Background: Cystic fibrosis (CF) is the autosomal recessive disorder most common in Caucasian populations. It is caused by mutations in the cystic fibrosis transmembrane regulator protein (CFTR). CFTR is predominantly expressed at the apical plasma membranes of the epithelial cells lining several organs, and functions as a cAMP-regulated chloride/bicarbonate channel. To address the underlying causes of cystic fibrosis, two biomolecular activities are required, namely correctors to increase CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel.

Objective: In our previous data, we demonstrated that some aminoarylthiazoles (AATs) have peculiar activity acting as correctors and as potentiator-like molecules.

Curiously, a compound called 1 has been shown to be markedly active as a potentiator. Now, we have further modified its scaffold at different portions, for the identification of molecules with improved potency and effectiveness on mutant CFTR.

Methods: Starting from this active compound, we synthesized a small library trying to improve the activity as potentiators. To extrapolate the contribution of a particular structural portion to bioactivity, we selectively modified one portion at a time.

Results: Our study has provided a structure-activity relationship (SAR) on AATs and led to the identification of some compounds, with a particular ability to act as CFTR potentiators.

Conclusion: Two compounds 2 and 13 appear to be promising molecules and could be used for the future development of potentiators of the chloride transport defect in cystic fibrosis.

背景：囊性纤维化 (CF) 是在白种人人群中最常见的常染色体隐性遗传疾病。它是由囊性纤维化跨膜调节蛋白 (CFTR) 的突变引起的。CFTR 主要在几个器官内衬的上皮细胞的顶端质膜上表达，并作为 cAMP 调节的氯化物/碳酸氢盐通道发挥作用。为了解决囊性纤维化的根本原因，需要两种生物分子活动，即增加细胞表面 CFTR 水平的校正剂，以及允许有效打开 CFTR 通道的增强剂。

目的：在我们之前的数据中，我们证明了一些氨基芳基噻唑 (AAT) 具有作为校正剂和增效剂样分子的特殊活性。

奇怪的是，一种名为 1 的化合物已被证明作为增效剂具有显着的活性。现在，我们在不同部分进一步修改了它的支架，用于鉴定对突变 CFTR 具有改进效力和有效性的分子。

方法：从这种活性化合物开始，我们合成了一个小型文库，试图提高作为增效剂的活性。为了推断特定结构部分对生物活性的贡献，我们一次选择性地修改一个部分。

结果：我们的研究提供了 AAT 的构效关系 (SAR)，并导致鉴定了一些具有作为 CFTR 增效剂的特殊能力的化合物。

结论：两种化合物 2 和 13 似乎是有前途的分子，可用于未来开发囊性纤维化中氯离子转运缺陷的增强剂。