Inhibitory effect of carboxylic acid group on hERG binding
- 1 November 2006
- journal article
- research article
- Published by Elsevier BV in Bioorganic & Medicinal Chemistry Letters
- Vol. 16 (21), 5507-5512
- https://doi.org/10.1016/j.bmcl.2006.08.039
Abstract
Drug-induced QT prolongation arising from drugs’ blocking of hERG channel activity presents significant challenges in drug development. Many, but not all, of our benzamidine-containing factor Xa inhibitors were found to have high hERG binding propensity. However, incorporation of a carboxylic acid group into these benzamidine molecules generally leads to hERG inactive compounds regardless where the carboxyl group is tethered within the molecules. The inhibitory effect of a carboxylic acid group on hERG binding has also been observed in many series of diverse structural scaffolds (including non-amidines). These findings suggest that the negatively charged carboxylate group causes unfavorable interaction within hERG channel binding cavity by electrostatic interaction.Keywords
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