Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bleomycin
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Cell Differentiation / drug effects
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Cyclic Nucleotide Phosphodiesterases, Type 1 / metabolism*
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Drug Design
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Humans
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Idiopathic Pulmonary Fibrosis / chemically induced
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Idiopathic Pulmonary Fibrosis / drug therapy*
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Idiopathic Pulmonary Fibrosis / pathology
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Lung / pathology
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Male
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Molecular Structure
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Myofibroblasts / drug effects
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / metabolism
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Phosphodiesterase Inhibitors / pharmacokinetics
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Phosphodiesterase Inhibitors / therapeutic use*
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Protein Binding
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Pyrazoles / chemical synthesis
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Pyrazoles / metabolism
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Pyrazoles / pharmacokinetics
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Pyrazoles / therapeutic use*
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Pyrimidinones / chemical synthesis
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Pyrimidinones / metabolism
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Pyrimidinones / pharmacokinetics
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Pyrimidinones / therapeutic use*
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Thermodynamics
Substances
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Phosphodiesterase Inhibitors
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Pyrazoles
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Pyrimidinones
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Bleomycin
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Cyclic Nucleotide Phosphodiesterases, Type 1