soluble epoxide hydrolase

Soluble epoxide hydrolase inhibitor is a soluble epoxide hydrolase inhibitor (human soluble epoxide hydrolase (h-sEH) with pIC50 of 8.4).

Soluble epoxide hydrolase (sEH) PROTAC 1a is a proteolysis-targeting chimera (PROTAC) comprising a cereblon ligand linked to the sEH inhibitor t-TUCB via a linker, promoting selective sEH degradation and inhibiting its hydrolase activity (IC50 = 0.8 nM) significantly more than its phosphatase activity (IC50 = >10,000 nM). This compound preferentially targets cytosolic sEH for lysosomal rather than proteasomal degradation. Furthermore, it mitigates thapsigargin-induced upregulation of phosphorylated inositol-requiring enzyme 1α (IRE1α) and X-box binding protein 1 (XBP1) splicing in HepG2 and 293T cells, thereby reducing endoplasmic reticulum stress.

Dual FAAH/sEH-IN-1 is a dual inhibitor of sEH (soluble epoxide hydrolase) (IC50: 9.6 nM) and FAAH (fatty acid amide hydrolase) (IC50: 7 nM) with high affinity and anti-inflammatory activity.

EC5026 (BPN-19186) has the potential to relieve pain by stabilizing natural analgesic and anti-inflammatory mediators.

(Rac)-EC5026 ((Rac)-BPN-19186) is a potent piperidine inhibitor of soluble epoxide hydrolase (sEH) with Ki of 0.06 nM. (Rac)-EC5026 can be used for the research of Parkinson's disease and dementia with Lewy Bodies (DLB) [1].

(±)12(13)-DiHOME is the diol form of (±)12(13)-EpOME , a cytochrome P450-derived epoxide of linoleic acid also known as isoleukotoxin. [1] It is formed from 12(13)-EpOME by soluble epoxide hydrolase (sEH) in neutrophils. [2] 12(13)-DiHOME is toxic to Sf21 cells expressing sEH and to lacZ-expressing control cells, unlike isoleukotoxin, which is only toxic to cells containing sEH.[1] [2] Levels of 12(13)-DiHOME are increased in rat spinal cord following burn injury, and it enhances cold tolerance, increases fatty acid uptake into brown adipocytes, and decreases serum triglyceride levels in mice. Levels are also elevated in bronchoalveolar lavage fluid (BALF) in humans following exposure to biodiesel exhaust and in exhaled breath condensate in patients with allergic asthma following allergen exposure.[5] [6] Plasma levels of 12(13)-DiHOME are increased immediately following moderate-intensity exercise in mice and humans, an effect that can be prevented by brown adipose tissue removal in the mouse.[7]

N,N'-Dicyclohexylurea (AURORA KA-3582) is a soluble epoxide hydrolase (sEH) inhibitor.

Docosahexaenoic acid is an ω-3 fatty acid that is abundant in the brain and the retina and is known to be important in early development.[1] [2] Maresin 2 (MaR2) is a 13R,14S-dihydroxy DHA formed by recombinant human macrophage 12-lipoxygenase and soluble epoxide hydrolase co-incubated with DHA. [3] At 1 ng/mouse, MaR2 was shown to reduce neutrophil infiltration by 40% in a mouse model of peritonitis, and at 10 pM, MaR2 can enhance human macrophage phagocytosis of zymosan A by 90%. [3] Analytical and biological comparisons of synthetic MaR2 with endogenously derived MaR2 have confirmed its identity as matching the natural product.[4]

Docosahexaenoic acid is the most abundant ω-3 fatty acid in neural tissues, especially in the brain and retina. (±)7(8)-EpDPA is an epoxide derivative of DHA that is generated by the action of cytochrome P450 epoxygenases. It is naturally occurring in plasma and brain and spinal cord tissues and is increased following dietary supplementation with ω-3 fatty acids. (±)7(8)-EpDPA and other epoxy metabolites of DHA modulate receptor and channel activities to evoke diverse effects, such as promoting vasodilation, inhibiting angiogenesis, and decreasing inflammatory and neuropathic pain. (±)7(8)-EpDPA is a substrate of soluble epoxide hydrolase (KM = 15 μM), which converts it to the corresponding diol.

