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CFTR activation in human bronchial epithelial cells by novel benzoflavone and benzimidazolone compounds

¹Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, 16148 Genova, Italy; ²Departments of Medicine and Physiology, University of California, San Francisco 94143; and ³Department of Chemistry, University of California, Davis, California 95616

Submitted 21 October 2002 ; accepted in final form 12 March 2003

Activators of the CFTR Cl^- channel may be useful for therapy of cystic fibrosis. Short-circuit current (I_sc) 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 µM) being much better than other flavones, such as apigenin. The benzimidazolone UCCF-853 gave similar I_sc but with lower potency (5–20 µM). 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, K_d for activation by UCCF-029 decreased from >5 to <0.4 µM with increasing basal I_sc from 4 µA/cm² to 12 µA/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.

airway epithelium; chloride secretion; drug discovery

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