# Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease

> **NIH NIH U01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $1,809,984

## Abstract

ABSTRACT
 Alzheimer’s disease (AD) is the most common cause of dementia and one of the leading causes of death in
the United States. AD is the only leading cause of death for which no disease-modifying therapy is currently
available. Neuroinflammation plays a major role in AD pathogenesis. Epoxyeicosanoid signaling is a key
integrator of cell-cell communication in the central nervous system (CNS), coordinating cellular responses across
different cell types. Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites of cytochrome P450
epoxygenase that have potent anti-inflammatory activity. In our preliminary study, we demonstrated that
pharmacological inhibition of sEH can attenuate neuroinflammation, enhance reduction of plaque pathology, and
eventually reverse spatial learning and memory deficits in preclinical models of AD. Although some sEH inhibitors
(sEHIs) have been reported, none of them are optimized for CNS applications. Blood brain barrier (BBB) is the
main hurdle for CNS drug development. Taking advantage of high throughput virtual screening and medicinal
chemistry optimization, we developed EHI-16 as a highly potent, orally available and brain permeable sEHI.
Additionally, EHI-16 reduces LPS-induced neuroinflammation in both primary astrocytes and in vivo. In this
project, we will further optimize EHI-16 to develop anti-inflammation therapy for AD treatment. To this end, we
assembled a highly motivated and experienced team with complementary expertise. Dr. Wang is an expert on
small molecule drug discovery and ADMET profiling. Dr. Zheng is a pioneer on AD pathophysiology and mouse
modeling. Our expertise, highly promising preliminary data, and proven collaboration track-record will ensure the
success of the proposed project. In Aim 1, we will develop potent, orally available, and CNS-penetrable sEHIs.
In Aim 2, we will determine the pharmacokinetics-pharmacodynamics relationship of sEHIs and in vivo efficacy
in attenuating neuroinflammation and improving cognitive impairment in AD mouse models. In Aim 3, we will
determine the toxicity and PK profile of sEHIs in rats and dogs and perform IND-enabling studies. The successful
accomplishment of this project will open a new avenue for treating and preventing AD and will advance our
scientific knowledge of multiple mechanisms of AD.

## Key facts

- **NIH application ID:** 10032662
- **Project number:** 1U01AG068031-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Jin Wang
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,809,984
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10032662

## Citation

> US National Institutes of Health, RePORTER application 10032662, Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease (1U01AG068031-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10032662. Licensed CC0.

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