U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy.
Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Bioorg Med Chem Lett. 2020 Nov 1;30(21):127473. doi: 10.1016/j.bmcl.2020.127473. Epub 2020 Aug 9.
Cystic fibrosis is a genetic disease caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator gene, encoding for CFTR protein. The most frequent mutation is the deletion of phenylalanine at position 508 (F508del), which leads to distinct defects in channel gating and cellular processing. In last years, several thiazole containing small molecules, endowed with dual F508del-CFTR modulator activity, proved to be able to target these defects. In search of new chemical entities able to restore CFTR function, we designed and synthesized a small series of sixteen thiazole derivatives. The designed compounds were studied as correctors and potentiators of F508del-CFTR. Although none of the molecules showed significant corrector activity, compounds 10 and 11 exhibited potentiator effects, thus allowing to determine some basic structural features which enable to obtain F508del-CFTR potentiator activity. In silico ADME studies showed that these derivatives obey Lipinski's rule of five and are expected to be orally bioavailable. Therefore, these molecules may represent a good starting point for the design of analogues endowed with improved CFTR potentiator activity and a good pharmacokinetic profile.
囊性纤维化是一种由囊性纤维化跨膜电导调节基因（编码 CFTR 蛋白）功能丧失突变引起的遗传性疾病。最常见的突变是第 508 位苯丙氨酸缺失（F508del），导致通道门控和细胞加工的明显缺陷。近年来，一些含有噻唑的小分子，具有双重 F508del-CFTR 调节剂活性，被证明能够针对这些缺陷。为了寻找能够恢复 CFTR 功能的新化学实体，我们设计并合成了一系列十六个噻唑衍生物。设计的化合物被研究为 F508del-CFTR 的校正剂和增强剂。尽管没有一种分子表现出显著的校正活性，但化合物 10 和 11 表现出增强作用，从而确定了获得 F508del-CFTR 增强活性的一些基本结构特征。基于计算机的 ADME 研究表明，这些衍生物符合 Lipinski 的五规则，预计具有口服生物利用度。因此，这些分子可能是设计具有改善的 CFTR 增强活性和良好药代动力学特征的类似物的良好起点。
