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Last update 08 May 2025

EPHX2

Last update 08 May 2025

Basic Info

Synonyms

ABHD20, Bifunctional epoxide hydrolase 2, CEH

+ [9]

Introduction

Bifunctional enzyme (PubMed:12574510). The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides (PubMed:12574510, PubMed:12869654, PubMed:22798687). Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides (By similarity). Also determines steady-state levels of physiological mediators (PubMed:12574510, PubMed:12869654, PubMed:21217101, PubMed:22798687). Bifunctional enzyme (PubMed:12574510). The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid and 12-phosphonooxy-octadec-9E-enoic acid (PubMed:12574510). Has phosphatase activity toward lyso-glycerophospholipids with also some lower activity toward lysolipids of sphingolipid and isoprenoid phosphates (PubMed:22217705, PubMed:22387545).

Drugs associated with EPHX2

TMS-007

Target

EPHX2 x PLPP

Mechanism

EPHX2 inhibitors [+1]

Active Org.

Corxel Pharmaceuticals (Shanghai) Co., Ltd [+2]

Originator Org.

TMS Co., Ltd.

Active Indication

Acute Ischemic Stroke

Inactive Indication-

Drug Highest PhasePhase 2/3

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

GSK-2256294

Target

EPHX2

Mechanism

EPHX2 inhibitors

Active Org.

Originator Org.

Active Indication

Inactive Indication

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

EC-5026

Target

EPHX2

Mechanism

EPHX2 inhibitors

Active Org.

Eicosis Human Health, Inc. [+1]

Originator Org.

University Of California - Davis Branch (513968)

Active Indication

Spinal Cord Injuries [+3]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with EPHX2

CTR20250984

/ RecruitingPhase 2/3

优化再灌注以改善结局和神经功能（ORION）：一项评价JX10治疗晚时间窗急性缺血性卒中的有效性和安全性的多中心、双盲、安慰剂对照、随机、平行组、2/3期研究

[Translation] Optimizing Reperfusion to Improve Outcome and Neurological Function (ORION): A Multicenter, Double-Blind, Placebo-Controlled, Randomized, Parallel-Group, Phase 2/3 Study to Evaluate the Efficacy and Safety of JX10 in the Treatment of Late-Time-Window Acute Ischemic Stroke

评估AIS发病后4.5至24小时内，符合静脉溶栓条件的患者在标准治疗基础上使用JX10在良好结局方面是否优于安慰剂

[Translation]

To evaluate whether JX10 is superior to placebo in achieving good outcomes in patients eligible for intravenous thrombolysis within 4.5 to 24 hours after onset of AIS in addition to standard care

Start Date02 Apr 2025

Sponsor / Collaborator

Fuji Yakuhin Co., Ltd.

[+1]

NCT06438471

/ RecruitingPhase 1

Development of a Novel Soluble Epoxide Hydrolase Inhibitor As a Strategy for Treating Neuropathic Pain in Patients with SCI

The goal of this clinical trial is to evaluate safety and tolerability of multiple oral doses of EC5026 in male and female patients with neuropathic pain due to spinal cord injury. The main question it aims to answer is whether EC5026 is safe and well tolerated in SCI patients with neuropathic pain. In addition, this trial will also study the effects of EC5026 on pain.
Researchers will compare EC5026 to placebo.
Participants will be asked to:
* Take EC5026 or placebo in a masked fashion, once daily, for 14 consecutive days.
* Undergo physical exams, vital signs assessments, ECGs, and blood draws
* Complete assessments of pain, sleep, functional status, and perception of change

Start Date01 Apr 2025

Sponsor / Collaborator

Eicosis Human Health, Inc.

NCT05764122

/ WithdrawnPhase 2

A Multicenter, Operationally Seamless, Double-Blind, Dose-Ranging, Placebo-Controlled, Randomized, Parallel-Group, Phase 2b Study to Evaluate the Efficacy and Safety of Intravenous BIIB131 for Participants With Ischemic Stroke Between 4.5 and 24 Hours After Last Known Well

The primary objective of the study is to evaluate the effects of BIIB131 on arterial revascularization (Part 1) and to determine if BIIB131 improves functional outcome as measured by the Modified Rankin Scale (mRS) when compared with placebo following acute ischemic stroke (AIS) (Part 2). The secondary objectives are to evaluate the effects of BIIB131 on angiographic reperfusion and infarct evolution, to determine if BIIB131 improves functional outcome, pharmacokinetic profile of BIIB131 (Part 1); to evaluate the effects of BIIB131 on acute and 90-day clinical outcomes (Part 2).

Start Date29 Mar 2024

Sponsor / Collaborator

Biogen, Inc.