9(S),12(S),13(S)-TriHOME is a linoleic acid-derived oxylipin that has diverse biological activities.1,2,3,4It has been found in various plants and is produced in human eosinophils in a 15-lipoxygenase-dependent, soluble epoxide hydrolase-independent manner.1,59(S),12(S)13(S)-TriHOME inhibits antigen-induced β-hexosaminidase release from RBL-2H3 mast cells (IC50= 28.7 μg/ml).2It inhibits LPS-induced nitric oxide (NO) production in BV-2 microglia (IC50= 40.95 μM).3In vivo, 9(S),12(S),13(S)-TriHOME (1 g/animal) enhances the antiviral IgA and IgG antibody responses induced by a nasal influenza hemagglutinin (HA) vaccine by 5.2- and 2-fold, respectively, in mice.4 1.Hamberg, M., and Hamberg, G.Peroxygenase-catalyzed fatty acid epoxidation in cereal seeds: Sequential oxidation of linoleic acid into 9(S),12(S),13(S)-trihydroxy-10(E)-octadecenoic acidPlant Physiol.110(3)807-815(1996) 2.Hong, S.S., and Oh, J.S.Inhibitors of antigen-induced degranulation of RBL-2H3 cells isolated from wheat branJ. Korean Soc. Appl. Biol. Chem.5569-74(2012) 3.Kim, C.S., Kwon, O.W., Kim, S.Y., et al.Five new oxylipins from Chaenomeles sinensisLipids49(11)1151-1159(2014) 4.Shirahata, T., Sunazuka, T., Yoshida, K., et al.Total synthesis, elucidation of absolute stereochemistry, and adjuvant activity of trihydroxy fatty acidsTetrahedron62(40)9483-9496(2006) 5.Fuchs, D., Tang, X., Johnsson, A.-K., et al.Eosinophils synthesize trihydroxyoctadecenoic acids (TriHOMEs) via a 15-lipoxygenase dependent processBiochim. Biophys. Acta Mol. Cell Biol. Lipids1865(4)158611(2020)

Cytochrome P450 metabolism of polyunsaturated fatty acids produces numerous bioactive epoxide regioisomers. (±)13(14)-EpDPA is a docosahexaenoic acid epoxygenase metabolite, derived via epoxidation of the 13,14-double bond of DHA. It has been detected in rat brain and spinal cord and is a preferred substrate for soluble epoxide hydrolase with a Km value of 3.2 μM. (±)13(14)-EpDPA demonstrates antihyperalgesic activity in inflammatory and neuropathic pain models. (±)13(14)-EpDPA and other epoxy metabolites of DHA are also reported to potently inhibit angiogenesis and tumor growth in in vitro assays.

Cytochrome P450 metabolism of polyunsaturated fatty acids produces numerous bioactive epoxide regioisomers. (±)10(11)-EpDPA is a docosahexaenoic acid epoxygenase metabolite, derived via epoxidation of the 10,11-double bond of DHA. It has been detected in rat brain and spinal cord, as well as human serum, and acts as a substrate for soluble epoxide hydrolase with a Km value of 5.1 μM. (±)10(11)-EpDPA and other epoxy metabolites of DHA are reported to demonstrate antihyperalgesic activity in inflammatory and neuropathic pain models and to potently inhibit angiogenesis and tumor growth in in vitro assays.

