Selective Kv1.5 blockers: Development of (R)-1-(methylsulfonylamino)-3-[2- (4-methoxyphenyl)ethyl]-4-(4-methoxyphenyl)-2-imidazolidinone (KVI-020/WYE-160020) as a potential treatment for atrial arrhythmia

Article abstract of DOI:10.1021/jm901042m

Atrial fibrillation is the most prevalent form of cardiac arrhythmia. Current treatments extend the atrial effective refractory period by nonselective blockade of cardiac ion channels. An alternative approach selectively targeting the Kv1.5 ion channel of

Full text of DOI:10.1021/jm901042m

J. Med. Chem. 2009, 52, 6531–6534 6531
DOI: 10.1021/jm901042m
Selective Kv1.5 Blockers: Development of
(R)-1-(Methylsulfonylamino)-3-[2-(4-
methoxyphenyl)ethyl]-4-(4-methoxyphenyl)-2-
imidazolidinone (KVI-020/WYE-160020) as a
Potential Treatment for Atrial Arrhythmia
Figure 1. Amiodarone (1) and vernakalant (2).
Benjamin E. Blass,*,† Andrew Fensome,† Eugene Trybulski,†
Ronald Magolda,† Stephen J. Gardell,‡ Kun Liu,§
Manoj Samuel,§ Irene Feingold, Christine Huselton,
Chris M. Jackson,^ Laurent Djandjighian,^ Douglas Ho,#
James Hennan,‡ and John M. Janusz^
†Chemical Sciences and ‡Metabolic Disease and §Screening Sciences
and Drug Metabolism, Wyeth Research, 500 Arcola Road,
Collegeville, Pennsylvania 19426, ^Proctor and Gamble
Pharmaceuticals, Mason, Ohio, and #Department of Chemistry and
Chemical Biology, Harvard University, Cambridge, Massachusetts
Figure 2. Acylthiazolidine (3) and 2-amino-2-imidazolidinones (4).
Received July 14, 2009
cells.7 It is an attractive target for the treatment of atrial
arrhythmia. The absence of Kv1.5 in human ventricular cells
should lead to a decreased risk of ventricular events and
improved therapeutic margins.
A series of acylthiazolidines (e.g., 3) was disclosed as Kv1.5
blockers (Figure 2).8 Our design objective was to preserve the
relative disposition of the aryl rings in the pharmacophore
presented by 3 while replacing the metabolically labile 1,
3-thiazolidine ring with the more stable imidazolidinone
system. The development of a series of 2-amino-2-imidazoli-
dinones (4) as potent Kv1.5 blockers useful for the prevention
of atrial arrhythmias will be described.
Compounds 4 were prepared in a six-step synthesis from
readily available nitrostyrenes (I) as shown in Scheme 1.
Michael addition with an appropriately substituted amine
(II) followed by reduction provided diamines III. Cyclization
with 1,10-carbonyldiimidazole provided the core 2-imidazoli-
dinones (IV). The penultimate 2-amino-2-imidazolidinones
(V) were generated in a one-pot, two-step nitrosation/reduc-
tion sequence. Sulfonylation with a sulfonyl chloride then
provided the target compounds (4).
Compounds were assessed for Kv1.5 potency on an auto-
mated electrophysiological patch clamp platform using
cloned human Kv1.5 channels expressed in CHO cells,
with follow-up assessment for hERG activity. Cross-reactiv-
ity data were obtained for the important cardiovascular
channels Nav1.5,9 Cav1.2,10 and Cav1.3.11 In addition, im-
portant ion channels with high homology to Kv1.5 were
examined, including Kv1.1, a neuronal target,12 Kv1.3, a
channel found in T-cells,13 and Kv4.3, a cardiac channel
involved in the early phase of repolarization of both chambers
of the heart.14
Abstract: Atrial fibrillation is the most prevalent form of cardiac
arrhythmia. Current treatments extend the atrial effective refrac-
tory period by nonselective blockade of cardiac ion channels. An
alternative approach selectively targeting the Kv1.5 ion channel
offers the opportunity for therapeutic benefit with decreased risk of
adverse cardiovascular events. KVI-020 (4g) successfully demon-
strated antiarrhythmic efficacy in a canine arrhythmia model, and
these findings support its utility as an antiarrhythmic agent.
Atrial fibrillation (AF), the most prevalent form of cardiac
arrhythmia, contributes to increased risk of heart failure,
ischemia, morbidity, and mortality.1 Current therapies extend
the atrial action potential duration and effective refractory
period by nonselective blockade of cardiac ion channels.
Amiodarone (1, Figure 1) increases the refractory period
and slows the intracardiac action potential conduction via
potassium and sodium channel blockade. Its utility is limited
by its actions on the thyroid and the risk of ventricular
arrhythmia via hERG blockade.2 Dronedarone (structure
not shown), an amiodarone analogue recently approved for
AF, has decreased thyroid activity but is less efficacious than
the parent compound (1) in AF patients.3 Vernakalant (2) is
currently in phase III clinical trials for atrial arrhythmia;
its mechanisms of action include equipotent blockade of
Kv1.5, hERG, and Nav1.5.4
Safety risks associated with current and emerging therapies
might be mitigated with a selective ion channel blocker.5
Elimination of hERG channel activity is of particular interest.
hERG is expressed in the atria and ventricle and is associated
with plateau and late stage repolarization. Blockade of the
hERG channel has been directly associated with ventricular
action potential prolongation, QT prolongation, ventricular
arrhythmia, torsade de pointes, and ultimately sudden cardiac
death.6
An early comparator compound (4a) demonstrated Kv1.5
potency (IC50 = 610 nM) and hERG selectivity (26-fold) but
limited aqueous solubility (pH 7.4 buffer) and human micro-
somal stability, as well as measurable Cyp 3A4 inhibition
(Table 1). Deletion of the 3-methyl substituent (4b) improved
Kv1.5 potency (IC50 = 240 nM) and hERG selectivity
(47-fold), but only modest pharmaceutical profiling improve-
ments were observed. Incorporation of a 4-cyclopropyl group
In contrast to hERG, the Kv1.5 voltage-gated potassium
channel plays a critical role in the early and plateau phases of
repolarization of atrial cells but has no function in ventricular
*To whom correspondence should be addressed. Phone: 484-865-
5514. Fax: 484-965-9399. E-mail: blassb@wyeth.com.
r
2009 American Chemical Society
Published on Web 10/02/2009
pubs.acs.org/jmc

