hERG Potassium Channels in Drug Discovery and Development - Ion Channels and Their Inhibitors - page 164

Inhibition of the hERG channel can increase the QT interval and the likelihood
of arrhythmias. If untreated, this undesired QT prolongation can lead to Tdp and
may be fatal. Genetic mutations in the hERG channel can result in LQTS, a disorder
in which the patient has a substantial risk of sudden death due to an arrhythmia
known as Tdp [ 43 ]. Several drugs have recently been withdrawn as a result of
multiple fatalities connected to hERG blockade. It is becoming increasingly neces-
sary to assess a compound's effect on hERG channel activity at the initial stages of
drug discovery process. High-throughput methods, such as rubidium (Rb + ) flux,
make it possible to perform this hERG assessment during lead generation and
optimization [ 54 ].
IK r is important in determining the timing of electrical repolarization of the
action potential in ventricular myocyte. Typically, an LQTS patient will have no
clinical signs except prolongation of QT interval on the electrocardiogram (ECG)
and the patient will appear otherwise healthy, having no other symptoms except
some patients will suffer from occasional syncope [ 7 , 55 , 56 ]. The hERG channel
has been shown to be the target antiarrhythmic drugs (e.g., amiodarone, sotalol and
dofetilide; Table 2 ), which reduce the risk of re-entrant arrhythmias by prolonging
the AP duration and the refractory period without slowing conduction velocity in
the myocardium. hERG also promiscuously interacts with many other drugs, and it
is the inadvertent target of myriad non-cardiac drugs [ 37 , 57 ], a phenomenon that
can under some circumstances lead to severe fatalities including acquired LQTS
and its concomitant risk of sudden death. As a result, since the mid-1990s a wide
variety of drugs found to be spoiled by this safety issue they have been reclassified
or withdrawn from the market. Intensive efforts in drug development are continuing
to root out compounds that might also suffer from this problem [ 13 ].

K + Channels Activators and Inhibitors Which Alters
QT Interval

4 hERG

The recent discovery of several structurally diverse hERG activators could be an
immense breakthrough in treating the clinical conditions with hERG targets. Some
of the compounds have been described as activators (Table 1 ) i.e., RPR260243,
PD-118057, NS 1463, NS 3623 and mallotoxin [ 58 , 59 ]. First, QT prolongation is
associated with those drugs that predictably prolong QT interval. They are used to
treat arrhythmias and include quinidine, procainamide, terfenadine, amiodarone,
sotalol and dofetilide (Class I drugs). Second, those drugs which have been shown
to prolong the QT interval, often at elevated serum concentrations may produce
arrhythmias (Class II such as amitriptyline, cisapride, erythromycin, pimozide and
thioridazine ). There are a large number of drugs with limited or minimal ability to
prolong the QT interval (Table 2 ) (Class III).
All of these drugs associated with QT prolongation could interact based on
pharmacodynamic (PD) and/or pharmacokinetic (PK) mechanisms. Following