Discovery of Selective PDE1 Inhibitors Alleviating Pulmonary Fibrosis by the Regulation of TGF-β/Smads and MAPK Pathways

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease with limited treatment options. Our preliminary research identified phosphodiesterase 1 (PDE1) as a potential therapeutic target for IPF treatment. However, both the molecular recognition mechanism between PDE1 inhibitors and the protein, as well as the antifibrotic mechanism, remain incompletely understood. In this study, structural modifications were carried out on a pan-PDE inhibitor 1 we previously developed. The lead compound 4b exhibited an IC₅₀ of 5 nM against PDE1, excellent selectivity across PDE subfamilies and favorable safety properties. Structure-activity relationship analysis combined with binding mode predictions demonstrated that targeting differential residues in the H-loop regions of PDEs is critical for improving selectivity over other PDEs. Furthermore, we demonstrated that the PDE1 inhibitor attenuated pulmonary fibrosis by suppressing both the TGF-β/Smad and MAPK pathways.