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.