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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, Christophe Morisseau, Sung Hee Hwang, 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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protostane type triterpenoids as natural soluble epoxide Hydrolase Inhibitors inhibition potentials and molecular dynamics
Bioorganic Chemistry, 2020Co-Authors: Chengpeng Sun, Christophe Morisseau, Juan Zhang, Wenyu Zhao, Jiankun Yan, Yali Wang, Zhongbo Liu, Bruce D HammockAbstract:Abstract The inhibition of soluble epoxide Hydrolase (sEH) is a promising therapeutic approach to treat inflammation and other disorders. In our present investigation on searching for sEH Inhibitors from traditional Chinese medicines, we found that Alisma orientale displayed inhibition of sEH. We constructed a small library of protostane-type triterpenoids (1–25) isolated from A. orientale, and screened their inhibitory activities. Alismanin B (1), 11-deoxy-25-anhydro alisol E (4), 11-deoxy alisol B (5), and 25-O-ethyl alisol A (15) displayed concentration-dependently inhibitory activities against sEH with IC50 values from 3.40 ± 0.57 μM to 9.57 ± 0.88 μM. 11-Deoxy-25-anhydro alisol E (4) and 11-deoxy alisol B (5) were defined as mixed-type competitive Inhibitors with Ki values of 12.6 and 3.48 μM, respectively, based on the result of inhibition kinetics. The potential interaction mechanism of 11-deoxy alisol B (5) with sEH was analyzed by molecular docking and molecular dynamics, revealing that amino acid residues Trp336 and Tyr466 were vital for its inhibitory activity.
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exploring the size of the lipophilic unit of the soluble epoxide Hydrolase Inhibitors
Bioorganic & Medicinal Chemistry, 2019Co-Authors: Sandra Codony, Christophe Morisseau, Bruce D Hammock, 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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humble beginnings with big goals small molecule soluble epoxide Hydrolase Inhibitors for treating cns disorders
Progress in Neurobiology, 2019Co-Authors: Sydney Zarriello, Bruce D Hammock, Julian P Tuazon, Sydney Corey, Samantha Schimmel, Mira Rajani, Anna Gorsky, Diego Incontri, Cesar V BorlonganAbstract:Soluble epoxide Hydrolase (sEH) degrades epoxides of fatty acids including epoxyeicosatrienoic acid isomers (EETs), which are produced as metabolites of the cytochrome P450 branch of the arachidonic acid pathway. EETs exert a variety of largely beneficial effects in the context of inflammation and vascular regulation. sEH inhibition is shown to be therapeutic in several cardiovascular and renal disorders, as well as in peripheral analgesia, via the increased availability of anti-inflammatory EETs. The success of sEH Inhibitors in peripheral systems suggests their potential in targeting inflammation in the central nervous system (CNS) disorders. Here, we describe the current roles of sEH in the pathology and treatment of CNS disorders such as stroke, traumatic brain injury, Parkinson's disease, epilepsy, cognitive impairment, dementia and depression. In view of the robust anti-inflammatory effects of stem cells, we also outlined the potency of stem cell treatment and sEH Inhibitors as a combination therapy for these CNS disorders. This review highlights the gaps in current knowledge about the pathologic and therapeutic roles of sEH in CNS disorders, which should guide future basic science research towards translational and clinical applications of sEH Inhibitors for treatment of neurological diseases.
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Adamantyl thioureas as soluble epoxide Hydrolase Inhibitors
Bioorganic & medicinal chemistry letters, 2018Co-Authors: V. V. Burmistrov, Gennady M. Butov, Christophe Morisseau, 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, Christophe Morisseau, Sung Hee Hwang, 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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protostane type triterpenoids as natural soluble epoxide Hydrolase Inhibitors inhibition potentials and molecular dynamics
Bioorganic Chemistry, 2020Co-Authors: Chengpeng Sun, Christophe Morisseau, Juan Zhang, Wenyu Zhao, Jiankun Yan, Yali Wang, Zhongbo Liu, Bruce D HammockAbstract:Abstract The inhibition of soluble epoxide Hydrolase (sEH) is a promising therapeutic approach to treat inflammation and other disorders. In our present investigation on searching for sEH Inhibitors from traditional Chinese medicines, we found that Alisma orientale displayed inhibition of sEH. We constructed a small library of protostane-type triterpenoids (1–25) isolated from A. orientale, and screened their inhibitory activities. Alismanin B (1), 11-deoxy-25-anhydro alisol E (4), 11-deoxy alisol B (5), and 25-O-ethyl alisol A (15) displayed concentration-dependently inhibitory activities against sEH with IC50 values from 3.40 ± 0.57 μM to 9.57 ± 0.88 μM. 11-Deoxy-25-anhydro alisol E (4) and 11-deoxy alisol B (5) were defined as mixed-type competitive Inhibitors with Ki values of 12.6 and 3.48 μM, respectively, based on the result of inhibition kinetics. The potential interaction mechanism of 11-deoxy alisol B (5) with sEH was analyzed by molecular docking and molecular dynamics, revealing that amino acid residues Trp336 and Tyr466 were vital for its inhibitory activity.
