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.