Sangeeta Singh, C. A. Syme, Ashvani K. Singh
Feb 1, 2001
Citations
9
Influential Citations
146
Citations
Quality indicators
Journal
The Journal of pharmacology and experimental therapeutics
Abstract
The diseases of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are characterized by mucus-congested airways. Agents that stimulate the secretion of Cl- are anticipated to facilitate mucociliary clearance and thus be of benefit in the treatment of CF and COPD. Recently 1-EBIO (1-ethyl-2-benzimidazolinone or 1-ethyl-1,3-dihydro-2H-benzimidazol-2-one) was shown to stimulate chloride secretion albeit at relatively high concentrations (0.6-1 mM). The studies reported here were undertaken to develop a more potent benzimidazolone. Structure activity studies with 30 benzimidazolone derivatives revealed that ethyl and hydrogen groups at the 1 and 3 nitrogen positions, respectively, were critical for the activation of hIK1 K+ channels and that other alkyl groups were not tolerated at these positions without some loss in potency. Substitutions at the 5 and 6 positions improved the potency of 1-EBIO. Compared with 1-EBIO, the most potent of these derivatives, DCEBIO (5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one) was severalfold better in a 86Rb+ uptake assay, 20-fold better in short circuit current measurements on T84 monolayers, and 100-fold better in patch-clamp assays of hIK1 activity. Short circuit current studies revealed DCEBIO stimulates Cl- secretion via the activation of hIK1 K+ channels and the activation of an apical membrane Cl- conductance. The improved potency of DCEBIO strengthens the possibility that compounds in this class may be of therapeutic benefit in the treatment of CF and COPD.