Structure–activity relationship studies of novel 3-oxazolidinedione-6-naphthyl-2-pyridinones as potent and orally bioavailable EP3 receptor antagonists

Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP3 receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed.

Graphical abstract3-Oxazolidinedione-6-napthyl-2-pyridinones are presented as novel and subtype selective EP3 antagonists. The synthesis and extensive SAR that led to the discovery of compound 29 are described.Figure optionsDownload full-size imageDownload as PowerPoint slide