Phosphodiesterase 5 (PDE5) is a cGMP-specific hydrolytic enzyme and widely distributed in versatile tissues. PDE5 has been identified as a valid therapeutic target for treating erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, a hit-to-lead structural optimizations were performed on the PDE1 inhibitor 10c, leading to compound 14b possessing great potency against PDE5A (IC₅₀ = 3 nM) with high selectivity over PDE1, PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11 by more than 1125-fold, and remarkable safety properties. Furthermore, oral administration of 14b (5.0 mg/kg) exerted much better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate (10.0 mg/kg) in a monocrotaline-induced PAH rat model. Overall, these results proposed a novel highly selective PDE5 inhibitor 14b which could serve as a potential candidate for treatment of PAH.

中文翻译：

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二氢喹啉-2（1H）-酮作为新型高选择性和口服生物可利用度的磷酸二酯酶 5 抑制剂治疗肺动脉高压的发现和优化


磷酸二酯酶 5 （PDE5） 是一种 cGMP 特异性水解酶，广泛分布在多种组织中。PDE5 已被确定为治疗勃起功能障碍和肺动脉高压 （PAH） 的有效治疗靶点。在此，对 PDE1 抑制剂 10c 进行了从头化合物到先导化合物的结构优化，导致化合物 14b 对 PDE5A 具有很强的效力 （IC₅₀ = 3 nM），对 PDE1、PDE2、PDE3、PDE4、PDE7、PDE8、PDE9、PDE10 和 PDE11 具有 1125 倍以上的选择性，并具有显著的安全性能。此外，在野百合碱诱导的 PAH 大鼠模型中，口服 14b （5.0 mg/kg） 对 mPAP （平均肺动脉压） 和 RVHI （右心室肥大指数） 的药效学效应比枸橼酸西地那非 （10.0 mg/kg） 好得多。总体而言，这些结果提出了一种新的高选择性 PDE5 抑制剂 14b，可以作为治疗 PAH 的潜在候选者。