Transcript hERG Blocking Effects

hERG Blocking
2014.03.07
Kiseon Baek
Contents
Overview
hERG Fundamentals
hERG Blocking Effects
hERG Blocking Structure-Activity Relationship
Structure Modification Strategies for hERG
Problems
Overview
 Certain compounds block the cardiac K+ (hERG) ion channel
and induce arrhythmia.
 The safety margin for hERG is IC50/Cmax, unbound >30.
 hERG blocking might be decreased by reducing the basicity,
reducing lipophilicity, and removing oxygen H-bond acceptors.
hERG?
 hERG has rapidly emerged as an important safety issue in
drug discovery.
 A gene that codes for a cardiac potassium ion channel. If this
channel is blocked, a mechanism is initiated that can lead to
cardiac arrhythmia.
 In recent years, hERG blocking has been one of the leading
causes for withdrawal from the market of drugs approved by the
FDA.
hERG?
 Examples of these drugs :
hERG Channel?
 초파리에 ether마취를 했을 경우 다리를 떨게 하는 유전자
▶‘eag'(에그)
 ’eag' 유전자와 49%정도 아미노기가 일치하는 사람에 존재하는
유사한 유전자 ▶ hERG(허그)
 "human ether-a-go-go related gene.“
 유전자가 발현이 되면 세포막 표면에 potassium channel 발현
▶ hERG channel
hERG Fundamentals
 The protein product of hERG is the inner pore-forming portion of a
critical membrane bound potassium (K+) channel in heart muscle tissue.
It forms a tetramer, with each monomer having six transmembrane
regions. It is controlled by voltage (membrane potential) and gates the
flow of K+ ions out of the cell
hERG Fundamentals
 Voltage-gated potassium channels are transmembrane channels
specific for potassium and sensitive to voltage changes in the cell's
membrane potential. During action potentials, they play a crucial role
in returning the depolarized cell to a resting state.
 Movement of K+ ions across the cell membrane creates the rapidly
activating delayed rectifier K+ current called IKr.
hERG Fundamentals
▶ action potential : membrane potential의 빠르고 순간적인 변화가 전기적인 신
호로 작용
① 세포막은 Na+, K+ 이온에 대한 투과성의 순간적, 단계적 변화를 겪는다.
② 이러한 투과성의 변화는 막 전위의 영향을 받음. (voltage-gate channel)
hERG Fundamentals
▶ Initiated with the opening of Na+ channels
▶ Na+ ions flow quickly into the cell, causing rapid depolarization of the
membrane potential from a resting state of about −90 mV to about +20 mV
▶Depolarization is maintained by subsequent opening of Ca2+ ion channels,
allowing Ca2+ ions to flow into the cell
hERG Fundamentals
▶Repolarization to −90 mV occurs by opening of the K+ ion channels, allowing
K+ions to move out of the cells.
The hERG channel is the most important potassium channel for repolarization.
hERG Fundamentals
▶ Action potential contributes to the overall electrical activity of the heart,
which is measured using an electrocardiogram (ECG) on the surface of the
heart tissue.
▶ On the ECG, the time from point Q to point T is called the QT interval.
▶ A change in the action potential will change the ECG.
hERG Blocking Effects
▶ If a compound binds within the hERG K+ channel, it can obstruct the flow of
K+ ions out of the cell.
▶ This causes a slower outflow of K+ ions, thus lengthening the time required
to repolarize the cell.
hERG Blocking Effects
EADs
▶ From the ECG, it can be seen that the T event is delayed, thus lengthening
the QT interval (long QT [LQT]).
▶ LQT may trigger life-threatening torsades de pointes (TdP) arrhythmia.
hERG Blocking Effects
 Although hERG blocking is a triggering factor for TdP, other
physiological and genetic factors also increase the chances of LQT.
▶low serum K+, slow heart rate, genetic factors,
▶other cardiac conditions,
▶coadministered drugs that also block hERG,
▶coadministered drugs that inhibit metabolism, and gender.
 The involvement of the hERG channel in LQT is further supported by
a naturally occurring inherited mutation in hERG that leads to LQT, TdP,
and ventricular fibrillation.
hERG Blocking Effects
 The number of drugs that induce TdP is estimated to be higher than the
number that induce more rare arrhythmias.
