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.
Ganesh et al. (Wed,) studied this question.