Related Experiment Video
Updated: Jun 7, 2025

Oropharyngeal Administration of Bleomycin in the Murine Model of Pulmonary Fibrosis
Published on: May 9, 2025
Discovery of Selective PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects by Targeting the Metal Pocket
Mei-Yan Jiang1, Chen Zhang2, Qing-Hua Huang1
1State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Abstract:
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no ideal drugs. Our previous research demonstrated that phosphodiesterase 1 (PDE1) could be a promising target for the treatment of IPF. However, only a few selective PDE1 inhibitors are available, and the mechanism of recognition between inhibitors and the PDE1 protein is not fully understood. This study carried out a step-by-step optimization of a dihydropyrimidine hit Z94555858. By targeting the metal pocket of PDE1, a lead compound 3f was obtained, exhibiting an IC50 value of 11 nM against PDE1, moderate selectivity over other PDEs, and significant anti-fibrotic effects in bleomycin-induced pulmonary fibrosis rats. The structure-activity relationship study aided by molecular docking revealed that forming halogen bonds with water in the metal pocket greatly enhanced the PDE1 inhibition, providing a novel strategy for further rational design of PDE1 inhibitors.
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