In vitro activity: TG6-10-1 is a cell-permeable, highly potent, selective, and competitive antagonist of prostaglandin E2 receptor (EP2) with Kb of 17.8 nM. TG6-10-1 has sufficient pharmacokinetic profiles to be used in vivo. In the mouse pilocarpine model of status epilepticus (SE), systemic administration of TG6-10-1 completely recapitulates the effects of conditional ablation of cyclooxygenase-2 from principal forebrain neurons, namely reduced delayed mortality, accelerated recovery from weight loss, reduced brain inflammation, prevention of blood-brain barrier opening, and neuroprotection in the hippocampus, without modifying seizures acutely. Prolonged SE in humans causes high mortality and morbidity that are associated with brain inflammation and injury, but currently the only effective treatment is to stop the seizures quickly enough with anticonvulsants to prevent brain damage. The results suggest that the prostaglandin receptor EP2 is critically involved in neuroinflammation and neurodegeneration, and point to EP2 receptor antagonism as an adjunctive therapeutic strategy to treat SE.

Kinase Assay: TG6-10-1 is a cell-permeable, highly potent, selective, and competitive antagonist of prostaglandin E2 receptor (EP2) with Kb of 17.8 nM.

Cell Assay: