Benzimidazolone activators of chloride secretion: potential therapeutics for cystic fibrosis and chronic obstructive pulmonary disease

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.