Cytochrome P450 metabolites of arachidonic acid, such as 11(12)-EpETrE and 14(15)-EpETrE have been identified as endothelium derived hyperpolarizing factors with vasodilator activity. Soluble epoxide hydrolase (sEH) catalyzes the conversion of EpETrEs to the corresponding DiHETrEs thereby diminishing their activity. Inhibitors of sEH may therefore have clinical utility for treating hypertension and systemic inflammation. S-NEPC is a colorimetric substrate used to measure sEH activity. It also is a substrate for Glutathione S-transferase, microsomal epoxide hydrolase and porcine liver carboxylesterase. Hydrolysis of S-NEPC by sEH yields 4-nitrophenol which can be quantified spectrophotometrically at 405 nm. S-NEPC is adaptable for use in 96-well microwell plate readers.

Murrangatin may be a valuable anti-tumor-promoting agent, it can significantly inhibit Epstein-Barr virus early antigen (EBV-EA) activation, and preserve the high viability of Raji cells, it also exhibits cytotoxicity against cholangiocarcinoma cell line,

sEH Inhibitor-16, a potent soluble epoxide hydrolase (sEH) inhibitor, exhibits an IC50 of 2 nM. It diminishes inflammatory damage associated with cerulein-induced acute pancreatitis (AP) in mice, making it suitable for inflammation and immunology research [1].

(±)9(10)-DiHOME, the diol derivative of (±)9(10)-EpOME—a cytochrome P450-derived epoxide of linoleic acid also known as leukotoxin—is formed through the action of soluble epoxide hydrolase (sEH) in neutrophils. It exhibits toxicity towards Sf21 cells expressing sEH as well as tolacZ-expressing control cells, differing from leukotoxin which only harms sEH-containing cells. Furthermore, combined exposure to 9(10)- and 12(13)-DiHOME leads to cell death in rabbit renal proximal tubule cells by disrupting mitochondrial respiration, and causes lung injury, respiratory distress, and mortality in mice, highlighting its role as a toxic lipid mediator. Specifically, 9(10)-DiHOME has been associated with acute respiratory distress syndrome (ARDS), a severe and often deadly complication in patients with major burns. Elevated levels of this compound have been detected in the bronchoalveolar lavage fluid (BALF) of women, but not men, with chronic obstructive pulmonary disease (COPD), and its levels are also increased in patients with allergic asthma, indicating its significance in respiratory conditions.

Diflapolin is a highly active dual 5-lipoxygenase-activating protein (FLAP)/soluble epoxide hydrolase (sEH) inhibitor with marked anti-inflammatory efficacy and high target selectivity.

sEH/AChE-IN-3 (15) serves as a dual inhibitor targeting both soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), demonstrating potent activity and the ability to cross the blood-brain barrier (BBB). It exhibits IC50 values of 0.4 nM for human sEH (hsEH), 1.94 nM for human AChE (hAChE), 615 nM for human butyrylcholinesterase (hBChE), 4.3 nM for mouse sEH (msEH), and 2.61 nM for mouse AChE (mAChE), indicating its efficacy across these enzymes.

sEH inhibitor-1 (compound TCPU) is a potent, orally active inhibitor of soluble epoxide hydrolase (sEH) with IC50 values of 0.4 and 5.3 nM for human and murine she, respectively.

trans-AUCB (t-AUCB) is an effective and selective soluble epoxide hydrolase inhibitor (IC50s: 1.3 nM, 8 nM, 8 nM for hsEH, mouse sEH and rat sEH, respectively).

Prostaglandin E2 (PGE2) inhibitor 3 is a selective inhibitor targeting microsomal prostaglandin E synthase-1 (mPGES-1; IC50 = 0.2 µM), demonstrating greater selectivity for mPGES-1 over COX-1, COX-2, 5-lipoxygenase (5-LO), and soluble epoxide hydrolase (sEH) in assays at 10 µM. This compound effectively reduces IL-1β-induced PGE2 production in A549 cells and decreases LPS-induced IL-6 and PGE2 in J774A.1 macrophages at concentrations of 10 and 1 µM, respectively. Additionally, it blocks the production of 5-LO-derived products, including leukotriene B4 (LTB4) and 5-H(p)ETE, in response to calcium ionophore A23187 alone or combined with arachidonic acid, with IC50 values of 4.9 and 5.2 µM, respectively. When administered in vivo at doses of 10 mg/kg, PGE2 inhibitor 3 effectively prevents leukocyte infiltration in a mouse model of zymosan-induced peritonitis.

sEH inhibitor-4 (compound B15) has been identified as a potent soluble epoxide hydrolase (SEH) inhibitor with a remarkable inhibitory potency of 0.03 ± 0.01 nm. Intensive structural modification efforts led to the discovery of this compound for its ability to decrease inflammation and alleviate pain in the presence of SEH.

