This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC₅₀ of 0.88 µM and 21 times more potent selectivity toward PDE4B over PDE4D when compared to rolipram. A primary structure-activity relationship study showed that the attachment of CH₃O group or CF₃O group to the phenyl ring at the para-position was helpful to enhance the inhibitory activity against PDE4B. Moreover, sulfonamide group played a key role in improving the inhibitory activity against PDE4B and subtype selectivity. In addition, the attachment of the additional rigid substituents at the C-3 position of 1,2,3,4-tetrahydroisoquinoline ring was favored to subtype selectivity, which was consistent well with the observed docking simulation.

本文介绍了我们在7-（环戊氧基）-6-甲氧基1,2,3,4-四氢异喹啉支架上的药物化学研究：使用构象限制方法和生物等位取代策略的设计，合成和生物学评估。生物数据显示，大多数这个系列的合成的化合物的显示中度至针对PDE4B有效抑制活性和LPS诱导的TNF的强烈抑制α释放。其中，化合物19对PDE4B表现出最强的抑制作用，IC ₅₀为0.88 µM，并且与咯利普兰相比，对PDE4B的选择性比PDE4D高21倍。初步的结构-活性关系研究表明，CH ₃ O基团或CF的附着对位的苯环上的₃ O基团有助于增强对PDE4B的抑制活性。此外，磺酰胺基在提高对PDE4B的抑制活性和亚型选择性方面起着关键作用。另外，在1,2,3,4-四氢异喹啉环的C-3位置附加的刚性取代基对亚型选择性有利，这与观察到的对接模拟吻合得很好。