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exploring the size of the lipophilic unit of the soluble epoxide Hydrolase Inhibitors
Bioorganic & Medicinal Chemistry, 2019Co-Authors: Sandra Codony, Christophe Morisseau, Bruce D Hammock, 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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Adamantyl thioureas as soluble epoxide Hydrolase Inhibitors
Bioorganic & medicinal chemistry letters, 2018Co-Authors: V. V. Burmistrov, Gennady M. Butov, Christophe Morisseau, 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.
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identification and optimization of soluble epoxide Hydrolase Inhibitors with dual potency towards fatty acid amide Hydrolase
Bioorganic & Medicinal Chemistry Letters, 2018Co-Authors: Sean D Kodani, Christophe Morisseau, Sung Hee Hwang, Svetlana Pakhomova, Marcia E Newcomer, Saavan Bhakta, Bruce D HammockAbstract:Multi-target Inhibitors have become increasing popular as a means to leverage the advantages of poly-pharmacology while simplifying drug delivery. Here, we describe dual Inhibitors for soluble epoxide Hydrolase (sEH) and fatty acid amide Hydrolase (FAAH), two targets known to synergize when treating inflammatory and neuropathic pain. The structure activity relationship (SAR) study described herein initially started with t-TUCB (trans-4-[4-(3-trifluoromethoxyphenyl-l-ureido)-cyclohexyloxy]-benzoic acid), a potent sEH inhibitor that was previously shown to weakly inhibit FAAH. Inhibitors with a 6-fold increase of FAAH potency while maintaining high sEH potency were developed by optimization. Interestingly, compared to most FAAH Inhibitors that inhibit through time-dependent covalent modification, t-TUCB and related compounds appear to inhibit FAAH through a time-independent, competitive mechanism. These Inhibitors are selective for FAAH over other serine Hydrolases. In addition, FAAH inhibition by t-TUCB appears to be higher in human FAAH over other species; however, the new dual sEH/FAAH Inhibitors have improved cross-species potency. These dual Inhibitors may be useful for future studies in understanding the therapeutic application of dual sEH/FAAH inhibition.
Benjamin F. Cravatt - One of the best experts on this subject based on the ideXlab platform.
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Design of Benzoxathiazin-3-one 1,1-Dioxides as a New Class of Irreversible Serine Hydrolase Inhibitors: Discovery of a Uniquely Selective PNPLA4 Inhibitor
Journal of the American Chemical Society, 2017Co-Authors: Anne F. Kornahrens, Benjamin F. Cravatt, Armand B. Cognetta, Daniel M. Brody, Megan L. Matthews, Dale L. BogerAbstract:The design and examination of 4,1,2-benzoxathiazin-3-one 1,1-dioxides as candidate serine Hydrolase Inhibitors are disclosed, and represent the synthesis and study of a previously unexplored heterocycle. This new class of activated cyclic carbamates provided selective irreversible inhibition of a small subset of serine Hydrolases without release of a leaving group, does not covalently modify active site catalytic cysteine and lysine residues of other enzyme classes, and was found to be amenable to predictable structural modifications that modulate intrinsic reactivity or active site recognition. Even more remarkable and within the small pilot series of candidate Inhibitors examined in an initial study, an exquisitely selective inhibitor for a poorly characterized serine Hydrolase (PNPLA4, patatin-like phospholipase domain-containing protein 4) involved in adipocyte triglyceride homeostasis was discovered.
