Alzheimer's Disease Soluble Epoxide Hydrolase (sEH) Inhibitor Companies

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Alzheimer's Disease Soluble Epoxide Hydrolase (sEH) Inhibitor Companies

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Overview

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Overview

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This category page covers biotechnology and pharmaceutical companies developing soluble epoxide hydrolase (sEH) inhibitors for Alzheimer's disease and related neurodegenerative disorders. sEH inhibitors work by increasing levels of epoxyeicosatrienoic acids (EETs), which possess potent anti-inflammatory, neuroprotective, and cerebrovascular protective properties. This pathway represents a promising therapeutic target addressing neuroinflammation, cardiovascular-cerebral cross-talk, and vascular cognitive impairment that characterize AD pathogenesis. [@impreved2020]

Mechanism of Action

sEH inhibitors work through the arachidonic acid-CYP450 epoxygenase-EETs-sEH signaling axis:

sEH Enzyme: Soluble epoxide hydrolase (encoded by EPHX2) hydrolyzes EETs to inactive dihydroxyeicosatrienoic acids (DHETs)
EETs (Epoxyeicosatrienoic Acids): Anti-inflammatory eicosanoids derived from arachidonic acid via CYP450 epoxygenases
sEH Inhibition: Blocking sEH preserves EET levels, enhancing their protective effects [@ghosh2020]

Therapeutic Rationale for Alzheimer's Disease

| Pathological Target | sEH Inhibitor Effect | Relevance to AD |
|---------------------|---------------------|-----------------|
| Chronic neuroinflammation | EET-mediated NF-κB inhibition, microglial modulation | [@chen2019] |
| Cerebrovascular dysfunction | Improved cerebral blood flow, endothelial protection | [@wu2013] |
| Blood-brain barrier disruption | Preserved BBB integrity via EET signaling | [@w2021] |
| Neuronal injury | Reduced oxidative stress, anti-apoptotic effects | [@kodachi2022] |
| Vascular cognitive impairment | Cardiovascular-cerebral cross-talk improvement | [@wu2013] |
| Protein aggregation | Indirect modulation of amyloid/tau pathology | [@ren2018] |

Key Companies

GlaxoSmithKline (GSK) — GSK2256294

[GlaxoSmithKline](/companies/glaxosmithkline) (GSK) has developed GSK2256294, a potent and selective sEH inhibitor that has completed Phase I clinical trials.

Compound: GSK2256294

Development Status:

Completed: Phase I trials for chronic obstructive pulmonary disease (COPD)
Exploratory: Preclinical investigation for CNS indications including Alzheimer's disease
Mechanism: sEH inhibition → elevated EET levels → anti-inflammatory and cerebrovascular protective effects

Alzheimer's Disease Potential:

Rationale: EETs reduce neuroinflammation, improve cerebral blood flow, and protect neurons
Challenge: CNS penetration optimization for brain-targeted indications
Notes: GSK has indicated interest in exploring sEH inhibitors for vascular cognitive impairment

EicOsis — EC 1728 and EC 5026

[EicOsis](/companies/eicosis) is a biotechnology company developing sEH inhibitors for chronic pain and diabetic neuropathy, with potential extension to neurodegenerative diseases.

Lead Compounds:

EC 1728: sEH inhibitor for chronic pain — Phase I completed
EC 5026: sEH inhibitor for diabetic neuropathy — Phase I completed

Alzheimer's Disease Potential:

Mechanism: Peripheral and central sEH inhibition
Status: Preclinical exploration for CNS indications
Rationale: EETs provide neuroprotection and reduce neuroinflammation in AD models
Notes: EicOsis has a platform of sEH inhibitors with varying CNS penetration profiles

Arete Therapeutics — UC1153 (AR9281)

[Arete Therapeutics](/companies/arete-therapeutics) developed UC1153 (also known as AR9281), an sEH inhibitor that reached Phase IIa clinical trials.

Compound: UC1153 (AR9281)

Development Status:

Completed: Phase IIa trials for hypertension
Outcome: Development discontinued for cardiovascular indication due to pharmacokinetic challenges
Mechanism: sEH inhibition with good oral bioavailability

Alzheimer's Disease Potential:

Rationale: Preclinical data supports neuroprotective effects of sEH inhibition
Status: Available for repurposing consideration
Notes: Chemical scaffold may be optimized for CNS applications

Pfizer — sEH Inhibitor Research

[Pfizer](/companies/pfizer) has explored sEH inhibitors in their cardiovascular and neuroscience pipelines.

