Discovery of HW201877: 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-1H-cyclopropa[c][1,8]naphthyridine derivatives as potential 15-PGDH inhibitors. HW201877 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, HW201877 demonstrated notable therapeutic efficacy in murine models of inflammatory bowel disease (IBD) and idiopathic pulmonary fibrosis (IPF). These findings establish HW201877 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.