Current
Topics in Medicinal Chemistry
ISSN:1568-0266
Current Topics
in Medicinal Chemistry
Volume 8, Number 13, 2008
Contents
Medicinal Chemistry Strategies to Minimize
hERG Channel Effects 23 May
Guest Editor: Mark T. Bilodeau
Editorial Pp.1101
The hERG Channel and Risk of Drug-Acquired Cardiac
Arrhythmia: An Overview Pp. 1102-1112
Armando A. Lagrutta, Elena Trepakova and Joseph J. Salata
[Abstract]
Ligand Structural Aspects of hERG Channel Blockade
Pp. 1113-1127
Alex M. Aronov
[Abstract]
The Impact of Ikr
Blockade on Medicinal Chemistry Programs Pp. 1128-1139
Ian M. Bell and Mark T. Bilodeau
[Abstract]
Overcoming hERG Affinity in the Discovery
of Maraviroc: A CCR5 Antagonist for the Treatment of HIV
Pp. 1140-1151
David A. Price, Duncan Armour, Marcel de Groot, Derek
Leishman, Carolyn Napier, Manos Perros, Blanda L. Stammen
and Anthony Wood
[Abstract]
Lead Optimization of Melanin Concentrating
Hormone Receptor 1 Antagonists with Low hERG Channel Activity
Pp. 1152-1157
Andrew S. Judd, Andrew J. Souers and Philip R. Kym
[Abstract]
Molecule
of Month Pp.1158
Abstracts
[Back to top]
Editorial
The discovery of the association between decreased cardiac
Ikr current and
increased risk of fatal ventricular arrhythmia has had a profound
impact on the drug discovery process. It has led not only
to the removal of drugs from the market but also to the addition
of a significant hurdle to the development of new entities.
Pharmacologic blockade of the IKr current has been shown to
result from binding to the channel underlying the current,
hERG. An amazing diversity of molecular structures has been
found to bind to the hERG channel with high affinity. As a
result, the off-target antagonism of hERG has become an impediment
to virtually all medicinal chemistry programs. Navigating
around this involves a complex interplay of molecule design
and synthesis and in vitro and in vivo assays.
The intent of this issue is to review some of the key issues
facing medicinal chemists in their struggles to work around
this issue.
In the first article Lagrutta, Trepakova and Salata review
the basic biology of hERG, Ikr,
QT-interval increase and the relatioship of these factors
to each other and to pro-arrhythmic risk. Aronov then provides
a review to guide the state of the art in rational drug design
around avoiding hERG, providing an overview of models for
hERG structure and determinants of binding by small molecules.
These reviews are followed by three articles detailing case
studies that present the application of these considerations
into medicinal chemistry programs. Price et al. present
the story of the discovery of Maraviroc, for which modulating
hERG affinities was a significant challenge. Bell and Bilodeau
then present an overview of a number of experiences at Merck,
beginning with the intentional development of Ikr
blockers as anti-arrhythmic agents, then through several more
recent medicinal chemistry programs. Lastly, Judd, Souers
and Kym then proivide a case history addressing the hERG issue
in the Melanin Concentrating Hormone Receptor 1 Antagonist
program at Abbott.
The medicinal chemistry around avoiding hERG as an off-target
activity has benefited significantly from the development
of a better understanding of the biology and structure of
the channel and from the development of high-throughput assays.
As with the medicinal chemistry of on-target activities, hERG
antagonism can at times be rationally guided by binding models
and general SAR trends across chemical series and at other
times purely by empirical data within a series. As a greater
understanding of this critical issue continues to develop,
it is hoped that this undesired activity can be avoided in
increasingly rational and efficient ways.
Mark T. Bilodeau
Department of Medicinal Chemistry,
Merck Research Laboratories,
Merck & Co., P.O. Box 4,
West Point, PA 19486
USA
[Back to top]
The hERG Channel and Risk of Drug-Acquired Cardiac Arrhythmia:
An Overview
Armando A. Lagrutta, Elena Trepakova and Joseph J. Salata
This review summarizes current knowledge of the cardiac
rapidly activating delayed rectifier potassium current (Ikr),
and its connection to drug-acquired QT prolongation and the
associated risk of ventricular arrhythmia and fibrillation.
The molecular characterization of hERG as the structural correlate
of Ikr and the link
between inherited long QT and the KCNH2 gene (hERG), have
facilitated mechanistic studies of drug-acquired QT prolongation.
