Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. It is caused by different mutations in the cystic fibrosis transmembrane regulator protein (CFTR) gene, with F508del being the most common. During the last years, small-molecule therapy chosen to contrast CF relied on compounds that correct CFTR misfolding and ER retention (correctors such as VX-809), or defective channel gating (potentiators such as VX-770). Combination therapy with the two series of drugs has been applied, leading to the approval of several multi-drugs such as Orkambi.

Despite this, this treatment proved to be only partially effective making the search for novel modulators an urgent need to contrast CF. Recently, we reported compound 2a as reference compound of a series of aminoarylthiazole-VX-809 hybrid derivatives exhibiting promising F508del-CFTR corrector ability. Herein, we report exploring the docking mode of the prototype VX-809 and of 2a in order to derive useful guidelines for the rational design of novel optimized analogues. To demonstrate experimentally their effective F508del-CFTR-binding and rescuing potential, the most promising derivatives had been synthesized and evaluated in biological assays including YFP functional assay on F508del-CFTR CFBE41o-cells, trans epithelial electrical resistance (TEER) and surface plasmon resonance (SPR). This multidisciplinary strategy led to the discovery of a second series of hybrids including 7j and 7m endowed with higher potency than the prototype.

囊性纤维化（CF）是高加索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）基因的不同突变引起的，其中最常见的是F508del。在过去的几年中，选择用于对比CF的小分子疗法依赖于可纠正CFTR折叠错误和ER滞留的化合物（校正剂，如VX-809），或通道门控不良（增强剂，如VX-770）。结合两种药物的联合疗法已被应用，导致了多种药物的批准，例如Orkambi。

尽管如此，事实证明，这种处理仅是部分有效的，这使得寻找新型调节剂成为对比CF的紧迫需求。最近，我们报道了化合物2a作为一系列氨基芳基噻唑-VX-809杂合衍生物的参考化合物，这些衍生物表现出有前途的F508del-CFTR校正能力。在此，我们报告了探索原型VX-809和2a的对接模式为了得出新颖优化类似物合理设计的有用指导。为了通过实验证明其有效的F508del-CFTR结合和抢救潜力，已经合成并评估了最有希望的衍生物，并在生物学测定中进行了评估，包括对F508del-CFTR CFBE41o细胞进行YFP功能测定，跨上皮电阻（TEER）和表面等离子体共振（ SPR）。这种多学科策略导致发现了第二系列杂种，包括比原型具有更高效能的7j和7m。