HERG ion channel

Inhibition of the hERG ion channel is firmly associated with cardiovascular toxicity in humans, and several drugs with this liability have been withdrawn. A number of studies show that basicity, lipophilicity, and the presence of aromatic rings [76] contribute to hERG binding. The 3D models of the hERG channel [77] are potentially useful to understand more subtle structure-activity relationships. In common with receptor promiscuity, both phospholipidosis and hERG inhibition are predominantly issues with lipophilic, basic compounds, and with the predictive models available, both risks should be well controlled. 

Further explorations around 4 led to identification of molecules such as tropane-based 5 and 6 (Figure 2), which were practically equipotent in both the MIP-1 (3 inhibition of binding and in the PM-1 /BaL antiviral assay [23]. However, 6 also proved to be a potent inhibitor of hERG ion channel (99% inhibition at 1 (iM concentration [23] and 80% inhibition at the rate of 300 nM [22]). 

B.K., Yu, S. and Hartman, G.D. (2004) Potent N-(l,3-thiazoyl-2-yl)pyridine-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel. Journal of Medicinal Chemistry, 47, 6363-6372. 

The cover shows a model of the hERG ion channel in the lower left (chapter 4), a CYP structure, lower right (chapter 10), a pharmacophore model for the alphala adrenergic receptor, upper right (chapter 6) and a schematic of the intestinal epithelium with some transporters, upper left (chapter 15). 

Figure 10.22 In vitro KDR kinase inhibitory activity and hERG binding data as determined in a radioligand binding assay for three compounds. (Dinges, J., et al. l,4-dihydroindeno[l,2-c]pyrazoles with acetylenic side chains as novel and potent multitargeled receptor tyrosine kinase inhibitors with low affinity for the hERG ion channel. J. Med. Chem. 2007, 50, 2011-2029.)...

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