Small molecule inhibitors of 15-prostaglandin dehydrogenase promote tissue repair and regeneration

Abstract: Prostaglandin E2 promotes tissue repair and regeneration in multiple tissues. Small molecule inhibitors of the PGE2-degrading enzyme, 15-prostaglandin dehydrogenase, could elevate PGE2 levels in vivo with applications in multiple disease contexts. We have discovered two chemical series of enzyme inhibitors. Medicinal chemistry efforts have led to sub-nM inhibitors with excellent bioavailability and physicochemical properties. Lead compounds demonstrate activity in mouse models of inflammatory bowel disease, recovery from bone marrow transplantation, and neurodegeneration.