2. Academic Validation
  3. Discovery of Selective PDE1 Inhibitors Alleviating Pulmonary Fibrosis by the Regulation of TGF-β/Smads and MAPK Pathways

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

  • J Med Chem. 2025 Sep 11;68(17):18423-18435. doi: 10.1021/acs.jmedchem.5c01238.
Mei-Yan Jiang 1,  Qian Zhou 2,  Xiao-Long Tian 1,  Jia-Ning Zhang 1 3,  Zhao-Hang Xue 4,  Chen Zhang 4,  Hai-Bin Luo 2,  Yinuo Wu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China.
  • 2 Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, P. R. China.
  • 3 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
  • 4 School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, P. R. China.
PMID: 40844145 DOI: 10.1021/acs.jmedchem.5c01238
Abstract

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.

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