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Vol. 296, Issue 2, 600-611, February 2001
Department of Cell Biology and Physiology, University of
Pittsburgh, Pittsburgh, Pennsylvania
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.
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