HERG blockers

Fig. 12.5 Key elements of hERG channel topology are schematically illustrated using one subunit of the X-ray structure of bacterial KvAP [17], A hERG blocker is represented according to published evidence [1 7]. The...

Neurons Does it contribute to the sudden death phenotype associated with LQT2 syndrome Several functions [11] Antiepileptic drugs Side effects of hERG blockers... 

Cancer Resting membrane potential Neuritogenesis [12] Spike-frequency adaptation [13] Properties of cancer cells hERG blockers as potential in the central nervous system Effect on cell proliferation... 

Use of a hERG blocker in a patient also taking drugs inducing electrolyte imbalance (e.g. risk of hypokalemia with diuretics) this is a pharmacodynamic interaction... 

In conclusion, QT prolongation by hERG channel blockers is per se dose dependent, whereas actual occurrence of TdP depends on the repolarization reserve, which is variable among subjects and over time. The exception to the mle are those hERG blockers with multiple, sometimes complementary electrophysiological actions, which lead to a bell-shaped concentration-response curve [109]. 

Figure 4.4 Placement of the hERG blocker pharmacophore in the inner cavity of the channel. The Cavalli pharmacophore [83] is placed within the pore illustrating its main features N (positively charged central nitrogen), CO (aromatic group), Cl and C2 (hydrophobic groups). The N feature is thought to form...

Witchel, H.J., Dempsey, C.E., Sessions, R.B., Perry, M., Milnes, J.T., Hancox, J.C. and Mitcheson, J.S. (2004) The low-potency, voltage-dependent HERG blocker propafenone-molecular determinants and drug trapping. Molecular Pharmacology, 66, 1201—... 

The relevance of size-related properties of hERG-blocking molecules was also detected in a 2D QSAR model developed by Coi et al. [22] after the analysis of 82 compounds through the CODESSA method. These authors developed two multiparameter models with strong predictive properties, from which, besides the involvement of hydrophobic features, the importance of linearity as opposed to globularity of the hERG blockers emerged. 

Property of hERG Blockers Sign of Correlation with hERG Blockade References... 

Table 5.2 Molecular properties identified as relevant in classification models of hERG blockers.

Aronov, A.M. (2006) Common pharmacophores for uncharged human ether-a-go-go-related gene (hERG) blockers. Journal of Medicinal Chemistry, 49, 6917-6921. 

However, when compound 15 was tested for h E RG K+ channel inhibition, a basic cardiovascular safety indicator related to the QT prolongation syndrome [32], and linked to ventricular fibrillation and sudden death [33], we were unpleasantly surprised. Although the lead compound 1 exhibited very weak binding to the hERG K+ channel (IC50 > 5000 nM), the optimized compound 15 was afairly potent hERG blocker with an inhibition concentration IC50 of 300 nM (in patch-clamp assay). 

Figure 13.1 hERG compound data obtained from PubChem BioAssay AID 376. Upper line Conventional hERG blockers. Lower line Atypical hERG blockers which do not contain the conventional pharmacophore of a basic nitrogen, decorated by a set of lipophilic rings, (also see Chapter 16). 

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