Inhibitory effect of carboxylic acid group on hERG binding |
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Authors: | Zhu Bing-Yan Jia Zhaozhong J Zhang Penglie Su Ting Huang Wenrong Goldman Erick Tumas Daniel Kadambi Vic Eddy Priya Sinha Uma Scarborough Robert M Song Yonghong |
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Institution: | Portola Pharmaceuticals, Inc., 270 East Grand Ave., Suite 22, South San Francisco, CA 94080, USA. bzhu@gene.com |
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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. |
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