100 Clinical Results associated with EPHX2

100 Translational Medicine associated with EPHX2

0 Patents (Medical) associated with EPHX2

2,910

Literatures (Medical) associated with EPHX2

31 Dec 2025·Journal of Enzyme Inhibition and Medicinal Chemistry

Indirubin-3′-oxime as a dual-action agent: mitigating heat-induced male infertility in Drosophila melanogaster and inhibiting soluble epoxide hydrolase

Article

Author: Phong, Nguyen Viet ; Kim, Hyo-Sung ; Yeom, Eunbyul ; Yang, Seo Young ; Zhao, Yan

This study investigated the potential of the indirubin-3'-oxime (I3O) compound to mitigate temperature-induced male infertility in Drosophila melanogaster. Elevated temperatures significantly reduced egg-hatching rates, but I3O supplementation improved these rates, suggesting it can partially restore fertility under heat stress. Additionally, I3O was found to inhibit soluble epoxide hydrolase (sEH), an enzyme involved in the metabolism of epoxyeicosatrienoic acids, which are vital for reproductive health. I3O exhibited sEH inhibitions with an IC₅₀ value of 59.74 ± 0.41 µM. Enzyme kinetics revealed that I3O acts as a non-competitive inhibitor of sEH with a K_i value of 78.88 µM. Molecular docking showed strong interactions between I3O and key residues in the allosteric regions within the sEH enzyme, with a binding affinity of -9.2 kcal/mol. These interactions were supported by 100 ns molecular dynamics simulations, which confirmed the stability of the sEH-I3O complex.

01 Jun 2025·Biochemistry and Biophysics Reports

Synthesis and evaluation of isoquinolinyl and pyridinyl-based dual inhibitors of fatty acid amide hydrolase and soluble epoxide hydrolase to alleviate orofacial hyperalgesia in the rat

Article

Author: Duong, Leah ; Hammock, Bruce D ; Garcia, Coral ; Salinas, Steve ; Tsang, Amanda ; Gunari, Siena ; Pavana, Lucy ; Mercado, Madison ; Kandasamy, Ram ; Gorostiza, Gabrielle ; Pecic, Stevan ; Gomez, Karen ; Morisseau, Christophe ; Carr, Daniel

The treatment of orofacial pain disorders is poor. Both opioids and serotonin agonists are commonly used; however, they produce dangerous and unpleasant side effects. Therefore, there is an urgent need to identify new pharmacological treatments that can resolve orofacial pain. Moreover, a treatment that engages multiple mechanisms using one compound may be advantageous. Fatty acid amide hydrolase (FAAH) and soluble epoxide hydrolase (sEH) are two enzymes that can regulate both pain and inflammation via independent pathways. Small molecules that inhibit both enzymes simultaneously were previously synthesized and produced antinociception in vivo. Quinolinyl-based dual inhibitors of FAAH and sEH can inhibit acute inflammatory pain in rats. Here, following on these findings, we generated 7 new isoquinolinyl- and 7 pyridinyl-based analogs and tested their inhibition at both enzymes. Structure-activity relationship study coupled with docking experiments, revealed that the isoquinoline moiety is well-tolerated in the binding pockets of both enzymes, yielding several analogs with nanomolar activity in enzymatic assays. All newly synthesized analogs were assessed in the solubility assay at pH 7.4, and we determined that isoquinolinyl- and substituted pyridinyl-analogs exhibit limited solubility under the experimental conditions. The most potent inhibitor, 4f, with IC₅₀ values in the low nanomolar range for both enzymes, was evaluated in a plasma stability assay in human and rat plasma where it showed a moderate stability. Primary binding assays revealed that 4f does not engage any opioid or serotonin receptors. A high dose (3 mg/kg) of 4f reversed orofacial hyperalgesia following pretreatment with nitroglycerin and orofacial injection of formalin; however, this same dose did not inhibit acute orofacial inflammatory pain or restore pain-depressed wheel running. These findings indicate that simultaneous inhibition of FAAH and sEH using isoquinolinyl-based dual inhibitors may only reverse certain components of orofacial hyperalgesia.

01 Jun 2025·European Journal of Medicinal Chemistry

Phenyl-benzyl-ureas with pyridazinone motif: Potent soluble epoxide hydrolase inhibitors with enhanced pharmacokinetics and efficacy in a paclitaxel-induced neuropathic pain model

Article

Author: Banoglu, Erden ; Çalışkan, Kübra ; Lengerli, Deniz ; Werz, Oliver ; Bakht, Arooj ; Bal, Nur Banu ; Dahlke, Philipp ; Jordan, Paul M ; Çalışkan, Burcu

The severe pain linked to chemotherapy-induced peripheral neuropathy (CIPN) often becomes a critical factor limiting the effective dosage of life-saving chemotherapy treatments. This debilitating side effect not only hampers the effectiveness of cancer therapy but also poses challenges due to the adverse effects of current treatment options for managing CIPN-related pain complications. Soluble epoxide hydrolase (sEH) inhibitors, which elevate endogenous epoxy-fatty acid levels, have been shown to mitigate CIPN-related pain in different rodent models. In our quest to develop potent sEH inhibitors, we developed novel benzyl phenyl urea derivatives incorporating a pyridazinone ring alongside the urea group as a secondary pharmacophore. These compounds demonstrated remarkable potency in inhibiting sEH, with IC₅₀ values ranging from 0.2 to 57 nM. Compound FP9 (IC₅₀ = 0.2 nM), the most potent in this series, exhibited enhanced metabolic stability, translating into significantly improved oral bioavailability (F = 78 %). It consistently relieved pain perception in mice with paclitaxel-induced peripheral neuropathy, achieving a significant and sustained effect compared to gabapentin. In addition, docking studies and molecular dynamics simulations with FP9 provided valuable insights into the binding interactions between the inhibitor and the sEH binding site, offering direction for further optimization of new analogs. These findings align with recent research that highlights the beneficial effects of sEH inhibitors in reducing pain thresholds associated with CIPN.

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EPHX2

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