Phosphodiesterase 5 (PDE5) hydrolyzes cyclic guanosine monophosphate (cGMP) leading to increased levels of the cAMP response element binding protein (CREB), a transcriptional factor involved with learning and memory processes. We previously reported potent quinoline-based PDE5 inhibitors (PDE5Is) for the treatment of Alzheimer's disease (AD). However, the low aqueous solubility rendered them undesirable drug candidates. Here we report a series of novel PDE5Is with two new scaffolds, 1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine and 2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one. Among them, compound 6c, 2-acetyl-10-((3-chloro-4-methoxybenzyl)amino)-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine-8-carbonitrile, the most potent compound, has an excellent in vitro IC50 (0.056 nM) and improved aqueous solubility as well as good efficacy in a mouse model of AD. Furthermore, we are proposing two plausible binding modes obtained through in silico docking, which provide insights into the structural basis of the activity of the two series of compounds reported herein.

中文翻译：

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鉴定一种新型 1,2,3,4-四氢苯并[b][1,6]萘啶类似物作为具有改善的水溶性的强效磷酸二酯酶 5 抑制剂，用于治疗阿尔茨海默病。

磷酸二酯酶 5 (PDE5) 水解环磷酸鸟苷 (cGMP)，导致 cAMP 反应元件结合蛋白 (CREB) 水平升高，这是一种参与学习和记忆过程的转录因子。我们之前报道了用于治疗阿尔茨海默病 (AD) 的强效喹啉基 PDE5 抑制剂 (PDE5Is)。然而，低水溶性使它们成为不受欢迎的候选药物。在这里，我们报告了一系列具有两个新支架的新型 PDE5Is，1,2,3,4-四氢苯并[b][1,6]萘啶和 2,3-二氢-1H-吡咯并[3,4-b]喹啉- 1-一个。其中，化合物6c，2-乙酰基-10-((3-氯-4-甲氧基苄基)氨基)-1,2,3,4-四氢苯并[b][1,6]萘啶-8-甲腈，最强效化合物，具有优异的体外 IC50 (0. 056 nM) 和改善的水溶性以及在 AD 小鼠模型中的良好功效。此外，我们提出了通过计算机对接获得的两种似是而非的结合模式，这提供了对本文报道的两个系列化合物活性的结构基础的见解。