Inhibitory effect of carboxylic acid group on hERG binding.

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.

Citation

Bing-Yan Zhu, Zhaozhong J Jia, Penglie Zhang, Ting Su, Wenrong Huang, Erick Goldman, Daniel Tumas, Vic Kadambi, Priya Eddy, Uma Sinha, Robert M Scarborough, Yonghong Song. Inhibitory effect of carboxylic acid group on hERG binding. Bioorganic & medicinal chemistry letters. 2006 Nov 1;16(21):5507-12

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PMID: 16931010

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