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Discovery of Novel Selective and Orally Bioavailable Phosphodiesterase‑1 Inhibitors for the Efficient Treatment of Idiopathic Pulmonary Fibrosis

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journal contribution
posted on 30.06.2020, 20:14 by Yinuo Wu, Yi-Jing Tian, Mei-Ling Le, Si-Rui Zhang, Chen Zhang, Meng-Xing Huang, Mei-Yan Jiang, Bei Zhang, Hai-Bin Luo
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disease lacking effective therapy. To identify whether phosphodiesterase-1 (PDE1) inhibition could act as a novel target for the treatment of IPF, hit-to-lead structural optimizations were performed on the PDE9/PDE1 dual inhibitor (R)-C33, leading to compound 3m with an IC50 of 2.9 nM against PDE1C, excellent selectivity across PDE subfamilies, reasonable drug-like properties, and remarkable pharmacodynamic effects as an anti-IPF agent. Oral administration of compound 3m (10 mg/kg) exerted more significant anti-pulmonary fibrosis effects than pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model and prevented transforming growth factor-β-induced fibroblast-to-myofibroblast conversion in vitro, indicating that PDE1 inhibition could serve as a novel target for the efficient treatment of IPF.