Inhibitory effect of carboxylic acid group on hERG binding.

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Zhu BY, Jia ZJ, Zhang P, Su T, Huang W, Goldman E, Tumas D, Kadambi V, Eddy P, Sinha U, Scarborough RM, Song Y

Inhibitory effect of carboxylic acid group on hERG binding.

Bioorg Med Chem Lett. 2006 Nov 1;16(21):5507-12. Epub 2006 Aug 22.

PubMed ID

16931010 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Terfenadine	Potassium voltage-gated channel subfamily H member 2	IC 50 (nM)	56000	N/A	N/A	Details