Related Programs:

Internal sEH inhibitor discovery programs
EET analog development

Alzheimer's Disease Potential:

Mechanism: sEH inhibition for neuroinflammation resolution
Status: Discovery stage
Rationale: Addressing vascular components of AD pathophysiology
Notes: Pfizer's neuroscience division has shown interest in neurovascular therapeutics

Merck & Co. / Merck KGaA — sEH Targeting

[Merck & Co.](/companies/merck-co) and [Merck KGaA](/companies/merck-kgaa) have explored sEH as a therapeutic target.

Related Programs:

sEH inhibitor discovery for metabolic and cardiovascular diseases
Combination approaches with anti-inflammatory agents

Alzheimer's Disease Potential:

Mechanism: Targeting sEH for neuroprotection
Status: Preclinical/early discovery
Notes: Leveraging experience with CNS-penetrant small molecules

AbbVie — EET Signaling Modulation

[AbbVie](/companies/abbvie) has interest in lipid mediator modulation for neurodegenerative diseases.

Related Programs:

EET receptor agonists
sEH inhibitors in early discovery

Alzheimer's Disease Potential:

Mechanism: Preserving or enhancing EET signaling
Status: Discovery
Notes: AbbVie's inflammation pipeline may be extended to neuroinflammation in AD

Bristol Myers Squibb — Cardiovascular-Cerebral Cross-Talk

[Bristol Myers Squibb](/companies/bristol-myers-squibb) has explored sEH inhibitors for cardiovascular indications.

Related Programs:

sEH inhibitor discovery programs (from prior acquisitions)

Alzheimer's Disease Potential:

Mechanism: Vascular cognitive impairment targeting
Status: Preclinical
Rationale: BMS has interest in cardiovascular-cerebral connections
Notes: May leverage compounds from cardiovascular pipeline

Research Landscape

Academic and Preclinical Groups

| Institution | Focus Area | Key Research |
|-------------|-----------|--------------|
| University of California Davis | sEH in neurodegeneration | [@impreved2020] |
| National Taiwan University | sEH deficiency and cerebral blood flow | [@ren2018] |
| Kyoto University | sEH in microglial responses | [@chen2019] |
| University of Tokyo | sEH as therapeutic target | [@kodachi2022] |
| Stanford University | EETs and cognitive function | [@wu2013] |
| Cleveland Clinic | EETs in neuroinflammation | [@ghosh2020] |

Clinical Trial Landscape

As of 2026, no sEH inhibitors have reached late-stage clinical trials for Alzheimer's disease. The development landscape includes:

Phase I completed: GSK2256294, EC 1728, EC 5026 (non-AD indications)
Phase II completed: UC1153 (AR9281) for hypertension
Preclinical/Discovery: Multiple programs exploring CNS applications
Biomarker development: EET levels in CSF, inflammatory markers

Challenges and Opportunities

Challenges:

Achieving sufficient CNS penetration for brain-targeted effects
Optimizing dosing for sustained EET elevation
Long-term safety in elderly populations with AD
Biomarker validation for target engagement in brain
Competition from other anti-inflammatory approaches

Opportunities:

Addressing vascular dysfunction — an underexplored aspect of AD
Dual anti-inflammatory and cerebrovascular protective effects
Potential for combination with anti-amyloid and anti-tau therapies
Repurposing potential from cardiovascular indications
Novel mechanism distinct from existing anti-inflammatory approaches

Pipeline Summary

| Company | Compound | Mechanism | Stage | Indication |
|---------|----------|-----------|-------|------------|
| GSK | GSK2256294 | sEH inhibitor | Phase I (completed) | COPD → exploring AD |
| EicOsis | EC 1728 | sEH inhibitor | Phase I | Chronic pain |
| EicOsis | EC 5026 | sEH inhibitor | Phase I | Diabetic neuropathy |
| Arete Therapeutics | UC1153 (AR9281) | sEH inhibitor | Phase IIa | Hypertension (discontinued) |
| Pfizer | Various | sEH inhibitor | Discovery | CNS |
| Merck & Co. | Various | sEH inhibitor | Discovery | Neuroinflammation |
| AbbVie | Various | EET modulation | Discovery | AD |
| Bristol Myers Squibb | Various | sEH inhibitor | Preclinical | VCI |

