Discovery of : A Highly Potent and Orally Bioavailable Inhibitor of 15-Prostaglandin Dehydrogenase to Potentiate Tissue Repair and Regeneration.

Prostaglandin E2 (PGE2), a crucial lipid mediator governing tissue stem cell expansion and regeneration, represents a promising therapeutic target for tissue repair. Based on the premise that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the principal enzyme responsible for PGE2 catabolism, could enhance endogenous PGE2 levels and accelerate tissue regeneration, we rationally designed and synthesized a novel series of tetrahydro-1-cyclopropa[c][1,8]naphthyridine derivatives as potential 15-PGDH inhibitors. was identified as the lead candidate, demonstrating exceptional enzymatic inhibition (IC50 = 3.6 nM) and robust cellular efficacy in elevating PGE2 levels in A549 cells (4.8-fold increase vs control). Crucially, with favorable pharmacokinetic profiles, demonstrated notable therapeutic efficacy in murine models of inflammatory bowel disease (IBD) and idiopathic pulmonary fibrosis (IPF). These findings establish as a promising clinical candidate targeting 15-PGDH with therapeutic potential for treating IBD and IPF, providing a novel pharmacological strategy for tissue regeneration therapy.