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
[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
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
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
[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/)