Mangostanin Derivatives as Novel and Orally Active Phosphodiesterase 4 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis with Improved Safety,Journal of Medicinal Chemistry

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Mangostanin Derivatives as Novel and Orally Active Phosphodiesterase 4 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis with Improved Safety
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-09-14 , DOI: 10.1021/acs.jmedchem.1c01085
Yi-You Huang _{1,

2} , Jinhui Deng ₃ , Yi-Jing Tian ₂ , Jinhao Liang ₃ , Xi Xie ₁ , Yue Huang ₂ , Jiaqi Zhu ₃ , Ziran Zhu ₁ , Qian Zhou ₂ , Xixin He ₃ , Hai-Bin Luo _{1,

2}

Affiliation

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.

中文翻译：

山竹素衍生物作为新型口服活性磷酸二酯酶 4 抑制剂，用于治疗特发性肺纤维化并提高安全性

特发性肺纤维化（IPF）是一种进行性肺部疾病，其发病率正在迅速上升。然而，仍然缺乏治疗IPF的有效疗法。据报道，磷酸二酯酶 4 (PDE4) 抑制剂是潜在的抗纤维化药物，但其临床应用受到呕吐和恶心等副作用的阻碍。在此，对天然山竹素进行基于结构的命中先导优化，产生了新型口服活性 PDE4 抑制剂18a ，其具有强大的抑制亲和力 (IC ₅₀ = 4.2 nM)、良好的理化性质以及与罗氟司特不同的结合模式。对狗的催吐活性试验表明，即使口服剂量为10mg/kg， 18a也不会引起呕吐，而咯利普兰在口服剂量为1mg/kg时有严重的催吐作用。最后，在博来霉素诱导的 IPF 大鼠模型中，口服18a （10 mg/kg）表现出与吡非尼酮（150 mg/kg）相当的抗肺纤维化作用，表明其作为安全性更高的新型抗 IPF 药物的潜力。

更新日期：2021-09-23

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