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Serine Hydrolase Inhibitors Block Necrotic Cell Death by Preventing Calcium Overload of the Mitochondria and Permeability Transition Pore Formation
The Journal of biological chemistry, 2013Co-Authors: Bogeon Yun, Ku-lung Hsu, Benjamin F. Cravatt, Heejung Lee, Moumita Ghosh, Joseph V. Bonventre, Heather Ewing, Michael H. Gelb, Christina S. LeslieAbstract:Perturbation of calcium signaling that occurs during cell injury and disease, promotes cell death. In mouse lung fibroblasts A23187 triggered mitochondrial permeability transition pore (MPTP) formation, lactate dehydrogenase (LDH) release, and necrotic cell death that were blocked by cyclosporin A (CsA) and EGTA. LDH release temporally correlated with arachidonic acid release but did not involve cytosolic phospholipase A2α (cPLA2α) or calcium-independent PLA2. Surprisingly, release of arachidonic acid and LDH from cPLA2α-deficient fibroblasts was inhibited by the cPLA2α inhibitor pyrrophenone, and another serine Hydrolase inhibitor KT195, by preventing mitochondrial calcium uptake. Inhibitors of calcium/calmodulin-dependent protein kinase II, a mitochondrial Ca(2+) uniporter (MCU) regulator, also prevented MPTP formation and arachidonic acid release induced by A23187 and H2O2. Pyrrophenone blocked MCU-mediated mitochondrial calcium uptake in permeabilized fibroblasts but not in isolated mitochondria. Unlike pyrrophenone, the diacylglycerol analog 1-oleoyl-2-acetyl-sn-glycerol and CsA blocked cell death and arachidonic acid release not by preventing mitochondrial calcium uptake but by inhibiting MPTP formation. In fibroblasts stimulated with thapsigargin, which induces MPTP formation by a direct effect on mitochondria, LDH and arachidonic acid release were blocked by CsA and 1-oleoyl-2-acetyl-sn-glycerol but not by pyrrophenone or EGTA. Therefore serine Hydrolase Inhibitors prevent necrotic cell death by blocking mitochondrial calcium uptake but not the enzyme releasing fatty acids that occurs by a novel pathway during MPTP formation. This work reveals the potential for development of small molecule cell-permeable serine Hydrolase Inhibitors that block MCU-mediated mitochondrial calcium overload, MPTP formation, and necrotic cell death.
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Evaluation of NHS carbamates as a potent and selective class of endocannabinoid Hydrolase Inhibitors.
ACS chemical neuroscience, 2013Co-Authors: Micah J. Niphakis, Armand B. Cognetta, Jae Won Chang, Matthew W. Buczynski, Loren H. Parsons, Frederika Maria Byrne, James J. Burston, Victoria Chapman, Benjamin F. CravattAbstract:Monoacylglycerol lipase (MAGL) is a principal metabolic enzyme responsible for hydrolyzing the endogenous cannabinoid (endocannabinoid) 2-arachidonoylglycerol (2-AG). Selective Inhibitors of MAGL offer valuable probes to further understand the enzyme’s function in biological systems and may lead to drugs for treating a variety of diseases, including psychiatric disorders, neuroinflammation, and pain. N-Hydroxysuccinimidyl (NHS) carbamates have recently been identified as a promising class of serine Hydrolase Inhibitors that shows minimal cross-reactivity with other proteins in the proteome. Here, we explore NHS carbamates more broadly and demonstrate their potential as Inhibitors of endocannabinoid Hydrolases and additional enzymes from the serine Hydrolase class. We extensively characterize an NHS carbamate 1a (MJN110) as a potent, selective, and in-vivo-active MAGL inhibitor. Finally, we demonstrate that MJN110 alleviates mechanical allodynia in a rat model of diabetic neuropathy, marking NHS carbamates...
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Erratum: Click-generated triazole ureas as ultrapotent in vivo-active serine Hydrolase Inhibitors (Nature Chemical Biology (2011) 7 (469-478))
Nature Chemical Biology, 2012Co-Authors: Alexander Adibekian, Brent R. Martin, Chu Wang, Ku-lung Hsu, Daniel A. Bachovchin, Sherry Niessen, Heather Hoover, Benjamin F. CravattAbstract:Corrigendum: Click-generated triazole ureas as ultrapotent in vivo –active serine Hydrolase Inhibitors
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O-hydroxyacetamide carbamates as a highly potent and selective class of endocannabinoid Hydrolase Inhibitors.
