Discovery and Optimization of Chromeno[2,3-c]pyrrol-9(2H)-ones as Novel Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension
Discovery and Optimization of Chromeno[2,3-c]pyrrol-9(2H)-ones as Novel Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension
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发现和优化 Chromeno[2,3-c]pyrrol-9(2H)-ones 作为新型选择性和口服生物可利用的磷酸二酯酶 5 抑制剂，用于治疗肺动脉高压。
DOI：
10.1021/acs.jmedchem.7b00523
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发表时间：
2017-08-10
影响因子：
7.3
通讯作者：
Luo, Hai-Bin
中科院分区：
文献类型：
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作者：
Wu, Deyan;Zhang, Tianhua;Luo, Hai-Bin
磷酸二酯酶 5 (PDE5) 抑制剂已被用作治疗勃起功能障碍和肺动脉高压 (PAH) 的临床药物。在此，我们详细介绍了一系列新型色并[2,3-c]吡咯-9(2H)-one衍生物作为磷酸二酯酶5的选择性和口服生物利用度抑制剂的发现。药物化学优化产生了2，它表现出5.6 nM的理想抑制效力，具有显着的选择性以及优异的药代动力学特性，口服生物利用度为63.4%。此外，口服2的5.0 mg/kg剂量对mPAP（平均肺动脉压）和RVHI（右心室肥厚指数）的药效学效果优于10.0 mg/kg剂量的枸橼酸西地那非。这些活性及其合理的药物特性，如人肝微粒体稳定性、细胞色素抑制、hERG 抑制和药理学安全性，表明 2 是治疗 PAH 的潜在候选者。
Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63.4%. In addition, oral administration of 2 at a dose of 5.0 mg/kg caused better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate at a dose of 10.0 mg/kg. These activities along with its reasonable druglike properties, such as human liver microsomal stability, cytochrome inhibition, hERG inhibition, and pharmacological safety, indicate that 2 is a potential candidate for the treatment of PAH.