble Epoxide Hydrolase as a therapeutic target for cardiovascular diseases
Nature Reviews Drug Discovery, 2009Co-Authors: John D Imig, Bruce D. HammockAbstract:The cardiovascular effects of epoxyeicosatrienoic acids (EETs) include vasodilation, antimigratory actions on vascular smooth muscle cells and anti-inflammatory actions. These endogenous lipid mediators are broken down into diols by soluble Epoxide Hydrolase (sEH), and so inhibiting this enzyme would be expected to enhance the beneficial cardiovascular properties of EETs. sEH inhibitors (sEHIs) that are based on 1,3-disubstituted urea have been rapidly developed, and have been shown to be antihypertensive and anti-inflammatory, and to protect the brain, heart and kidney from damage. Although challenges for the future exist — including improving the drug-like properties of sEHIs and finding better ways to target sEHIs to specific tissues — the recent initiation of the first clinical trials of sEHIs has highlighted the therapeutic potential of these agents.
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soluble Epoxide Hydrolase gene deletion attenuates renal injury and inflammation with doca salt hypertension
American Journal of Physiology-renal Physiology, 2009Co-Authors: Marlina Manhiani, Bruce D. Hammock, John D Imig, Jeffrey E Quigley, Sarah F Knight, Shiva Tasoobshirazi, Tar Rhonda Moore, Michael W BrandsAbstract:Inhibition of soluble Epoxide Hydrolase (sEH) has been shown to be renal protective in rat models of salt-sensitive hypertension. Here, we hypothesize that targeted disruption of the sEH gene (Ephx...
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soluble Epoxide Hydrolase inhibition protects the kidney from hypertension induced damage
Journal of The American Society of Nephrology, 2004Co-Authors: Xueying Zhao, Bruce D. Hammock, John W. Newman, Tatsuo Yamamoto, In Hae Kim, Takaho Watanabe, Janet Stewart, Jennifer S Pollock, David M Pollock, John D ImigAbstract:Epoxyeicosatrienoic acids (EET) have antihypertensive and anti-inflammatory properties and play a role in the maintenance of renal vascular function. A novel approach to increase EET levels is to inhibit Epoxide Hydrolase enzymes that are responsible for conversion of biologically active EET to dihydroxyeicosatrienoic acids (DHET). We hypothesized that soluble Epoxide Hydrolase (SEH) inhibition would improve renal vascular function and ameliorate hypertension induced renal damage. Chronic administration of the specific SEH inhibitor 1-cyclohexyl-3-dodecylurea (CDU, 3 mg/d) for 10 d lowered BP in angiotensin hypertensive rats. The contribution of renal vascular SEH to afferent arteriolar function in angiotensin hypertension was also assessed. SEH protein expression was increased in renal microvessels from hypertensive rats. Although CDU did not change afferent arteriolar responsiveness to angiotensin in normotensive animals, CDU treatment significantly attenuated afferent arteriolar diameter responses to angiotensin in hypertensive kidneys from 51% +/- 8% to 28% +/- 7%. Protection of the renal vasculature and glomerulus during chronic CDU administration was demonstrated by histology. Urinary albumin excretion, an index of renal damage, was also lower in CDU-treated hypertensive rats. These data demonstrate that SEH inhibition has antihypertensive and renal vascular protective effects in angiotensin hypertension and suggests that SEH inhibitors may be a useful therapeutic intervention for cardiovascular diseases.
Darryl C. Zeldin - One of the best experts on this subject based on the ideXlab platform.
