Mangostanin Derivatives as Novel and Orally Active Phosphodiesterase 4 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis with Improved Safety
| Autor: | Qian Zhou, Xixin He, Yi-Jing Tian, Jiaqi Zhu, Jinhao Liang, Yue Huang, Ziran Zhu, Yi-You Huang, Jinhui Deng, Hai-Bin Luo, Xi Xie |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Epithelial-Mesenchymal Transition Nausea Pharmacology Heterocyclic Compounds 4 or More Rings Rats Sprague-Dawley Structure-Activity Relationship Idiopathic pulmonary fibrosis Dogs Fibrosis Oral administration Drug Discovery medicine Animals Humans Lung IC50 Roflumilast Rolipram Molecular Structure Chemistry Pirfenidone medicine.disease Idiopathic Pulmonary Fibrosis Cyclic Nucleotide Phosphodiesterases Type 4 A549 Cells Molecular Medicine Phosphodiesterase 4 Inhibitors medicine.symptom Protein Binding medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 64:13736-13751 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c01085 |
| Popis: | Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, and its incidence rate is rapidly rising. However, effective therapies for the treatment of IPF are still lacking. Phosphodiesterase 4 (PDE4) inhibitors were reported to be potential anti-fibrotic agents, but their clinical use was hampered by side effects like emesis and nausea. Herein, structure-based hit-to-lead optimizations of natural mangostanin resulted in the novel and orally active PDE4 inhibitor 18a with potent inhibitory affinity (IC50 = 4.2 nM), favorable physico-chemical properties, and a different binding pattern from roflumilast. Emetic activity tests on dogs demonstrated that 18a cannot cause emesis even at an oral dose of 10 mg/kg, whereas rolipram had severe emetic effects at an oral dose of 1 mg/kg. Finally, the oral administration of 18a (10 mg/kg) exhibited comparable anti-pulmonary fibrosis effects with pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model, indicating its potential as a novel anti-IPF agent with improved safety. |
| Databáze: | OpenAIRE |
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