Novel Hits in the Correction of ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein: Synthesis, Pharmacological, and ADME Evaluation of Tetrahydropyrido[4,3‑d]pyrimidines for the Potential Treatment of Cystic Fibrosis

Cystic fibrosis (CF) is a lethal genetic disease caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) with a prevalence of the ΔF508 mutation. Whereas the detailed mechanisms underlying disease have yet to be fully elucidated, recent breakthroughs in clinical trials have demonstrated that CFTR dysfunction can be corrected by drug-like molecules. On the basis of this success, a screening campaign was carried out, seeking new drug-like compounds able to rescue ΔF508-CFTR that led to the discovery of a novel series of correctors based on a tetrahydropyrido­[4,3-d]­pyrimidine core. These molecules proved to be soluble, cell-permeable, and active in a disease relevant functional-assay. The series was then further optimized with emphasis on biological data from multiple cell systems while keeping physicochemical properties under strict control. The pharmacological and ADME profile of this corrector series hold promise for the development of more efficacious compounds to be explored for therapeutic use in CF.囊性纤维化（Cystic fibrosis, CF）是一种致命的遗传性疾病，由编码囊性纤维化跨膜传导调节因子（cystic fibrosis transmembrane conductance regulator, CFTR）的基因突变引发，其中ΔF508突变具有较高的流行率。尽管该病的具体发病机制尚未完全阐明，但近期临床试验的重大突破已证实，类药物分子可纠正CFTR的功能异常。基于这一进展，研究团队开展了筛选工作，旨在寻找能够挽救ΔF508-CFTR功能的类药物化合物，最终发现了一系列以四氢吡啶并[4,3-d]嘧啶（tetrahydropyrido[4,3-d]pyrimidine）为母核的新型矫正剂。该类分子经证实具备良好的溶解性与细胞通透性，且在疾病相关的功能实验中表现出活性。随后，研究团队以多细胞体系的生物学数据为优化核心，同时严格管控化合物的理化性质，对该系列分子进行了深度优化。该系列矫正剂的药理学特性及ADME（吸收、分布、代谢、排泄）谱展现出良好的开发潜力，有望助力研发更高效的化合物，用于囊性纤维化的临床治疗探索。