6532 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 21
Scheme 1. General Synthesis of 4
Blass et al.
Table 2. Modified Upper Side Chain, 4f,g,j-m
IW IC50 (nM)
Cyp 3A4
stability % inhib
aq solc
R
n
Kv1.5a
hERGb (μg/mL) (t1/2 min)d at 3 μMe
4f (S)-4-OMe
4g (R)-4-OMe
4j (S)-4-OMe
4k (R)-4-OMe
4l OEt
1
1
2
2
1
1
330 ( 66
480 ( 44
100 ( 40
560 ( 9
770 ( 238 12200
520 ( 110 5600
26700
15100
14100
14300
100
65
18
15
43
4
16
30
29
12
17
15
50
45
84
50
4
4m OCF3
53
Table 1. Modified Lower Aryl Ring, 4a-i
a Kv1.5 IC50 determined on an IonWorks platform with CHO-
hKv1.5. b hERG IC50 values were obtained from Essen Instruments
Inc. c pH 7.4 buffer, direct UV method. d Human liver microsomal.15
e Fluorescent method.16
achieved by incorporation of a 4-methoxyethoxy group (4i),
but Kv1.5 activity was reduced (IC50 = 2130 nM).
IW IC50 (nM)
Cyp 3A4,
aq solc stability % inhib
hERGb (μg/mL) (t1/2, min)d at 3 μMe
R1
Kv1.5a
4a 3,4-di-Me
4b 4-Me
4c 4-cycprop
4d 4-Cl
4e 4-CF3
4f (S)-4-OMe
4g (R)-4-OMe
4h 4-i-PrO
610 ( 101
240 ( 57
160 ( 21
200 ( 66
250 ( 72
330 ( 66
480 ( 44
240 ( 60
15800
11200
8400
17
42
1
13
18
30
30
30
16
30
30
30
77
58
78
27
67
50
45
53
50
Modification of the upper side chain was then examined,
as shown in Table 2. Chain elongation from two to three
carbon atoms provided mixed results. The (S)-isomer (4j)
demonstrated improved Kv1.5 potency (IC50 = 100 nM)
and hERG selectivity (141-fold), but aqueous solubility de-
creased (18 μg/mL) and Cyp 3A4 inhibition increased (84% at
3 μM). The (R)-isomer (4k) possessed comparable Kv1.5
potency (IC50 = 560 nM) and hERG selectivity (26-fold)
relative to the original lead (4a), but microsomal stability and
aqueous solubility were not improved. Incorporation of a
trifluoromethoxy group in place of a methoxy group or
extension of the ether moiety to an ethoxy group reduced
hERG selectivity (4l and 4m, 16-fold and 11-fold,
respectively).
8700
9100
4
13
100
65
26
100
26700
15100
17000
4i 4-O(CH2)2OMe 7450 ( 1950 33000
a Kv1.5 IC50 determined on an IonWorks platform with CHO-
hKv1.5. b hERG IC50 values were obtained from Essen Instruments
Inc. c pH 7.4 buffer, direct UV method. d Human liver microsomal.15
e Fluorescent method.16
(4c) improved Kv1.5 potency (IC50 = 160 nM), increased
hERG selectivity (53-fold), and also increased human micro-
somal stability (t1/2 = 30 min); however, aqueous solubility
remained an issue. Electron withdrawing substituents (4d and
4e) also afforded potent inhibitors (Kv1.5 IC50 = 200 and
250 nM) with improved microsomal stability (t1/2 = 30 min),
but aqueous solubility remained an issue. Incorporation of a
4-methoxy substituent (4f and 4g) provided potent Kv1.5
blockade (Kv1.5 IC50 = 480 and 330 nM, respectively),
hERG selectivity (81- and 31-fold, respectively), with im-
proved aqueous solubility (100 and 65 μg/mL, respectively).
Human microsomal stability increased for 4f (t1/2 = 30 min)
but not 4g (t1/2 = 16 min). Increasing the steric bulk of the
ether to an isopropyl ether (4h) provided improved Kv1.5
potency (IC50 = 240 nM), increased hERG selectivity
(71-fold), and also increased human microsomal stability
(t1/2 = 30 min); however, aqueous solubility decreased
(26 μg/mL). Solubilization and metabolic stabilization were
In the sulfonyl hydrazide region of the phamacophore (R3),
Kv1.5 activity was maintained with a range of different
functionality (Table 3). A benzyl group was tolerated (4n,
Kv1.5 IC50 = 340 nM), but hERG selectivity (13-fold) and
microsomal stability (t1/2 = 3 min) decreased. The nitrile
derivative 4o provided excellent Kv1.5 potency (IC50 =230nM),
hERG selectivity (143 fold), and increased aqueous solubility
(100 μg/mL), but microsomal stability decreased relative to 4g
(t1/2 = 21 min). Monofluorination of the sulfonyl hydrazide (4p)
also led to decreased microsomal stability (t1/2 = 13 min).
The 3-pyridyl analogue (4q) demonstrated Kv1.5 activity
(IC50 = 600 nM), but decreases in microsomal stability (t1/2 =
3 min) and increased inhibition of Cyp 3A4 (90% at 3 μM) were
observed.