ACS chemical neuroscience, 2011Co-Authors: Micah J. Niphakis, Douglas S. Johnson, T. Eric Ballard, Cory Michael Stiff, Benjamin F. CravattAbstract:The two major endocannabinoid transmitters, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are degraded by distinct enzymes in the nervous system, fatty acid amide Hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. FAAH and MAGL Inhibitors cause elevations in brain AEA and 2-AG levels, respectively, and reduce pain, anxiety, and depression in rodents without causing the full spectrum of psychotropic behavioral effects observed with direct cannabinoid receptor-1 (CB1) agonists. These findings have inspired the development of several classes of endocannabinoid Hydrolase Inhibitors, most of which have been optimized to show specificity for either FAAH or MAGL or, in certain cases, equipotent activity for both enzymes. Here, we investigate an unusual class of O-hydroxyacetamide carbamate Inhibitors and find that individual compounds from this class can serve as selective FAAH or dual FAAH/MAGL Inhibitors in vivo across a dose range (0.125–12.5 mg kg–1) suitable for behavioral studies. Competitive and click chemistry activity-based protein profiling confirmed that the O-hydroxyacetamide carbamate SA-57 is remarkably selective for FAAH and MAGL in vivo, targeting only one other enzyme in brain, the additional 2-AG Hydrolase ABHD6. These data designate O-hydroxyacetamide carbamates as a versatile chemotype for creating endocannabinoid Hydrolase Inhibitors that display excellent in vivo activity and tunable selectivity for FAAH-anandamide versus MAGL (and ABHD6)-2-AG pathways.
Sung Hee 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, Christophe Morisseau, Sung Hee Hwang, 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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identification and optimization of soluble epoxide Hydrolase Inhibitors with dual potency towards fatty acid amide Hydrolase
Bioorganic & Medicinal Chemistry Letters, 2018Co-Authors: Sean D Kodani, Christophe Morisseau, Sung Hee Hwang, Svetlana Pakhomova, Marcia E Newcomer, Saavan Bhakta, Bruce D HammockAbstract:Multi-target Inhibitors have become increasing popular as a means to leverage the advantages of poly-pharmacology while simplifying drug delivery. Here, we describe dual Inhibitors for soluble epoxide Hydrolase (sEH) and fatty acid amide Hydrolase (FAAH), two targets known to synergize when treating inflammatory and neuropathic pain. The structure activity relationship (SAR) study described herein initially started with t-TUCB (trans-4-[4-(3-trifluoromethoxyphenyl-l-ureido)-cyclohexyloxy]-benzoic acid), a potent sEH inhibitor that was previously shown to weakly inhibit FAAH. Inhibitors with a 6-fold increase of FAAH potency while maintaining high sEH potency were developed by optimization. Interestingly, compared to most FAAH Inhibitors that inhibit through time-dependent covalent modification, t-TUCB and related compounds appear to inhibit FAAH through a time-independent, competitive mechanism. These Inhibitors are selective for FAAH over other serine Hydrolases. In addition, FAAH inhibition by t-TUCB appears to be higher in human FAAH over other species; however, the new dual sEH/FAAH Inhibitors have improved cross-species potency. These dual Inhibitors may be useful for future studies in understanding the therapeutic application of dual sEH/FAAH inhibition.
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Unique mechanistic insights into the beneficial effects of soluble epoxide Hydrolase Inhibitors in the prevention of cardiac fibrosis
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Padmini Sirish, Sung Hee Hwang, Jun-yan Liu, Kin Sing Stephen Lee, Hong Qiu, Cuifen Zhao, Siu Mei, Javier López, Bruce D HammockAbstract:Tissue fibrosis represents one of the largest groups of diseases for which there are very few effective therapies. In the heart, myocardial infarction (MI) resulting in the loss of cardiac myocytes can culminate in adverse cardiac remodeling leading to eventual heart failure. Adverse cardiac remodeling includes myocyte hypertrophy, fibrosis, and electrical remodeling. We have previously demonstrated the beneficial effects of several potent soluble epoxide Hydrolase Inhibitors (sEHIs) in different models of cardiac hypertrophy and failure. Here, we directly determine the molecular mechanisms underlying the beneficial effects of sEHIs in cardiac remodeling post-MI. Treatment with a potent sEHI, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU), which was started 1 wk post-MI in a murine model, results in a significant improvement in cardiac function. Importantly, treatment with TPPU results in a decrease in cardiac fibrosis as quantified using histological and immunostaining techniques. Moreover, single-cell–based assays demonstrate that treatment with TPPU results in a significant decrease not only in the percentages but also the proliferative capacity of different populations of cardiac fibroblasts as well as a reduction in the migration of fibroblasts into the heart from the bone marrow. Our study provides evidence for a possible unique therapeutic strategy to reduce cardiac fibrosis and improve cardiac function post-MI.
