Discovery of Non-prostanoid EP4 Agonists for the Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic autoimmune disease typified by disruption of the intestinal epithelium. The prostaglandin E2 receptor EP4 is linked to intestinal homeostasis, wound repair, and immune cell activation, and EP4 agonists hold promise as a novel treatment for IBD via a tissue repair mechanism. A high-throughput screening campaign resulted in the discovery of a non-prostanoid, selective EP4 agonist chemotype, which was optimized through structure-activity relationship (SAR) studies. Lead compound 11a was profiled in a mouse pharmacokinetic study and demonstrated efficacy in a mouse model of IBD. Blood exposure of 11a was shown to induce hemodynamic changes in mouse, a known on-target effect of EP4 agonists in systemic circulation. High-throughput mutagenesis studies and computational modeling indicate that this series of agonists binds orthosterically to the PGE2 site in the EP4 receptor despite structural differentiation from prostanoids.