Prostanoid receptor EP2 has emerged as important contributor to the neuroinflammation in acute and chronic neurodegenerative diseases including status epilepticus (SE), traumatic brain injury (TBI) and Alzheimer’s disease (AD). Upon brain injury, the inducible cyclooxygenase-2 (COX-2) synthesizes five prostanoid ligands (PGE2, PGD2, PGF2, PGI2, and TxA2), Among these, PGE2 activates EP2 receptor to promote cAMP-mediated cell signaling pathways. Recently, we and others have hypothesized and demonstrated that EP2 receptor will carry-forward major inflammatory pathway that is mediated through COX-2, and targeting EP2 with small molecule can provide therapeutics that can bypass the adverse cardiovascular events found with the use of COX-2 inhibitors. Our laboratory has identified a novel class of EP2 inhibitors recently beginning HTS-screening and then SAR studies. We investigated further lead-optimization studies on the recently developed EP2 antagonists with a goal to improve ADME-PK and to determine the in vivo PK/PD efficacy in an acute brain injury model. A fleeting exposure of the lead candidate EP2 antagonist BPN-30343 in a pilocarpine induced-SE mouse model resulted not only the suppression of inflammation in dose-dependent manner, but also the cognitive deficits determined by Y-maze test. This novel candidate has shown several promising attributes including Ames negativity, non-significant hERG and off-target activity across panel of 50 enzymes and receptors and is currently going through a number non-GLP tests towards IND enabling studies. I will present the characterization of EP2 receptor antagonist using in vitro and in vivo models, PK/PD and non-GLP tox studies (all of these are unpublished so far) to conclude EP2 serves as a novel and alternative target for development of therapeutics for several CNS diseases.

EP2 receptor antagonist alleviates post seizure cognitive deficits

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