hERG Potassium Channels in Drug Discovery and Development - Ion Channels and Their Inhibitors - page 181

false-positive and false-negative findings with respect to QT prolongation, the clini-
cally relevant endpoint. In silico hERG -SAR assay is best for investigations within
chemical class. The advantages of this approach include ability to rationalize
predictions based on structural similarity to, as well as presence or absence of specific
pharmacophore features shared by known hERG blockers [ 134 , 135 ]. Computer
modeling of electrophysiological information is an important technique for
organizing and integrating generated data. The role of in silico modeling in predicting
Tdp arrhythmia is likely to become increasingly important, as a vast amount of data
needs to be exploited. An important strength of computer models is to reach down to
the genetic level connecting the physiome with the genome [ 136 , 137 ].

6.2 In Vitro Assay

Numerous structurally and functionally unrelated drugs block the hERG K + chan-
nel. hERG channels are involved in cardiac action potential repolarization and
reduced function of hERG lengthens ventricular action potentials, prolongs the
QT interval in an electrocardiogram and increases the risk for potentially fatal
ventricular arrhythmias. To reduce the risk of investing resources in a drug candi-
date that fails preclinical safety studies because of QT prolongation, it is important
to screen compounds for activity on hERG channels early in the lead optimization
process [ 7 , 11 ]. A number of hERG assays are available, ranging from high-
throughput binding assays on stably expressed recombinant channels to very time-
consuming electrophysiological examinations in cardiac myocyte. Depending on
the number of compounds to be tested, binding assays or functional assays measur-
ing membrane potential or Rb + flux, combined with electrophysiology on a few
compounds, can be used to efficiently develop the structure-function relationship of
hERG interactions. The inhibition of the hERG -encoded potassium channel can lead
to prolongation of the cardiac action potential-manifested as a prolongation of QT
interval on the ECG. Although QT interval prolongation is not dangerous per se, in
a small percentage of cases, it is associated with a potentially fatal arrhythmia, that is
Tdp . This channel type is pharmacologically promiscuous, so many compounds
have caused QT interval prolongation in man, and this has led to drugs being
withdrawn from the market following evidence of Tdp . From a drug discovery
perspective, focusing as early as possible on screening out hERG activity is impor-
tant. Retrospective analysis of hERG potency versus clinical incidence of Tdp
suggests provisional safety margins that could be used as target values by medicinal
chemists [ 129 , 138 ]. Large safety margins will not always be possible; however and
in such circumstances, if the risk-benefit ratio still favors developing the compound,
a pre-clinical assessment of the likelihood that any QT interval prolongation will or
will not lead to Tdp in man may be important. An isolated rabbit heart model of
arrhythmia shows promise in this respect, based on a comparison of clinical
data with that obtained from this assay. Clinical guideline (E14) suggests that