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Regulation of cardiovascular biology by microsomal Epoxide Hydrolase
Toxicological Research, 2021Co-Authors: Matthew L. Edin, Darryl C. ZeldinAbstract:Microsomal Epoxide Hydrolase/Epoxide Hydrolase 1 (mEH/EPHX1) works in conjunction with cytochromes P450 to metabolize a variety of compounds, including xenobiotics, pharmaceuticals and endogenous lipids. mEH has been most widely studied for its role in metabolism of xenobiotic and pharmaceutical compounds where it converts hydrophobic and reactive Epoxides to hydrophilic diols that are more readily excreted. Inhibition or genetic disruption of mEH can be deleterious in the face of many industrial, environmental or pharmaceutical exposures and EPHX1 polymorphisms are associated with the development of exposure-related cancers. The role of mEH in endogenous epoxy-fatty acid (EpFA) metabolism has been less well studied. In vitro, mEH metabolizes most EpFAs at a far slower rate than soluble Epoxide Hydrolase (sEH) and has thus been generally considered to exert a minor role in EpFA metabolism in vivo. Indeed, sEH inhibitors or sEH-deficiency increase EpFA levels and are protective in animal models of cardiovascular disease. Recently, however, mEH was found to have a previously unrecognized and substantial role in EpFA metabolism in vivo. While few studies have examined the role of mEH in cardiovascular homeostasis, there is now substantial evidence that mEH can regulate cardiovascular function through regulation of EpFA metabolism. The discovery of a prominent role for mEH in epoxyeicosatrienoic acid (EET) metabolism, in particular, suggests that additional studies on the role of mEH in cardiovascular biology are warranted.
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Epoxide Hydrolase 3 ephx3 gene disruption reduces ceramide linoleate Epoxide hydrolysis and impairs skin barrier function
Journal of Biological Chemistry, 2021Co-Authors: Matthew L. Edin, Darryl C. Zeldin, Haruto Yamanashi, William E Boeglin, Joan P Graves, Laura M Degraff, Fred B Lih, Alan R BrashAbstract:The mammalian Epoxide Hydrolase (EPHX)3 is known from in vitro experiments to efficiently hydrolyze the linoleate Epoxides 9,10-epoxyoctadecamonoenoic acid (EpOME) and epoxyalcohol 9R,10R-trans-epoxy-11E-13R-hydroxy-octadecenoate to corresponding diols and triols, respectively. Herein we examined the physiological relevance of EPHX3 to hydrolysis of both substrates in vivo. Ephx3−/− mice show no deficiency in EpOME-derived plasma diols, discounting a role for EPHX3 in their formation, whereas epoxyalcohol-derived triols esterified in acylceramides of the epidermal 12R-lipoxygenase pathway are reduced. Although the Ephx3−/− pups appear normal, measurements of transepidermal water loss detected a modest and statistically significant increase compared with the wild-type or heterozygote mice, reflecting a skin barrier impairment that was not evident in the knockouts of mouse microsomal (EPHX1/microsomal Epoxide Hydrolase) or soluble (EPHX2/sEH). This barrier phenotype in the Ephx3−/− pups was associated with a significant decrease in the covalently bound ceramides in the epidermis (40% reduction, p
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Epoxide Hydrolase 3 ephx3 gene disruption reduces ceramide linoleate Epoxide hydrolysis and impairs skin barrier function
Journal of Biological Chemistry, 2021Co-Authors: Matthew L. Edin, Darryl C. Zeldin, Haruto Yamanashi, William E Boeglin, Joan P Graves, Laura M Degraff, Fred B Lih, Alan R BrashAbstract:The mammalian Epoxide Hydrolase EPHX3 is known from in vitro experiments to efficiently hydrolyze the linoleate Epoxides 9,10-epoxyoctadecamonoenoic acid (EpOME) and epoxyalcohol 9R,10R-trans-epoxy-11E-13R-hydroxy-octadecenoate to corresponding diols and triols, respectively. Herein we examined the physiological relevance of EPHX3 to hydrolysis of both substrates in vivo. Ephx3-/- mice show no deficiency in EpOME-derived plasma diols, discounting a role for EPHX3 in their formation, whereas epoxyalcohol-derived triols esterified in acylceramides of the epidermal 12R-lipoxygenase pathway are reduced. Although the Ephx3-/- pups appear normal, measurements of trans-epidermal water loss detected a modest and statistically significant increase compared to the wild-type or heterozygote mice, reflecting a skin barrier impairment that was not evident in the knockouts of mouse microsomal Epoxide Hydrolase (EPHX1/mEH) or soluble Epoxide Hydrolase (EPHX2/sEH). This barrier phenotype in the Ephx3-/- pups was associated with a significant decrease in the covalently bound ceramides in the epidermis (40% reduction, p<0.05), indicating a corresponding structural impairment in the integrity of the water barrier. Quantitative LC-MS analysis of the esterified linoleate-derived triols in the murine epidermis revealed a marked and isomer-specific reduction (~85%) in the Ephx3-/- epidermis of the major trihydroxy isomer 9R,10S,13R-trihydroxy-11E-octadecenoate. We conclude EPHX3 (and not EPHX1 or EPHX2) catalyzes hydrolysis of the 12R-LOX/eLOX3-derived epoxyalcohol esterified in acylceramide, and may function to control flux through the alternative and crucial route of metabolism via the dehydrogenation pathway of SDR9C7. Importantly, our findings also identify a functional role for EPHX3 in transformation of a naturally esterified Epoxide substrate, pointing to its potential contribution in other tissues.
