Orally Bioavailable Potent Soluble Epoxide Hydrolase Inhibitors

Hwang, Sung Hee; Tsai, Hsing-Ju; Liu, Jun-Yan; Morisseau, Christophe; Hammock, Bruce D.

doi:10.1021/jm070270t

Cited by 215 publications

(273 citation statements)

References 51 publications

(135 reference statements)

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“…1C). These levels are significantly higher than the IC 50 concentration determined with in vitro experiments using the recombinant murine sEH enzyme (21,24). Additionally, liver, epididymal fat, and pancreas extracts revealed elevated levels of TUPS, with liver homogenates exhibiting the highest concentrations (45 μg∕g tissue or 0.12 μmol∕g tissue) compared with epididymal fat and pancreas [3 and 10 μg∕g tissues, or 0.01 and 0.026 μmol∕g tissue, respectively (Fig.…”

Section: Whole-body Soluble Epoxide Hydrolase Deletion and Inhibition Inmentioning

confidence: 79%

Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance

Luria

Bettaieb

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Visceral obesity has been defined as an important element of the metabolic syndrome and contributes to the development of insulin resistance and cardiovascular disease. Increasing endogenous levels of epoxyeicosatrienoic acids (EETs) are known for their analgesic, antihypertensive, and antiinflammatory effects. The availability of EETs is limited primarily by the soluble epoxide hydrolase (sEH, EPHX2), which metabolizes EETs to their less active diols. In this study, we tested the hypothesis that EETs are involved in glucose regulation and in retarding the development of insulin resistance. To address the role of EETs in regulating glucose homeostasis and insulin signaling, we used mice with targeted gene deletion of sEH (Ephx2-null mice) and a subsequent study with a selective sEH inhibitor. When wild-type mice are fed a high fat diet, insulin resistance develops. However, knockout or inhibition of sEH activity resulted in a significant decrease in plasma glucose. These findings are characterized by enhancement of tyrosyl phosphorylation of the insulin receptor, insulin receptor substrate 1, and their downstream cascade. In addition, pancreatic islets were larger when sEH was disrupted. This effect was associated with an increase in vasculature. These observations were supported by pharmacological inhibition of sEH. These data suggest that an increase in EETs due to sEH-gene knockout leads to an increase in the size of islets and improved insulin signaling and sensitivity.type 2 diabetes | pancreas | arachidonic acid pathway

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Section: Whole-body Soluble Epoxide Hydrolase Deletion and Inhibition Inmentioning

confidence: 79%

Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance

Luria

Bettaieb

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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136

151

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“…The 14,15-, 11,12-EET or vehicle were administered intraperitoneally via osmotic minipump (Alzet) at a dose of 15 μg·kg −1 ·d −1 . TUPS was synthesized as described (24,25), and TUPS was completely dissolved in PEG 400 at a concentration of 10 mg/mL and mixed into Vanicream to obtain a 0.1% (wt:vol) formulated cream. The sEHi (TUPS) was administered orally by gavage in an aqueous solution of 10% (vol/vol) DMSO in 0.5% methylcellulose (10 mg·kg −1 ·d −1 ) or as a 0.1% cream applied topically; control mice received vehicle.…”

Section: Methodsmentioning

confidence: 99%

“…We first studied compounds that increase EETs by inhibiting sEH, the main metabolizing enzyme of EETs. Notably, several structurally distinct sEH inhibitors (sEHis) are being evaluated for clinical indications (3,24,25). Systemic administration of the sEHi 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS, UC1709) increased liver regeneration by 38% compared with vehicle-treated mice (Fig.…”

Section: Pharmacological Manipulation Of Eets and Their Action In Organmentioning

confidence: 99%

Epoxyeicosanoids promote organ and tissue regeneration

Panigrahy

Kalish

Huang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.

