# Development of EP2 Receptor Antagonist to Treat Alzheimer's Disease

> **NIH NIH U01** · EMORY UNIVERSITY · 2024 · $1,737,244

## Abstract

Lay Summary
Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Currently, about 6.5 million
Americans are living with AD. Alzheimer’s and other dementias are estimated to cost the US $321 billion per
year and this number is expected to 1 trillion by 2050, yet no small molecule therapeutic agent on the horizon
that clearly alters the disease progression and inevitable cognitive decline. The small molecule drugs and
anti-bodies that have been developed based on the amyloid cascade hypothesis showed a limited (if any)
disease modifying benefit so far. Thus, it would be very important to validate novel drug targets and small
molecules that work through a novel mechanism of action for future AD therapy. Neuroinflammation is
recognized as a key phenotype in the AD brain that is associated with the development of dementia.
Prostaglandin-E2 receptor EP2, which acts downstream of complex signaling by cyclooxygenase-2 (COX-2)
appears as a key driver of neuroinflammation. Activation of this receptor further induces COX-2 creating a
vicious reactive cycle in the brain. We have recently developed a suite of small-molecule antagonists for this
receptor and derived a proof-of-concept in 5xFAD mouse models demonstrating antagonism of EP2
attenuates neuroinflammation and the amyloid load in the brain. Moreover, we have validated that EP2
receptor antagonism is associated with cognition sparing benefits in acute brain injury models of status
epilepticus and a peripheral inflammatory sepsis model. We have identified several preclinical lead
candidates for development into a clinical lead and candidate drug to mitigate neuroinflammation and
cognitive deficits in Alzheimer’s patients. We now propose to define PK/PD relations of the lead EP2
antagonists on Alzheimer’s pathology markers in the brain and determine PK/PD relation on the AD relevant
biomarkers in the blood (plasma), CSF and the brain tissue in two different mouse (5xFAD and APPSAA)
models that that display features of early-onset of AD (EOAD) and late-onset of AD (LOAD) in human.
Furthermore, we proposed to conduct drug development studies to determine therapeutic index and NOAEL
for the lead EP2 antagonist and complete all other IND-enabling studies required by the FDA. Our overall
goal is to achieve a disease modifying efficacy by the EP2 drug that delays the progression of Alzheimer’s
dementia at least by 5 years. We envision 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
that will bypass the adverse cardiovascular events found with chronic dosing of COX-2 drugs.

## Key facts

- **NIH application ID:** 10944958
- **Project number:** 1U01AG088113-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Thota Ganesh
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,737,244
- **Award type:** 1
- **Project period:** 2024-09-20 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10944958

## Citation

> US National Institutes of Health, RePORTER application 10944958, Development of EP2 Receptor Antagonist to Treat Alzheimer's Disease (1U01AG088113-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10944958. Licensed CC0.

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