 TdP : Class Ⅰa, Ⅲ drugs
 Class Ⅰ drugs
: Na+ channel blockers
 Class Ⅰa drugs : Similar Class3
drugs, occur TdP
ex) quinidine, procainamide,
disopyramide
① Quinidine (1%–3%),
hERG Blocking Effects
 The number of drugs that induce TdP is estimated to be higher than the
number that induce more rare arrhythmias.
 Class Ⅲ drugs
: K+ ion channel blockers
재분극 지연,
활동전위시간 연장
② sotalol (1%–5%),
hERG Blocking Effects
③ dofetilide (1%–5%)
④ ibutilide (12.5%)
 Arrhythmia was produced in 1:105 to 1:106 person taking antihistamines.
 The incidence of arrhythmia was about 1:50000 for patients taking
terfenadine.
hERG Blocking Effects
 The safety margin for hERG blocking typically is evaluated as the
ratio between the hERG IC50 and Cmax,unbound.
▶ Recommended a large value (often cited as >30)
▶ Based on the experimental observation that for compounds
▶ A ratio <30, 95% produce TdP and only 5% do not,
▶ A ratio >30, 15% produce TdP and 85% do not produce.
 Another safety margin is the time of QT interval lengthening.
▶Concern about the drug candidate when LQT exceeds an
additional 5 ms compared to normal.
hERG Blocking Structure-Activity
Relationship(SAR)
 The amino acid residues in the hERG K+ channel to which blocking drugs
bind have been studied by means of single-site mutations.
 Interaction can occur with non-aromatic hydrophobic substructures in the
drug.
 Tyr652 residues able to establish either π-π or π-cation interactions with
drugs. (K+ channel open).
 Phe656 residues generate a hydrophobic crown at the bottom of the
inner cavity.
 In the closed state this crown closes, trapping the drug molecule inside
the cavity.
hERG Blocking Structure-Activity
Relationship(SAR)
 Studies agree on several structural features that are common to
binding in the hERG channel:
▶ A basic amine (positively ionizable, pKa >7.3)
▶ Hydrophobic/lipophilic substructure(s) (ClogP >3.7)
▶ Absence of negatively ionizable groups
▶ Absence of oxygen H-bond acceptors
hERG Blocking Structure-Activity
Relationship(SAR)
In one hERG structure–activity relationship (SAR) model, the basic
nitrogen is the top of a pyramid, with three or four hydrophobic
substructures at the other loci, thus forming a plug of the channel.
<Terfenadine>
Structure Modification Strategies
for hERG
 Reduce the pKa (basicity) of the amine
 Reduce the liphophilicity and number of substructures in the
binding region
 Add acid moiety
 Add oxygen H-bond acceptors
 Rigidify linkers
Problems
1. hERG is the gene for what protein?
Ans) potassium ion channel in heart muscle.
2. What is the function of the hERG protein?
Ans) Outflow of K+ ions from the cell is part of the action potential
and reestablishes the internal negative potential of the cells.
3. What is LQT?
Ans) Lengthened QT interval on electrocardiogram (ECG).
4. What is TdP?
Ans) Torsades de pointes arrhythmia, which can be triggered by LQT.
Problems
5. How common in the population is TdP that is triggered by LQT?
Ans) 1 in 105 to 106 patients for antihistamines, 1 in 5×104 patients
for terfenadine.
6. What safety margin can be used in drug discovery for hERG
blocking?
Ans) hERG IC50/Cmax,unbound >30, or <5 seconds lengthening of
QT interval.
Problems
7. Where do most hERG blocking drugs bind?
(a) ATP binding site, (b) hinge region, (c) within the channel cavity,
(d) at the allosteric site.
Ans) (c) within the channel cavity
8. Which of the following structural features are favorable toward
hERG blocking?
(a) Low lipophilicity, (b) carboxylic acid,
(c) secondary amine, (d) lipophilic moiety,
(e) Oxygen H-bond acceptors.
Ans) (c) secondary amine, (d) lipophilic moiety
Problems
9. What structural modifications might be tried to
reduce hERG blocking of the following structure?
Ans)
Problems
10. Compounds that cause hERG blocking are at risk
for causing which of the following?
(a) K+ channel opening, (b) myocardial infarction,
(c) arrhythmia, (d) metabolic inhibition,
(e) QT interval shortening.
Ans) (c) arrhythmia
Thank you