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“…The area under the curve (AUC) of orally administered AUDA is 0.4 ϫ 10 4 nmol/L . minute, 12 and the half-life for AUDA after oral gavage is 7.3 hours. 29 As a result, the withdrawal period should be sufficient to exclude the effects of the plasma presence of the drug AUDA.…”

Section: Auda Provides Vascular Protection In the Shrsp Ratsmentioning

confidence: 99%

“…23,24 Thus, we treated a separate set of SHRSP rats with tAUCB, a potent SEH inhibitor 12,13 that lacks potential for PPAR agonistic activity ( Figure 1). As expected, tAUCB protected against cerebral ischemia in the SHRSPs, reducing infarct size to 43 Ϯ 3%, P Ͻ 0.05, hemispheric infarct size and neurodeficit score to 6.3 Ϯ 0.7, n ϭ 9, P Ͻ 0.05.…”

Section: Auda Decreases Infarct Size Without Preventing Hypertensionmentioning

confidence: 99%

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Simpkins

Rudic

Schreihofer

et al. 2009

The American Journal of Pathology

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Inhibition of soluble epoxide hydrolase (SEH), the enzyme responsible for degradation of vasoactive epoxides, protects against cerebral ischemia in rats. However, the molecular and biological mechanisms that confer protection in normotension and hypertension remain unclear. Here we show that 6 weeks of SEH inhibition via 2 mg/day of 12-(3-adamantan-1-ylureido) dodecanoic acid (AUDA) in spontaneously hypertensive stroke-prone (SHRSP) rats protects against cerebral ischemia induced by middle cerebral artery occlusion, reducing percent hemispheric infarct and neurodeficit score without decreasing blood pressure. This level of cerebral protection was similar to that of the angiotensin-converting enzyme inhibitor, enalapril, which significantly lowered blood pressure. SEH inhibition is also protective in normotensive WistarKyoto (WKY) rats, reducing both hemispheric infarct and neurodeficit score. In SHRSP rats, SEH inhibition reduced wall-to-lumen ratio and collagen deposition and increased cerebral microvessel density, although AUDA did not alter middle cerebral artery structure or microvessel density in WKY rats. An apoptosis mRNA expression microarray of brain tissues from AUDAtreated rats revealed that AUDA modulates gene expression of mediators involved in the regulation of apoptosis in neural tissues of both WKY and SHRSP rats. Hence, we conclude that chronic SEH inhibition protects against cerebral ischemia via vascular protection in SHRSP rats and neural protection in both the SHRSP and WKY rats, indicating that SEH inhibition has broad pharmacological potential for treating ischemic stroke. Epoxyeicosatrienoic acids (EETs), lipid metabolites produced from arachidonic acid by CYP450 enzymes, are novel mediators that antagonize the sequela of hypertension, 1 match cerebral blood flow to increased neural activity and metabolic demand, promotes angiogenesis, 2 and protect against ischemia.3,4 Because ischemic stroke occurs with loss of cerebral blood flow and is strongly associated with hypertension, modulation of epoxide degradation has potential in managing ischemic stroke. Unfortunately, pharmacological utility of exogenous EETs is impractical because the epoxides are rapidly degraded by the soluble epoxide hydrolase (SEH) into their less active diol, dihydroxyeicosatrienoic acids. 5In fact, human SEH polymorphisms are linked to the incidence of ischemic stroke, 6 and this association could be related to modifications in SEH activity, and thus epoxide catabolism. 7 An alternative strategy that has been used to increase EETs systemically is SEH inhibition. 1 We previously showed that the SEH inhibitor 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) protects against cerebral ischemia in spontaneously hypertensive stroke-prone (SHRSP) rats, an animal model of essential hypertension.8 Interestingly, chronic AUDA treatment in SHRSP rats effectively decreased infarct size induced by middle cerebral artery occlusion (MCAO)

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Orally Bioavailable Potent Soluble Epoxide Hydrolase Inhibitors

Cited by 215 publications

References 51 publications

Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance

Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance

Epoxyeicosanoids promote organ and tissue regeneration

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

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