Structural determinants for histamine H(1) affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs.

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Aslanian R, Piwinski JJ, Zhu X, Priestley T, Sorota S, Du XY, Zhang XS, McLeod RL, West RE, Williams SM, Hey JA

Structural determinants for histamine H(1) affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs.

Bioorg Med Chem Lett. 2009 Sep 1;19(17):5043-7. doi: 10.1016/j.bmcl.2009.07.047. Epub 2009 Aug 5.

PubMed ID

19660947 [ View in PubMed

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Abstract

In the late 1980's reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H(1) binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H(1) assays.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Fexofenadine	Histamine H1 receptor	Ki (nM)	27	N/A	N/A	Details
Terfenadine	Histamine H1 receptor	Ki (nM)	40	N/A	N/A	Details
Terfenadine	Potassium voltage-gated channel subfamily H member 2	IC 50 (nM)	312	N/A	N/A	Details