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comparative efficacy of 3 soluble epoxide Hydrolase Inhibitors in rat neuropathic and inflammatory pain models
European Journal of Pharmacology, 2013Co-Authors: Karen Wagner, Christophe Morisseau, Sung Hee Hwang, Paul D. Jones, Hua Dong, J. Yang, Bora Inceoglu, Bruce D HammockAbstract:Epoxy-fatty acids have been recognized as important cell signaling molecules with multiple biological effects including anti-nociception. The main degradation pathway of these signaling molecules is via the soluble epoxide Hydrolase (sEH) enzyme. Inhibitors of sEH extend the anti-nociceptive effects of fatty acid epoxides. In this study two models of pain with different etiology, streptozocin induced type I diabetic neuropathic pain and lipopolysaccharide induced inflammatory pain were employed to test sEH Inhibitors. A dose range of three sEH Inhibitors with the same central pharmacophore but varying substituent moieties was used to investigate maximal anti-allodynic effects in these two models of pain. Inhibiting the sEH enzyme in these models successfully blocked pain related behavior in both models. The sEH Inhibitors were more potent and more efficacious than celecoxib in reducing both diabetic neuropathic pain and lipopolysaccharide induced inflammatory pain. Because of their ability to block diabetic neuropathic pain sEH inhibition is a promising new approach to treat chronic pain conditions.
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Substituted phenyl groups improve the pharmacokinetic profile and anti-inflammatory effect of urea-based soluble epoxide Hydrolase Inhibitors in murine models.
European Journal of Pharmaceutical Sciences, 2013Co-Authors: Jun-yan Liu, Christophe Morisseau, Sung Hee Hwang, Tristan E. Rose, Hong Qiu, Yanping Lin, Nipavan Chiamvimonvat, Bruce D HammockAbstract:Soluble epoxide Hydrolase Inhibitors (sEHIs) are anti-inflammatory, analgesic, anti-hypertensive, cardioand renal-protective in multiple animal models. However, the earlier adamantyl-containing urea-based Inhibitors are rapidly metabolized. Therefore, new potent Inhibitors with the adamantyl group replaced by a substituted phenyl group were synthesized to presumptively offer better pharmacokinetic (PK) properties. Here we describe the improved PK profile of these Inhibitors and the anti-inflammatory effect of the most promising one in a murine model. The PK profiles of Inhibitors were determined following p.o. administration and serial bleeding in mice. The anti-inflammatory effect of 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), the most promising inhibitor among the five sEHIs tested, was investigated in a lipopolysaccharide (LPS)-challenged murine model. The earlier broadly-used adamantyl-containing sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), was used for comparison. Compared with the earlier adamantyl-containing urea-based Inhibitors, substituted phenyl-containing urea-based Inhibitors afford more favorable PK properties, such as higher Cmaxs, larger AUCs and longer t1/2s, which, as expected, show more stable metabolic stability. Moreover, oral administration of TPPU dramatically reversed the shifts caused by LPS-challenge in plasma levels of inflammatory cytokines, epoxides and corresponding diols, which is more potent than t-AUCB. The substituted phenyl-containing sEHIs are more metabolically stable than those with adamantyl group, resulting in more potent efficacy in vivo. This indicates a new strategy for development of sEHIs for further study toward clinical trials. 2013 Elsevier B.V. All rights reserved.
Jun-yan Liu - One of the best experts on this subject based on the ideXlab platform.