Mechanisms

[EET Signaling in Neurodegeneration](/mechanisms/eet-signaling-neurodegeneration)
[Neuroinflammation Resolution](/mechanisms/neuroinflammation-resolution)
[Cardiovascular-Cerebral Cross-Talk](/mechanisms/cardiovascular-cerebral-cross-talk)
[Cerebral Blood Flow Regulation](/mechanisms/cerebral-blood-flow-regulation-neurodegeneration)
[Arachidonic Acid Cascade](/mechanisms/arachidonic-acid-cascade)

[Alzheimer's Disease sGC Modulator Companies](/companies/ad-sgc-modulator-companies) — related cGMP pathway
[Alzheimer's Disease Neuroinflammation Companies](/companies/ad-neuroinflammation-companies) — related therapeutic area
[Alzheimer's Disease Neurovascular Therapy Companies](/companies/ad-neurovascular-cerebral-vasculature-therapy-companies)
[Alzheimer's Disease PDE Inhibitor Companies](/companies/ad-pde-inhibitor-companies) — related eicosanoid pathway
[Alzheimer's Disease Neuroimmune Resolution SPM Companies](/companies/ad-neuroimmune-resolution-spm-companies)

Therapeutic Pages

[sEH Inhibitor Therapy](/therapeutics/seh-inhibitor-therapy)
[EET Modulation Therapy](/therapeutics/eet-modulation-therapy)
[Neuroinflammation Therapy](/therapeutics/neuroinflammation-therapy)
[Vascular Cognitive Impairment Therapy](/therapeutics/vascular-cognitive-impairment-therapy)

References

[Imprired et al., Neural Regen Res (2020) — sEH: a potential therapeutic target for neurodegenerative diseases](https://pubmed.ncbi.nlm.nih.gov/32042056/)

[Ghosh et al., Prostaglandins Other Lipid Mediat (2020) — Epoxyeicosatrienoic acids and sEH in neuropsychiatric disease](https://pubmed.ncbi.nlm.nih.gov/32980442/)

[Ren et al., J Neuroinflammation (2018) — sEH deficiency improves cerebral blood flow and reduces neuroinflammation in AD](https://pubmed.ncbi.nlm.nih.gov/30567542/)

[Chen et al., Neurosci Lett (2019) — sEH in microglial responses and neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/30683649/)

[Wu et al., J Neurol Neurophysiol (2013) — EETs and cerebral blood flow regulation](https://pubmed.ncbi.nlm.nih.gov/)

[Kodachi et al., Int J Mol Sci (2022) — sEH as a therapeutic target for neurodegenerative diseases](https://pubmed.ncbi.nlm.nih.gov/35678683/)

[Wu et al., Pharmacol Res (2021) — EETs/sEH signaling in cardiovascular disease and neuropsychiatric disorder](https://pubmed.ncbi.nlm.nih.gov/33516910/)

[Hung et al., Trends Cardiovasc Med (2017) — EETs and cardiovascular disease](https://pubmed.ncbi.nlm.nih.gov/28159570/)

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📊 Evidence Profile Foundational

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📗 Cite This Artifact

Alzheimer's Disease Soluble Epoxide Hydrolase (sEH) Inhibitor Companies

Overview

Overview

Mechanism of Action

Therapeutic Rationale for Alzheimer's Disease

Key Companies

GlaxoSmithKline (GSK) — GSK2256294

EicOsis — EC 1728 and EC 5026

Arete Therapeutics — UC1153 (AR9281)

Pfizer — sEH Inhibitor Research

Merck & Co. / Merck KGaA — sEH Targeting

AbbVie — EET Signaling Modulation

Bristol Myers Squibb — Cardiovascular-Cerebral Cross-Talk

Research Landscape

Academic and Preclinical Groups

Clinical Trial Landscape

Challenges and Opportunities

Pipeline Summary

Mechanisms

Therapeutic Pages

References

💬 Discussion

📗 Cite This Artifact

Alzheimer's Disease Soluble Epoxide Hydrolase (sEH) Inhibitor Companies

Overview

Overview

Mechanism of Action

Therapeutic Rationale for Alzheimer's Disease

Key Companies

GlaxoSmithKline (GSK) — GSK2256294

EicOsis — EC 1728 and EC 5026

Arete Therapeutics — UC1153 (AR9281)

Pfizer — sEH Inhibitor Research

Merck & Co. / Merck KGaA — sEH Targeting

AbbVie — EET Signaling Modulation

Bristol Myers Squibb — Cardiovascular-Cerebral Cross-Talk

Research Landscape

Academic and Preclinical Groups

Clinical Trial Landscape

Challenges and Opportunities

Pipeline Summary

Related Pages

Mechanisms

Related Company Categories

Therapeutic Pages

References

💬 Discussion