Cystic fibrosis (CF) is caused by the functional expression defect of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Despite the recent success in CFTR modulator development, the available correctors only partially restore the F508del-CFTR channel function, and several rare CF mutations show resistance to available drugs. We previously identified compound 4172 that synergistically rescued the F508del-CFTR folding defect in combination with the existing corrector drugs VX-809 and VX-661. Here, novel CFTR correctors were designed by applying a classical medicinal chemistry approach on the 4172 scaffold. Molecular docking and three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were conducted to propose a plausible binding site and design more potent and effective analogs. We identified three optimized compounds, which, in combination with VX-809 and the investigational corrector 3151, increased the plasma membrane density and function of F508del-CFTR and other rare CFTR mutants resistant to the currently approved therapies.

中文翻译：

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作为一类新型囊性纤维化跨膜电导调节剂（CFTR）校正剂的吡唑-嘧啶酮的合成和生物学评价


囊性纤维化（CF）是由囊性纤维化跨膜电导调节蛋白（CFTR）的功能表达缺陷引起的。尽管最近 CFTR 调节剂开发取得了成功，但可用的校正剂只能部分恢复 F508del-CFTR 通道功能，并且一些罕见的 CF 突变显示出对可用药物的耐药性。我们之前鉴定出化合物4172与现有的校正药物 VX-809 和 VX-661 组合可协同挽救 F508del-CFTR 折叠缺陷。在这里，通过在4172支架上应用经典药物化学方法设计了新型 CFTR 校正器。进行分子对接和三维定量结构-活性关系（3D-QSAR）研究以提出合理的结合位点并设计更有效的类似物。我们鉴定了三种优化的化合物，它们与 VX-809 和研究校正剂3151结合，增加了 F508del-CFTR 和其他对目前批准的疗法耐药的罕见 CFTR 突变体的质膜密度和功能。