Cystic Fibrosis (CF) results from the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel of key importance in the airway epithelia. CFTR helps control optimal hydration of the airways, a crucial requirement for healthy lungs. CFTR modulators have recently been approved as an effective treatment option for many genetic variants of CF. The epithelial sodium channel (ENaC), unlike CFTR which is secretory, is an absorptive pathway, and therefore its inhibition is an alternative and potentially complementary approach to aid hydration of the airways. Due to the adverse effect of ENaC inhibition in the kidney we, as have several others, focused on the design and synthesis of novel ENaC inhibitors for direct delivery to the airways via inhalation. A new series of ENaC inhibitors is described, wherein the well-established pyrazine core of first-generation inhibitors was replaced with a pyrrolopyrazine. Aiming for high retention at the surface of the lung following inhalation, optimisation of this template focused on significantly increasing polarity to minimize passive cellular permeability. The resulting optimized clinical candidate ETD001 demonstrates potent inhibition of ENaC (59 nM) prolonged retention in the airways of rats (13 % of the delivered dose retained after 6h) following intratracheal administration and a potent and long-acting effect in a sheep model of mucociliary clearance following inhalation (ED100 (4–6h) = 9 μg/kg). ETD001 entered a phase II study in CF patients in July 2024.

中文翻译：

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优化一系列新型 ENaC 抑制剂，从而选择长效吸入临床候选药物 ETD001，这是一种潜在的囊性纤维化新疗法


囊性纤维化 （CF） 是由于囊性纤维化跨膜电导调节剂 （CFTR） 功能丧失引起的，CFTR 是气道上皮细胞中至关重要的离子通道。CFTR 有助于控制气道的最佳水合作用，这是健康肺部的关键要求。CFTR 调节剂最近已被批准作为 CF 许多遗传变异的有效治疗选择。上皮钠通道 （ENaC） 与分泌性 CFTR 不同，是一种吸收途径，因此其抑制是帮助气道水合作用的另一种潜在补充方法。由于 ENaC 抑制对肾脏的不利影响，我们和其他几个人一样，专注于设计和合成新型 ENaC 抑制剂，通过吸入直接输送到气道。描述了一系列新的 ENaC 抑制剂，其中第一代抑制剂的成熟吡嗪核心被吡咯吡嗪取代。为了在吸入后在肺表面实现高保留，该模板的优化侧重于显着增加极性以最小化被动细胞通透性。所得的优化临床候选药物 ETD001 证明对 ENaC （59 nM） 的有效抑制，在气管内给药后延长在大鼠气道中的滞留（6 小时后保留 13% 的输送剂量），并且在吸入后粘膜纤毛清除的绵羊模型中具有有效和长效作用 （ED100 （4-6h） = 9 μg/kg）。ETD001 于 2024 年 7 月进入 CF 患者的 II 期研究。