We previously identified a spiro[piperidine-4,1-pyrido[3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro[piperidine-4,1-pyrido[3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6’-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC₅₀ ∼600 nM representing an ∼17-fold improvement over the original compound identified in a small molecule screen.

我们之前鉴定了螺[哌啶-4,1-吡啶并[3,4-b]吲哚]类共增强剂，其与现有 CFTR 增强剂（例如 VX-770 或 GLGP1837）协同作用，以恢复指定子集的通道活性最小功能囊性纤维化跨膜电导调节器（CFTR）突变体。在这里，进行了结构-活性研究，以提高其相对于先前鉴定的化合物20 （最初称为 CP-A01）的效力。 37种螺[哌啶-4,1-吡啶并[3,4-b]吲哚]的靶向合成通常使用通用的两步或三步反应方案来完成，每个步骤都具有高效率。结构-活性关系研究表明，具有 6'-甲氧基吲哚和 2,4,5-三氟苄基取代基的类似物2i对 N1303K-CFTR 的激活具有最大效力，EC ₅₀ ∼600 nM 代表比 N1303K-CFTR 提高了 ∼17 倍。在小分子筛选中鉴定出的原始化合物。