(±)17(18)-EpETE-Ethanolamide, an ω-3 endocannabinoid epoxide, originates from eicosapentaenoic ethanolamide (EPEA) through cytochrome P450 (CYP) epoxygenases action and is decomposed by soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FA, AH). Its endogenous synthesis occurs in LPS-stimulated and EPEA-supplemented BV-2 microglia cells, a process inhibited by the CYP inhibitor ketoconazole. This compound mitigates IL-6 and nitrite levels while enhancing IL-10 production following LPS exposure in BV-2 microglia. At a dose of 50 µM, it prevents platelet aggregation caused by arachidonic acid but not that triggered by ADP, collagen, or ristocetin. Additionally, it facilitates the dilation of constricted bovine coronary arteries (ED50= 1.1 µM) and blocks VEGF-driven tubulogenesis in human microvascular endothelial cells (HMVECs).

sEH/AChE-IN-4 -15 is a potent, blood-brain barrier-penetrating dual inhibitor targeting soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE). It demonstrates notable inhibition efficacy, with IC50 values of 3.1 nM (hsEH), 1660 nM (hAChE), 179 nM (hBChE, human butyrylcholinesterase), 14.5 nM (msEH), and 102 nM (mAChE), indicating its significant inhibitory action across both targeted enzymes in human and mouse models.

sEH inhibitor-5 is a potent inhibitor of sEH (soluble epoxide hydrolase) (IC50: 0.1 nM).

sEH/AChE-IN-1 (Compound 12a) is a dual inhibitor of soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE). sEH/AChE-IN-1 has a cumulative effect against neuroinflammation and memory impairment. sEH/AChE-IN-1 has shown research potential in Alzheimer's disease (AD).

SWE101 is a potent human and rat soluble epoxide hydrolase (sEH)-P inhibitor(IC50s of 4 μM and 2.8 μM, respectively).

SEH inhibitor-2 (compound 5l) is a soluble epoxide hydrolase (sEH) inhibitor with oral activity (IC50=0.9 nM), and the predicted oral absorption percentage is 71.2-88.4%. SEH inhibitor-2 can maintain a high concentration of eicosanoic acid (EETs) in serum. SEH inhibitor-2 has research value in cardiovascular protection.

sEH-IN-12 is an effective inhibitor of the enzyme soluble epoxide hydrolase (sEH).

AUDA is an inhibitor of sEH(IC50 values of 18 and 69 nM for the mouse and human enzymes, respectively)

COX-2/sEH-IN-1 is an orally active dual inhibitor of COX-2 (IC50: 1.24 μM) and sEH (IC50: 0.40 μM), a soluble epoxide hydrolase. COX-2/sEH-IN-1 increases anti-inflammatory effects and significantly reduces cardiovascular risk.

Orniplabin, also known as SMTP-7 is a dual inhibitor of thrombolysis and soluble epoxide hydrolase. SMTP-7 promotes thrombolysis and inhibits soluble epoxide hydrolase.

sEH inhibitor-7 is a soluble epoxide hydrolase (sEH) inhibitor that inhibits sEH in human and mouse with IC 50 s of 6.2 μM and 0.15 μM, respectively. sEH inhibitor-7 is associated with anti-inflammatory active molecules.

UC-1728 (t-TUCB) is an effective rabbit soluble epoxide hydrolase inhibitor (IC50: 2 nM on rabbit liver).

