Bioorganic & Medicinal Chemistry Letters
Successful reduction of off-target hERG toxicity by structural
modification of a T-type calcium channel blocker
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Yeon Jae Choi, Jae Hong Seo, Kye Jung Shin
Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon, Gyeonggi-do 420-743, Republic
of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
To obtain an optimized T-type calcium channel blocker with reduced off-target hERG toxicity, we mod-
ified the structure of the original compound by introducing a zwitterion and reducing the basicity of the
nitrogen. Among the structurally modified compounds we designed, compounds 5 and 6, which incorpo-
rate amides in place of the original compound’s amines, most appreciably alleviated hERG toxicity while
maintaining T-type calcium channel blocking activity. Notably, the benzimidazole amide 5 selectively
blocked T-type calcium channels without inhibiting hERG (hERG/T-type P 220) and L-type channels
(L-type/T-type = 96), and exhibited an excellent pharmacokinetic profile in rats.
Received 30 September 2013
Revised 9 December 2013
Accepted 19 December 2013
Available online 27 December 2013
Keywords:
T-type calcium channel blocker
hERG
Ó 2013 Elsevier Ltd. All rights reserved.
L-type calcium channel
Pharmacokinetics
Voltage-gated calcium channels are important regulators of
calcium ion influx upon membrane potential depolarization in a
number of cell types. This property translates electrical signals
on the membrane surface into an intracellular chemical signal;
the rise in cytosolic calcium concentration triggers cellular pro-
cesses such as muscle contraction, hormone secretion, and gene
transcription.1–3 Voltage-dependent calcium channels are divided
into high voltage-activated (HVA) and low voltage-activated
(LVA) calcium channels by activation voltage range.4 HVA calcium
channels are classified into L-type and non-L-type (N-, P-, Q-, R-),
and LVA calcium channels are also called T-type calcium channels.
T-type calcium channels are expressed throughout the body,
including in nervous tissue, heart, kidney, smooth muscle, and
many endocrine organs.5 Moreover, T-type calcium channels’ prop-
erties differ from those of L-type channels: T-type channels have a
more negative range of activation and inactivation and faster gat-
ing kinetics, and are resistant to standard L-type calcium channel
blockers such as dihydropyridines, diltiazem and verapamil. Thus,
T-type calcium channels are now anticipated to be novel targets for
the treatment of various cardiovascular disorders such as heart
failure, arrhythmia, hypertension, and neurological disorders such
as epilepsy and pain.6
molecule T-type calcium channel blockers ever found. However,
the absolute hERG IC50 value of compound 1 was too low for devel-
opment as a drug, though the ratio of T-type to hERG IC50 was
moderately high (hERG IC50/T-type IC50 = 21.8). In recent years,
blockade of the hERG channel has arisen as a significant hurdle
for drug discovery, as it can lead to a heart rhythm disorder known
as long QT interval syndrome.8 Even some commercial drugs such
as terfenadine, sertindole, and grepafloxacine have been with-
drawn from market because of hERG inhibition.
To identify compounds with decreased off-target effects against
hERG channels, we structurally modified the original compounds 1
and 2. A number of simple structural modifications to mitigate
hERG channel activity have been reported including controlling
lipophilicity,9 reducing pKa,10 and introducing zwitterions.11 In
this paper we reduce undesirable hERG toxicity in T-type calcium
channel blockers by structurally modifying 1 and 2 to allow forma-
tion of zwitterions and reduce basicity of the nitrogen.
First, we attempted to make our inhibitors zwitterionic to
reduce hERG inhibition, a widely accepted approach. Zwitterions
appear to have lower hERG-blocking activity because of poor cell
permeability and/or conformational changes relative to parent
compounds.12 Since compounds 1 and 2 possess amine and ester
groups, which are acid derivatives, we can easily obtain zwitteri-
ons 3 and 4 by simple ester hydrolysis of compounds 1 and 2,
respectively (Scheme 1).
An increasing number of publications have showed that po-
tency of hERG blockade is associated with basic nitrogens capable
of protonation at physiological pH.13 Therefore, lowering the basi-
city of the nitrogen should reduce unwanted hERG activity. With
In a previous paper,7 we identified a0-disubstituted phenylac-
a,
etate derivatives 1 and 2 as T-type calcium channel blockers
(Fig. 1). Compound 1, which has a benzimidazole moiety in its side
chain, seems to be one of the most potent and selective small
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Corresponding author. Tel.: +82 2 2164 4060; fax: +82 2 2164 4059.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.