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deficiency of soluble Epoxide Hydrolase protects cardiac function impaired by lps induced acute inflammation
Frontiers in Pharmacology, 2019Co-Authors: Victor Samokhvalov, Matthew L. Edin, Darryl C. Zeldin, Fred B Lih, Lockhart K Jamieson, Ahmed M Darwesh, Hedieh Keshavarzbahaghighat, Tim Y T Lee, John M SeubertAbstract:Lipopolysaccharide (LPS) is a bacterial wall endotoxin producing many pathophysiological conditions including myocardial inflammation leading to cardiotoxicity. Linoleic acid (18:2n6, LA) is an essential n-6 PUFA which is converted to arachidonic acid (20:4n6, AA) by desaturation and elongation via enzyme systems within the body. Biological transformation of PUFA through CYP-mediated hydroxylation, epoxidation, and allylic oxidation produces lipid mediators, which may be subsequently hydrolyzed to corresponding diol metabolites by soluble Epoxide Hydrolase (sEH). In the current study, we investigate whether inhibition of sEH, which alters the PUFA metabolite profile, can influence LPS induced cardiotoxicity and mitochondrial function. Our data demonstrate that deletion of soluble Epoxide Hydrolase provides protective effects against LPS-induced cardiotoxicity by maintaining mitochondrial function. There was a marked alteration in the cardiac metabolite profile with notable increases in sEH-derived vicinal diols, 9,10- and 12,13-dihydroxyoctadecenoic acid (DiHOME) in WT hearts following LPS administration, which was absent in sEH null mice. We found that DiHOMEs triggered pronounced mitochondrial structural abnormalities, which also contributed to the development of extensive mitochondrial dysfunction in cardiac cells. Accumulation of DiHOMEs may represent an intermediate mechanism through which LPS-induced acute inflammation triggers deleterious alterations in the myocardium in vivo and cardiac cells in vitro. This study reveals novel research exploring the contribution of DiHOMEs in the progression of adverse inflammatory responses toward cardiac function in vitro and in vivo.
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deletion of soluble Epoxide Hydrolase enhances coronary reactive hyperemia in isolated mouse heart role of oxylipins and pparγ
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2016Co-Authors: Ahmad Hanif, Christophe Morisseau, Matthew L. Edin, Darryl C. Zeldin, Mohammed A NayeemAbstract:The relationship between soluble Epoxide Hydrolase (sEH) and coronary reactive hyperemia (CRH) response to a brief ischemic insult is not known. Epoxyeicosatrienoic acids (EETs) exert cardioprotect...
Sunghee Hwang - One of the best experts on this subject based on the ideXlab platform.
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discovery of soluble Epoxide Hydrolase inhibitors from chemical synthesis and natural products
Journal of Medicinal Chemistry, 2021Co-Authors: Chengpeng Sun, Sunghee Hwang, Christophe Morisseau, Xinyue Zhang, Zhanjun Zhang, Bruce D. HammockAbstract:Soluble Epoxide Hydrolase (sEH) is an α/β Hydrolase fold protein and widely distributed in numerous organs including the liver, kidney, and brain. The inhibition of sEH can effectively maintain endogenous epoxyeicosatrienoic acids (EETs) levels and reduce dihydroxyeicosatrienoic acids (DHETs) levels, resulting in therapeutic potentials for cardiovascular, central nervous system, and metabolic diseases. Therefore, since the beginning of this century, the development of sEH inhibitors is a hot research topic. A variety of potent sEH inhibitors have been developed by chemical synthesis or isolated from natural sources. In this review, we mainly summarized the interconnected aspects of sEH with cardiovascular, central nervous system, and metabolic diseases and then focus on representative inhibitors, which would provide some useful guidance for the future development of potential sEH inhibitors.
