# Optimization of EP2 Antagonists for Post-Seizure Cognitive Deficits

> **NIH NIH UH3** · EMORY UNIVERSITY · 2024 · $648,477

## Abstract

Lay Summary
Epilepsy, the 4th most prevalent neurological disorder after stroke, Alzheimer’s and migraine, is often
accompanied by cognitive deficits. Cognitive comorbidities substantially reduce quality of life in people with
epilepsy. Although a number of anti-seizure drugs are available, no approved drugs mitigate either the cognition
problems or progression of the disease. Inflammation is a component of all chronic diseases including epilepsy,
and is the consequence of several broad signaling cascades including cyclooxygenase-2 (COX-2). We have
shown that activation of the EP2 receptor for prostaglandin E2 is responsible for blood-brain barrier leakage and
much of the inflammatory reaction, neuronal injury and cognitive deficit that follows seizure-provoked COX-2
induction in brain. We have earlier synthesized and tested >500 compounds as competitive antagonists of the
human EP2 receptor, and demonstrated in vivo efficacy with two research lead compounds in three animal
models of epilepsy. In a recent UG3 project, we investigated the candidate development activities on a lead EP2
antagonist BPN30343 (TG11-77.HCl). However, it showed two weaknesses in ADMET assays. Therefore, we
now propose to conduct additional discovery phase lead-optimization studies to identify an EP2 antagonist
candidate to promote for IND-enabling studies. In specific aim 1 (UG3), we will test recently synthesized 13 novel
EP2 antagonists for key ADMET tests to select up to 3 compounds that have requisite pharmacokinetics in dogs.
If shortcomings are found in Aim 1, we will do lead-optimization studies in Aim 2 (UH3 phase) on backup EP2
antagonist scaffolds to develop 3 novel compounds for efficacy and preclinical testing. In Aim 3, we confirm the
efficacy of the lead EP2 antagonist in rat model of status epilepticus and identify formulation that allows us to
conduct DRF-pharmacokinetic and DRF-toxicokinetic studies in rat and dog. The deliverable of the UH3 phase
is a development candidate compound and its backup (s) for the clinical test of the hypothesis that EP2 receptor
modulation after seizures can provide the first preventive treatment for one of the chief comorbidities of epilepsy.

## Key facts

- **NIH application ID:** 10877946
- **Project number:** 5UH3NS127386-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Thota Ganesh
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $648,477
- **Award type:** 5
- **Project period:** 2022-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877946

## Citation

> US National Institutes of Health, RePORTER application 10877946, Optimization of EP2 Antagonists for Post-Seizure Cognitive Deficits (5UH3NS127386-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10877946. Licensed CC0.

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