# EP2 Antagonist Development for Post-seizure Cognitive Deficits

> **NIH NIH UG3** · EMORY UNIVERSITY · 2020 · $475,368

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Dingledine, Ray
Abstract
Epilepsy, the 4th most prevalent neurological disorder after stroke, Alzheimer's and migraine with an
incidence of 1 in 26 individuals, 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
synthesized and tested >500 compounds as competitive antagonists of the human EP2 receptor, and
demonstrated in vivo efficacy in three animal models of epilepsy. We now wish to progress one of our EP2
antagonists, TG11-77HCl, through phase 1 clinical trials. This compound, TG11-77HCl, is potent (Schild Kb
10 nM against EP2), >300-fold selective against the other eight prostanoid receptors, orally active with
acceptable plasma half-life (2.4 hr) and brain-to plasma ratio (0.4) in mice. The SAR for potency and selectivity
are well understood. Our compounds show therapeutic efficacy in rodent models of seizure-induced brain
injury and memory deficits, and lack common forms of toxicity after 30 days exposure to doses higher than the
efficacious dose. The compound series is protected by three awarded and two pending patents. In specific aim
1 we will complete all requirements to enter the Development phase. In specific aim 2 we will submit an IND. In
specific aim 3 both single and multiple ascending dose phase 1 clinical trials will be completed. Successful
completion of this project would lay the groundwork for the first 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.
OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page

## Key facts

- **NIH application ID:** 9869538
- **Project number:** 1UG3NS113879-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** RAYMOND J DINGLEDINE
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $475,368
- **Award type:** 1
- **Project period:** 2020-01-15 → 2022-01-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869538

## Citation

> US National Institutes of Health, RePORTER application 9869538, EP2 Antagonist Development for Post-seizure Cognitive Deficits (1UG3NS113879-01). Retrieved via AI Analytics 2026-06-07 from https://api.ai-analytics.org/grant/nih/9869538. Licensed CC0.

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