Prostaglandin E receptor 3 (EP3) is a Gi-coupled class-A G-protein coupled receptor (GPCR) that is activated by its endogenous agonist PGE2. EP3 antagonists have been studied for treating several clinical indications such as thrombosis, cardiovascular disease, and type-2 diabetes. The majority of previously reported EP3 antagonists are acidic with high molecular weight and lipophilicity (molecular weight &gt;500, cLogP&gt;5), while recent publications indicate that neutral EP3 antagonists within the rule of five space can be identified for this target. This presentation will describe the optimization of neutral EP3 antagonists based on the lactam scaffold, ultimately leading to the discovery of a potent and selective EP3 antagonist PF-06748962. Rigorous property-based optimizations translated into several candidate-quality attributes of PF-06748962, including good ADME/safety profile and high lipophilic efficiency. The presentation will also highlight cases where relatively minor structural changes within the same chemical series led to dramatic improvements in potency and in vivo safety profile.

Discovery of PF-06748962: A potent and selective lactam-based EP3 antagonist

253rd National Meeting (2017)

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