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.