The development of high throughput assays to evaluate drug
effects on hERG has provided an avenue to determine structure
activity relations (SAR) within chemical series. More than
10 years of collective data and structural considerations
support the notion that hERG is an unusually promiscuous target
among potassium channels, but that defining SAR within a chemical
series is a viable strategy to reduce or eliminate hERG activity.
Despite a critical need to minimize drug effects on hERG,
one should always keep in mind that hERG is not the only structural
correlate of QT prolongation, and that QT prolongation is
a sub-optimal biomarker for ventricular arrhythmia and fibrillation.
[Back to top]
Ligand Structural Aspects of hERG Channel Blockade
Alex M. Aronov
Sudden death as a side effect of action of non-antiarrhythmic
drugs is a major pharmacological safety concern facing the
pharmaceutical industry and the health regulatory authorities.
A number of drugs have been withdrawn from the market in recent
years due to cardiovascular toxicity associated with undesirable
blockade of hERG potassium channel. Pharmaceuticals of widely
varying structure have been shown to interact with hERG. Defining
the molecular features that confer hERG inhibitory activity
has therefore become a focus of considerable computational
and statistical modeling efforts. Some of the approaches are
aimed primarily at filtering out potential hERG blockers in
the context of virtual libraries, while others involve understanding
structure-activity relationships governing hERG-drug interactions.
The ability of models to produce structural hypotheses that
can be tested by the project teams has become the key prerequisite
driving their organization-wide adoption.
[Back to top]
The Impact of Ikr
Blockade on Medicinal Chemistry Programs
Ian M. Bell and Mark T. Bilodeau
Inhibition of the cardiac Ikr
current leads to prolongation of the QT interval and to a
risk of ventricular arrhythmia. This activity has been observed
for a wide range of small molecules and results from their
binding to the hERG ion channel. The off-target inhibition
of Ikr presents
a daunting challenge for many medicinal chemistry programs.
This review article presents case studies that describe a
rang of findings across several projects at Merck. The article
begins with a review of findings from the original efforts
to identify Ikr
blockers as antiarrhythmic therapeutics. A discussion follows
of in vitro and in vivo assays that have
been utilized for the assessment of IKr inhibition. General
SAR rules that have been found to be useful guides for diminishing
hERG activity in lead compounds are discussed and case studies
are presented that illustrate specific observations. The case
studies highlight how the issue of hERG antagonism was navigated
on four distinct medicinal chemistry programs.
[Back to top]
Overcoming hERG Affinity in the Discovery of Maraviroc: A
CCR5 Antagonist for the Treatment of HIV
David A. Price, Duncan Armour, Marcel de Groot, Derek
Leishman, Carolyn Napier, Manos Perros, Blanda L. Stammen
and Anthony Wood
Avoiding cardiac liability associated with blockade
of hERG (human ether a go-go) is key for successful drug discovery
and development. This paper describes the work undertaken
in the discovery of a potent CCR5 antagonist, maraviroc 34,
for the treatment of HIV. In particular the use of a pharmacophore
model of the hERG channel and a high throughput binding assay
for the hERG channel are described that were critical to elucidate
SAR to overcome hERG liabilities. The key SAR involves the
introduction of polar substituents into regions of the molecule
where it is postulated to undergo hydrophobic interactions
with the ion channel. Within the CCR5 project there appeared
to be no strong correlation between hERG affinity and physiochemical
parameters such as pKa or lipophilicity. It is believed that
chemists could apply these same strategies early in drug discovery
to remove hERG interactions associated with lead compounds
while retaining potency at the primary target.
[Back to top]
Lead Optimization of Melanin Concentrating Hormone Receptor
1 Antagonists with Low hERG Channel Activity
Andrew S. Judd, Andrew J. Souers and Philip R. Kym
The discovery of small molecule melanin concentrating
hormone receptor (MHCr1) antagonists as novel therapeutic
agents has been widely pursued across the pharmaceutical industry.
While multiple chemotypes of small molecule MCHr1 antagonists
have been identified and shown to induce weight loss in rodent
models of obesity, many of these lead compounds have been
found to cross react with the hERG channel. This review describes
efforts that led to the identification of two sub-series of
MCHr1 antagonists with low affinity for the hERG channel.
Ultimately, however, the modifications introduced to thwart
hERG channel activity resulted in lead compounds with sub-optimal
CNS behavior.
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