AR-9281 (APAU) is a potent and selective inhibitor of soluble epoxide hydrolase (s-EH) potentially for the treatment of hypertension and type 2 diabetes

CAY10640 (sEH inhibitor-1) is a potent, orally active, water-soluble epoxide hydrolase (sEH) inhibitor that inhibits sEH in humans and mice with IC50s of 0.4 and 5.3 nM, respectively.

N-Desbutyl dronedarone is an active metabolite of the antiarrhythmic agent dronedarone .1,2,3It is formed from dronedarone by cytochrome P450s (CYPs) and monoamine oxidase (MAO) in human hepatocyte preparations.4N-Desbutyl dronedarone inhibits the binding of 3,3’,5-triiodo-L-thyronine to the thyroid hormone receptors TRα1and TRβ1(IC50s = 59 and 280 μM for the chicken and human receptors, respectively).1It inhibits CYP2J2-mediated formation of 14,15-EET from arachidonic acid and soluble epoxide hydrolase-mediated formation of 14,15-DHET from 14,15-EET (IC50s = 1.59 and 2.73 μM, respectively, in cell-free assays).2N-Desbutyl dronedarone decreases intracellular ATP levels in H9c2 rat cardiomyocytes (IC50= 1.07 μM) and inhibits mitochondrial complex I, also known as NADH dehydrogenase, and mitochondrial complex II, also known as succinate dehydrogenase, activities in isolated rat heart mitochondria (IC50s = 11.94 and 24.54 μM, respectively).3 1.Van Beeren, H.C., Jong, W.M.C., Kaptein, E., et al.Dronerarone acts as a selective inhibitor of 3,5,3’-triiodothyronine binding to thyroid hormone receptor-α1: in vitro and in vivo evidenceEndocrinology144(2)552-558(2003) 2.Karkhanis, A., Tram, N.D.T., and Chan, E.C.Y.Effects of dronedarone, amiodarone and their active metabolites on sequential metabolism of arachidonic acid to epoxyeicosatrienoic and dihydroxyeicosatrienoic acidsBiochem. Pharmacol.146188-198(2017) 3.Karkhanis, A., Leow, J.W.H., Hagen, T., et al.Dronedarone-induced cardiac mitochondrial dysfunction and its mitigation by epoxyeicosatrienoic acidsToxicol. Sci.163(1)79-91(2018) 4.Klieber, S., Arabeyre-Fabre, C., Moliner, P., et al.Identification of metabolic pathways and enzyme systems involved in the in vitro human hepatic metabolism of dronedarone, a potent new oral antiarrhythmic drugPharmacol. Res. Perspec.2(3)e00044(2014)

BI-1935 is an inhibitor of soluble epoxide hydrolase (sEH). For diseases related to cardiovascular disease.

sEH inhibitor-3 is an orally available, selective and potent inhibitor of soluble epoxide hydrolase (sEH) for the study of cancer.

CUDA is an effective soluble cyclohydrolase inhibitor with IC50 of 11.1 nM and 112 nM for mouse sEH and human sEH, respectively. CUDA selectively increases the activity of peroxisome proliferator-activated receptor (PPAR) alpha. CUDA may be valuable for the study of cardiovascular diseases.

N-(3-methoxybenzyl)-octadecanamide deverts from Maca (Lepidium meyenii Walp.).

sEH inhibitor-14, a benzoxazolone-5-urea analogue, acts as an efficient soluble Epoxide Hydrolase (sEH) inhibitor, demonstrating significant activity with an IC50 value of 0.39 nM.

TUPS is a selective soluble epoxide hydrolase inhibitor which protects against isoprenaline-induced cardiac hypertrophy.

1-Cyclohexyl-3-dodecyl urea (NCND) is a highly selective soluble epoxide hydrolase (sEH) inhibitor.

sEH inhibitor-6 (Compound 3g) is a highly potent soluble epoxide hydrolase (sEH) inhibitor, exhibiting an IC 50 value of 0.5 nM [1].