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orally available soluble Epoxide Hydrolase phosphodiesterase 4 dual inhibitor treats inflammatory pain
Journal of Medicinal Chemistry, 2018Co-Authors: Rene Blocher, Sunghee Hwang, Christophe Morisseau, Karen Wagner, Todd R. Harris, Bogdan Barnych, Raghavender Reddy Gopireddy, Yang Kevin Xiang, Ewgenij Proschak, Bruce D. HammockAbstract: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.
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soluble Epoxide Hydrolase activity and pharmacologic inhibition in horses with chronic severe laminitis
Equine Veterinary Journal, 2017Co-Authors: Alonso G P Guedes, David M Hood, Sunghee Hwang, Larry D. Galuppo, Christophe Morisseau, Bruce D. HammockAbstract:SummaryBackground The roles of soluble Epoxide Hydrolase and lipid mediators in inflammatory and neuropathic pain could be relevant in laminitis pain management. Objectives To determine soluble Epoxide Hydrolase (sEH) activity in the digital laminae, sEH inhibitor potency in vitro, and efficacy of a sEH inhibitor as an adjunct analgesic therapy in chronic laminitic horses. Study design In vitro experiments and clinical case series. Methods sEH activity was measured in digital laminae from euthanised healthy and laminitic horses (n = 5-6/group). Potency of seven synthetic sEH inhibitors was determined in vitro using equine liver cytosol. One of them (t-TUCB; 0.1 mg/kg bwt i.v. every 24 hours) was selected based on potency and stability, and used as adjunct therapy in 10 horses with severe chronic laminitis (Obel grades 2, one horse; 3-4, 9 horses). Daily assessments of forelimb lifts, pain scores, physiologic and laboratory examinations were performed before (baseline) and during t-TUCB treatment. Data are presented as mean ± s.d. and 95% confidence intervals (CI). Results sEH activity in the digital laminae from laminitic horses (0.9 ± 0.6 nmol/min/mg; CI: 0.16-1.55 nmol/min/mg) was significantly greater (P = 0.01) than in healthy horses (0.17 ± 0.09 nmol/min/mg; CI: 0.07-0.26 nmol/min/mg). t-TUCB as an adjunct analgesic up to 10 days (4.3 ± 3 days) in laminitic horses was associated with significant reduction in forelimb lifts (36 ± 22%; CI: 9-64%) and in pain scores (18 ± 23%; CI: 2-35%) compared to baseline (P = 0.04). One horse developed gas colic and another corneal vascularisation in a blind eye during treatment. No other significant changes were observed. Main limitations Absence of control group and evaluator blinding in case series. Conclusions sEH activity is significantly higher in the digital laminae of actively laminitic compared to healthy horses, and use of a potent inhibitor of equine sEH as adjunct analgesic therapy appears to decrease signs of pathologic pain in laminitic horses. This article is protected by copyright. All rights reserved.
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soluble Epoxide Hydrolase dependent regulation of myogenic response and blood pressure
American Journal of Physiology-heart and Circulatory Physiology, 2014Co-Authors: Dong Sun, Sunghee Hwang, Bruce D. Hammock, Azita J Cuevas, Katherine H Gotlinger, Michal L Schwartzman, An HuangAbstract:Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid via cytochrome P450 (CYP)/epoxygenases. EETs possess cardioprotective properties and are catalyzed by soluble Epoxide Hydrolase ...
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soluble Epoxide Hydrolase inhibitor trans 4 4 3 adamantan 1 yl ureido cyclohexyloxy benzoic acid is neuroprotective in rat model of ischemic stroke
American Journal of Physiology-heart and Circulatory Physiology, 2013Co-Authors: Jafar Sadik B Shaik, Sunghee Hwang, Bruce D. Hammock, Muzamil Ahmad, Marie E Rose, Lesley M Foley, Kevin T Hitchens, Steven H Graham, Samuel M PoloyacAbstract:Soluble Epoxide Hydrolase (sEH) diminishes vasodilatory and neuroprotective effects of epoxyeicosatrienoic acids by hydrolyzing them to inactive dihydroxy metabolites. The primary goals of this stu...