The EP2 receptor plays an important role in microglial stimulation, and studies have suggested it contributes to neurodegeneration. EP2 knockout mice show an increase in microglial A� phagocytosis and a reduction in amyloid plaques is observed in APP overexpressing mice with EP2 deletion.We have discovered EP2 antagonists that dramatically increase phagocytosis of A� plaques in a dose dependent manner using A�-containing brain slices and mouse macrophages. We optimized an HTS lead with moderate EP2 potency and poor pharmacokinetic properties to provide an extremely potent and selective human EP2 antagonist (Ki = 8 nM, > 1500-fold selectivity over EP1, EP3, EP4, IP and DP) with good pharmacokinetic properties and excellent CNS permeability.

Selective EP2 antagonists for the treatment of Alzheimer's disease

243rd National Meeting (2012)

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