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Unique mechanistic insights into the beneficial effects of soluble epoxide Hydrolase Inhibitors in the prevention of cardiac fibrosis
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Padmini Sirish, Sung Hee Hwang, Jun-yan Liu, Kin Sing Stephen Lee, Hong Qiu, Cuifen Zhao, Siu Mei, Javier López, Bruce D HammockAbstract:Tissue fibrosis represents one of the largest groups of diseases for which there are very few effective therapies. In the heart, myocardial infarction (MI) resulting in the loss of cardiac myocytes can culminate in adverse cardiac remodeling leading to eventual heart failure. Adverse cardiac remodeling includes myocyte hypertrophy, fibrosis, and electrical remodeling. We have previously demonstrated the beneficial effects of several potent soluble epoxide Hydrolase Inhibitors (sEHIs) in different models of cardiac hypertrophy and failure. Here, we directly determine the molecular mechanisms underlying the beneficial effects of sEHIs in cardiac remodeling post-MI. Treatment with a potent sEHI, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU), which was started 1 wk post-MI in a murine model, results in a significant improvement in cardiac function. Importantly, treatment with TPPU results in a decrease in cardiac fibrosis as quantified using histological and immunostaining techniques. Moreover, single-cell–based assays demonstrate that treatment with TPPU results in a significant decrease not only in the percentages but also the proliferative capacity of different populations of cardiac fibroblasts as well as a reduction in the migration of fibroblasts into the heart from the bone marrow. Our study provides evidence for a possible unique therapeutic strategy to reduce cardiac fibrosis and improve cardiac function post-MI.
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Substituted phenyl groups improve the pharmacokinetic profile and anti-inflammatory effect of urea-based soluble epoxide Hydrolase Inhibitors in murine models.
European Journal of Pharmaceutical Sciences, 2013Co-Authors: Jun-yan Liu, Christophe Morisseau, Sung Hee Hwang, Tristan E. Rose, Hong Qiu, Yanping Lin, Nipavan Chiamvimonvat, Bruce D HammockAbstract:Soluble epoxide Hydrolase Inhibitors (sEHIs) are anti-inflammatory, analgesic, anti-hypertensive, cardioand renal-protective in multiple animal models. However, the earlier adamantyl-containing urea-based Inhibitors are rapidly metabolized. Therefore, new potent Inhibitors with the adamantyl group replaced by a substituted phenyl group were synthesized to presumptively offer better pharmacokinetic (PK) properties. Here we describe the improved PK profile of these Inhibitors and the anti-inflammatory effect of the most promising one in a murine model. The PK profiles of Inhibitors were determined following p.o. administration and serial bleeding in mice. The anti-inflammatory effect of 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), the most promising inhibitor among the five sEHIs tested, was investigated in a lipopolysaccharide (LPS)-challenged murine model. The earlier broadly-used adamantyl-containing sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), was used for comparison. Compared with the earlier adamantyl-containing urea-based Inhibitors, substituted phenyl-containing urea-based Inhibitors afford more favorable PK properties, such as higher Cmaxs, larger AUCs and longer t1/2s, which, as expected, show more stable metabolic stability. Moreover, oral administration of TPPU dramatically reversed the shifts caused by LPS-challenge in plasma levels of inflammatory cytokines, epoxides and corresponding diols, which is more potent than t-AUCB. The substituted phenyl-containing sEHIs are more metabolically stable than those with adamantyl group, resulting in more potent efficacy in vivo. This indicates a new strategy for development of sEHIs for further study toward clinical trials. 2013 Elsevier B.V. All rights reserved.
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Substituted phenyl groups improve the pharmacokinetic profile and anti-inflammatory effect of urea-based soluble epoxide Hydrolase Inhibitors in murine models.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2013Co-Authors: Jun-yan Liu, Christophe Morisseau, Sung Hee Hwang, Tristan E. Rose, Hong Qiu, Yanping Lin, Nipavan Chiamvimonvat, Bruce D HammockAbstract:Soluble epoxide Hydrolase Inhibitors (sEHIs) are anti-inflammatory, analgesic, anti-hypertensive, cardio- and renal-protective in multiple animal models. However, the earlier adamantyl-containing urea-based Inhibitors are rapidly metabolized. Therefore, new potent Inhibitors with the adamantyl group replaced by a substituted phenyl group were synthesized to presumptively offer better pharmacokinetic (PK) properties. Here we describe the improved PK profile of these Inhibitors and the anti-inflammatory effect of the most promising one in a murine model. The PK profiles of Inhibitors were determined following p.o. administration and serial bleeding in mice. The anti-inflammatory effect of 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), the most promising inhibitor among the five sEHIs tested, was investigated in a lipopolysaccharide (LPS)-challenged murine model. The earlier broadly-used adamantyl-containing sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), was used for comparison. Compared with the earlier adamantyl-containing urea-based Inhibitors, substituted phenyl-containing urea-based Inhibitors afford more favorable PK properties, such as higher Cmaxs, larger AUCs and longer t1/2s, which, as expected, show more stable metabolic stability. Moreover, oral administration of TPPU dramatically reversed the shifts caused by LPS-challenge in plasma levels of inflammatory cytokines, epoxides and corresponding diols, which is more potent than t-AUCB. The substituted phenyl-containing sEHIs are more metabolically stable than those with adamantyl group, resulting in more potent efficacy in vivo. This indicates a new strategy for development of sEHIs for further study toward clinical trials.
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Soluble Epoxide Hydrolase Inhibitors and Heart Failure
Cardiovascular therapeutics, 2011Co-Authors: Hong Qiu, Bruce D Hammock, Jun-yan Liu, Todd R. Harris, Nipavan ChiamvimonvatAbstract:Cardiovascular disease remains one of the leading causes of death in the Western societies. Heart failure (HF) is due primarily to progressive myocardial dysfunction accompanied by myocardial remodeling. Once HF develops, the condition is, in most cases, irreversible and is associated with a very high mortality rate. Soluble epoxide Hydrolase (sEH) is an enzyme that catalyzes the hydrolysis of epoxyeicosatrienoic acids (EETs), which are lipid mediators derived from arachidonic acid through the cytochrome P450 epoxygenase pathway. EETs have been shown to have vasodilatory, antiinflammatory, and cardioprotective effects. When EETs are hydrolyzed by sEH to corresponding dihydroxyeicosatrienoic acids, their cardioprotective activities become less pronounced. In line with the recent genetic study that has identified sEH as a susceptibility gene for HF, the sEH enzyme has received considerable attention as an attractive therapeutic target for cardiovascular diseases. Indeed, sEH inhibition has been demonstrated to have antihypertensive and antiinflammatory actions, presumably due to the increased bioavailability of endogenous EETs and other epoxylipids, and several potent sEH Inhibitors have been developed and tested in animal models of cardiovascular disease including hypertension, cardiac hypertrophy, and ischemia/reperfusion injury. sEH inhibitor treatment has been shown to effectively prevent pressure overload- and angiotensin II-induced cardiac hypertrophy and reverse the pre-established cardiac hypertrophy caused by chronic pressure overload. Application of sEH Inhibitors in several cardiac ischemia/reperfusion injury models reduced infarct size and prevented the progressive cardiac remodeling. Moreover, the use of sEH Inhibitors prevented the development of electrical remodeling and ventricular arrhythmias associated with cardiac hypertrophy and ischemia/reperfusion injury. The data published to date support the notion that sEH Inhibitors may represent a promising therapeutic approach for combating detrimental cardiac remodeling and HF.
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Pharmacokinetic optimization of four soluble epoxide Hydrolase Inhibitors for use in a murine model of inflammation
British journal of pharmacology, 2009Co-Authors: Jun-yan Liu, Christophe Morisseau, Sung Hee Hwang, Paul D. Jones, Hsing Ju Tsai, Bruce D HammockAbstract:Background and purpose: Early soluble epoxide Hydrolase Inhibitors (sEHIs) such as 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA) are effective anti-hypertensive and anti-inflammatory agents in various animal models. However, their poor metabolic stability and limited water solubility make them difficult to use pharmacologically. Here we present the evaluation of four sEHIs for improved pharmacokinetic properties and the anti-inflammatory effects of one sEHI. Experimental approach: The pharmacokinetic profiles of Inhibitors were determined following p.o. (oral) administration and serial bleeding in mice. Subsequently the pharmacokinetics of trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), the most promising inhibitor, was further studied following s.c. (subcutaneous), i.v. (intravenous) injections and administration in drinking water. Finally, the anti-inflammatory effect of t-AUCB was evaluated by using a lipopolysaccharide (LPS)-treated murine model. Key results: Better pharmacokinetic parameters (higher Cmax, longer t1/2 and greater AUC) were obtained from the tested Inhibitors, compared with AUDA. Oral bioavailability of t-AUCB (0.1 mg·kg -1 ) was 68 22% (n = 4), and giving t-AUCB in drinking water is recommended as a feasible, effective and easy route of administration for chronic studies. Finally, t-AUCB (p.o.) reversed the decrease in plasma ratio of lipid epoxides to corresponding diols (a biomarker of soluble epoxide Hydrolase inhibition) in lipopolysaccharide-treated mice. The in vivo potency of 1 mg·kg -1
