We report the effects of new N-acylated ambroxol derivatives (TEI-588a, TEI-588b, TEI-589a, TEI-589b, TEI-602a and TEI-602b: a, aromatic amine-acylated derivative; b, aliphatic amine-acylated derivative) induced from ambroxol (a mucolytic agent to treat human lung diseases) on Cl- secretion in human submucosal serous Calu-3 cells under a Na+/K+/2Cl(-) cotransporter-1 (NKCC1)-mediated hyper-secreting condition. TEI-589a, TEI-589b and TEI-602a diminished hyper-secretion of Cl- by diminishing the activity of NKCC1 without blockade of apical Cl- channel (TEI-589a > TEI-602a > TEI-589b), while any other tested Compounds including ambroxol had no effects on Cl- secretion. These indicate that the inhibitory action of an aromatic amine-acylated derivative on Cl- secretion is stronger that that of an aliphatic amine-acylated derivative, and that 3-(2,5-dimethyl)furoyl group has a strong action in inhibition of Cl- secretion than cyclopropanoyl group. We here indicate that TEI-589a, TEI-589b and TEI-602a reduce hyper-secretion to an appropriate level in the airway, providing a possibility that the compound can be an effective drug in airway obstructive diseases including COPD by reducing the airway resistance under a hypersecreting condition. (C) 2009 Elsevier Inc. All rights reserved