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. [1]
sEH inhibitors work through the arachidonic acid-CYP450 epoxygenase-EETs-sEH signaling axis:
| Pathological Target | sEH Inhibitor Effect | Relevance to AD |
|---|---|---|
| Chronic neuroinflammation | EET-mediated NF-κB inhibition, microglial modulation | [3] |
| Cerebrovascular dysfunction | Improved cerebral blood flow, endothelial protection | [4] |
| Blood-brain barrier disruption | Preserved BBB integrity via EET signaling | [@w2021] |
| Neuronal injury | Reduced oxidative stress, anti-apoptotic effects | [5] |
| Vascular cognitive impairment | Cardiovascular-cerebral cross-talk improvement | [4:1] |
| Protein aggregation | Indirect modulation of amyloid/tau pathology | [6] |
GlaxoSmithKline (GSK) has developed GSK2256294, a potent and selective sEH inhibitor that has completed Phase I clinical trials.
Compound: GSK2256294
Development Status:
Alzheimer's Disease Potential:
EicOsis is a biotechnology company developing sEH inhibitors for chronic pain and diabetic neuropathy, with potential extension to neurodegenerative diseases.
Lead Compounds:
Alzheimer's Disease Potential:
Arete Therapeutics developed UC1153 (also known as AR9281), an sEH inhibitor that reached Phase IIa clinical trials.
Compound: UC1153 (AR9281)
Development Status:
Alzheimer's Disease Potential:
Pfizer has explored sEH inhibitors in their cardiovascular and neuroscience pipelines.
Related Programs:
Alzheimer's Disease Potential:
Merck & Co. and Merck KGaA have explored sEH as a therapeutic target.
Related Programs:
Alzheimer's Disease Potential:
AbbVie has interest in lipid mediator modulation for neurodegenerative diseases.
Related Programs:
Alzheimer's Disease Potential:
Bristol Myers Squibb has explored sEH inhibitors for cardiovascular indications.
Related Programs:
Alzheimer's Disease Potential:
| Institution | Focus Area | Key Research |
|---|---|---|
| University of California Davis | sEH in neurodegeneration | [1:1] |
| National Taiwan University | sEH deficiency and cerebral blood flow | [6:1] |
| Kyoto University | sEH in microglial responses | [3:1] |
| University of Tokyo | sEH as therapeutic target | [5:1] |
| Stanford University | EETs and cognitive function | [4:2] |
| Cleveland Clinic | EETs in neuroinflammation | [2:1] |
As of 2026, no sEH inhibitors have reached late-stage clinical trials for Alzheimer's disease. The development landscape includes:
Challenges:
Opportunities:
| 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 |
Soluble epoxide hydrolase: a potential therapeutic target for neurodegenerative diseases. Neural Regeneration Research. 2020. ↩︎ ↩︎
Epoxyeicosatrienoic acids and soluble epoxide hydrolase in neuropsychiatric disease. Prostaglandins Other Lipid Mediat. 2020. ↩︎ ↩︎
Soluble epoxide hydrolase in microglial responses and neurodegeneration. Neurosci Lett. 2019. ↩︎ ↩︎
Role of epoxyeicosatrienoic acids in cerebral blood flow regulation and vascular cognitive impairment. J Neurol Neurophysiol. 2013. ↩︎ ↩︎ ↩︎
Soluble epoxide hydrolase as a therapeutic target for neurodegenerative diseases. Int J Mol Sci. 2022. ↩︎ ↩︎
Soluble epoxide hydrolase deficiency improves cerebral blood flow and reduces neuroinflammation in Alzheimer's disease. J Neuroinflammation. 2018. ↩︎ ↩︎