Activators of the CFTR Cl- channel may be useful for therapy of cystic fibrosis. Short-circuit current (Isc) measurements were done on human bronchial epithelial cells to characterize the best flavone and benzimidazolone CFTR activators identified by lead-based combinatorial synthesis and high-throughput screening. The 7,8-benzoflavone UCcf-029 was a potent activator of Cl- transport, with activating potency (<1 microM) being much better than other flavones, such as apigenin. The benzimidazolone UCcf-853 gave similar Isc but with lower potency (5-20 microM). In combination, the effect induced by maximal UCcf-029 and UCcf-029, UCcf-853, and apigenin increased strongly with increasing basal CFTR activity: for example, Kd for activation by UCcf-029 decreased from >5 to <0.4 microM with increasing basal Isc from approximately 4 microA/cm2 to approximately 12 microA/cm2. This dependence was confirmed in permeabilized Fischer rat thyroid cells stably expressing CFTR. Our results demonstrate efficacy of novel CFTR activators in bronchial epithelia and provide evidence that activating potency depends on basal CFTR activity.

中文翻译：

---

新型苯并黄酮和苯并咪唑酮化合物对人支气管上皮细胞的 CFTR 活化。

CFTR Cl-通道的激活剂可用于治疗囊性纤维化。对人支气管上皮细胞进行短路电流 (Isc) 测量，以表征通过基于铅的组合合成和高通量筛选确定的最佳黄酮和苯并咪唑酮 CFTR 激活剂。7,8-苯并黄酮 UCcf-029 是一种有效的 Cl-转运激活剂，其激活效力 (<1 microM) 远优于其他黄酮，如芹菜素。苯并咪唑酮 UCcf-853 给出了类似的 Isc，但效力较低 (5-20 microM)。结合起来，最大 UCcf-029 和 UCcf-029、UCcf-853 和芹菜素诱导的效果随着基础 CFTR 活性的增加而强烈增加：例如，UCcf-029 激活的 Kd 从 >5 降低到 <0。4 microM，基础 Isc 从大约 4 microA/cm2 增加到大约 12 microA/cm2。这种依赖性在稳定表达 CFTR 的通透性 Fischer 大鼠甲状腺细胞中得到证实。我们的结果证明了新型 CFTR 激活剂在支气管上皮细胞中的功效，并提供了激活效力取决于基础 CFTR 活性的证据。