# Development of EP2 receptor antagonists for suppression of Alzheimer's neuropathology

> **NIH NIH U01** · EMORY UNIVERSITY · 2020 · $214,285

## Abstract

Lay Summary
Alzheimer's disease (AD), a neurodegenerative disorder, is a leading cause of dementia in elderly. AD leads to
progressive loss of cognitive functions. Currently about 5.4 million Americans (1 in 8 persons 65 or older) are living
with AD, and the number is expected to triple by the year 2050. Approximately $200 billion per year is spent on all
aspects of caring for AD patients, yet there is no therapy on the horizon that clearly alters the disease progression and
inevitable cognitive decline. The small molecule drugs that have been developed based on amyloid cascade hypothesis
have not shown a clear clinical benefit so far. Thus it would be very important to focus on identification of novel drug
targets and small molecules that work through novel mode of biological action for future AD therapy.
COX-2 levels are increased at the early stage of AD, and its levels are correlated with levels of A-peptides. Clinical
studies suggest that COX-2 inhibitors may be useful as preventative for AD if they were given at asymptomatic stage of
the disease, but they may offer little or no benefit to clinically diagnosed patients with cognitive deficits. However,
chronic use of COX-2 drugs (examples, Vioxx and Bextra) resulted in adverse cardiovascular events, which is worrying
for the AD patients who already are at increased risk for heart disease. Thus, future use of COX-2 drugs on patients will
be limited. COX-2 catalyzes the first-step towards synthesis of five prostaglandins; PGD2, PGE2, PGF2, PGI2, and TxA2,
which activate eleven prostanoid receptors, DP1, DP2, EP1, EP2, EP3, EP4, FPα, , IP and TPα,  respectively. We
hypothesize that targeting EP2, a specific prostanoid receptor downstream of COX-2, rather than a generic block of the
entire COX-2 signaling is a superior therapeutic strategy for AD with an EP2 specific antagonist. In this study, we
propose to develop an EP2 selective antagonist, to demonstrate a proof of concept whether EP2 antagonist suppresses
inflammation, neurodegeneration and cognitive deficits in 5XFAD model of AD, and to establish a preliminary safety
package for using EP2 drugs potentially on AD patients.

## Key facts

- **NIH application ID:** 9972213
- **Project number:** 3U01AG052460-04S1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Thota Ganesh
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $214,285
- **Award type:** 3
- **Project period:** 2016-09-15 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972213

## Citation

> US National Institutes of Health, RePORTER application 9972213, Development of EP2 receptor antagonists for suppression of Alzheimer's neuropathology (3U01AG052460-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9972213. Licensed CC0.

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