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
Dingledine, Ray Proposal narrative Epilepsy is a highly prevalent neurological disorder that is frequently associated with psychiatric and neurologic comorbidities, such as difficulty with memory, which degrade the quality of life. We have developed novel anti- inflammatory drug-like compounds that target the EP2 receptor for prostaglandin E2, the major mediator of inflammation driven by cyclooxygenase 2. We have carried out extensive testing, in vitro and in animal models of epilepsy, of a battery of novel EP2 inhibitors and now propose to take one of these compounds through FDA-mandated safety tests and then complete phase 1 clinical safety trials. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page