Novel EP2 Antagonist Attenuates Microgliosis and Memory Deficits in Pilocarpine-Induced Status Epilepticus Mice

EP2 receptors promote neuroinflammation in several central nervous system diseases including status epilepticus (SE). Our laboratory has been optimizing selective small-molecule antagonists for EP2 receptors to determine their functional role in neuropathology and behavioral deficits in SE models, with a goal of developing an EP2 antagonist for clinical use. Through lead-optimization, we identified a novel brain- penetrant compound BPN-37440, which possesses excellent EP2 potency, selectivity against other prostanoid receptors, demonstrates anti-inflammatory actions in the BV2-hEP2 cellular model, and exhibits suitable in vitro ADME and in vivo PK properties. A brief exposure of BPN-37440 after SE onset in mice attenuated microgliosis in the amygdala, cortex, and hippocampus CA3 region 4 days following recovery from SE. Moreover, memory deficits were prevented in mice at 1-1.5 months following SE. The results validate the notion that neuroinflammation promoted by EP2 exacerbates behavioral deficits, supporting further exploration of EP2 antagonists in the clinical setting.