Cystic fibrosis (CF) is a life-threatening autosomal recessive disease, caused by mutations in the CF transmembrane conductance regulator (CFTR) chloride channel. CFTR modulators have been reported to address the basic defects associated with CF-causing mutations, partially restoring the CFTR function in terms of protein processing and/or channel gating. Small-molecule compounds, called potentiators, are known to ameliorate the gating defect. In this study, we describe the identification of the 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole core as a novel chemotype of potentiators. In-depth structure–activity relationship studies led to the discovery of enantiomerically pure 39 endowed with a good efficacy in rescuing the gating defect of F508del- and G551D-CFTR and a promising in vitro druglike profile. The in vivo characterization of γ-carboline 39 showed considerable exposure levels and good oral bioavailability, with detectable distribution to the lungs after oral administration to rats. Overall, these findings may represent an encouraging starting point to further expand this chemical class, adding a new chemotype to the existing classes of CFTR potentiators.

中文翻译：

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2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚作为一类新型的CFTR增效剂的鉴定，结构-活性关系和生物学特性。

囊性纤维化（CF）是一种威胁生命的常染色体隐性疾病，由CF跨膜电导调节剂（CFTR）氯化物通道的突变引起。据报道，CFTR调节剂可解决与CF引起的突变相关的基本缺陷，可以部分恢复CFTR在蛋白质加工和/或通道门控方面的功能。小分子化合物（称为增强剂）可改善门控缺陷。在这项研究中，我们描述了2,3,4,5-tetrahydro-1 H -pyrido [4,3- b ]吲哚核作为增效剂的新型化学型的鉴定。深入的结构-活性关系研究导致发现对映体纯39在挽救F508del-和G551D-CFTR的门控缺陷方面具有良好的功效，并且有望在体外发挥类似药物的作用。该体内γ -咔啉的表征39表现出相当的暴露水平和良好的口服生物利用度，以检测分配到肺部口服后大鼠。总体而言，这些发现可能是进一步扩展该化学类别的令人鼓舞的起点，为现有CFTR增强剂类别增加了新的化学型。