Letter
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 21 6533
Table 3. Modified Sulfonyl Hydrazide, 4g,n-q
Table 5. Selected ADME Properties of 4g
microsomal
stability
(t1/2 min)a
Cyp450,
IC50 (μM)b
Caco-2
(10-6 cm/s) f
plasma protein
binding (%)g
dog human 3A4c 2D6d 2C9e A-B
B-A beagle human
11
30
37
38
180
47
40
39
90
94
a 1 μM substrate (4 g) in 1 mg/mL male beagle dog or male human
liver microsomal protein. b Reversible inhibition in human liver micro-
somes (0.2 mg/mL) with probe substrates. c Substrates = 2.5 μM
midazolam and 50 μM testosterone. d Substrate = 10 μM bufuralol.
e Substrate = 10 μM diclofenac. f [3H]WYE-160020 (500 ng/mL) deter-
mined by equilibrium dialysis in male beagle dog or male human plasma.
g pH 7.4, bidirectional transport from A to B and from B to A.
IW IC50 (nM)
Cyp 3A4,
% inhib
aq solc
stability
R3
Kv1.5a
hERGb (μg/mL) (t1/2 min)d at 3 μMe
4g (R)-Me
4n Bn
480 ( 44
340 ( 90
230 ( 50
900 ( 222 28300
ND
15100
4400
33000
65
1
30
3
45
82
7
Table 6. Beagle Pharmacokinetics of 4g
dose = 3 mg/kg, iva
dose = 3 mg/kg, pob
parameter
4o CH2CN
4p CH2F
100
100
23
21
13
3
parameter
0
90
4q CH2-3-Py 600 ( 160
Clp ((mL/min)/kg)
Vss (L/kg)
t1/2 (h)
23
Cmax (ng/mL)
469
1
a Kv1.5 IC50 determined on an IonWorks platform with CHO-
hKv1.5. b hERG IC50 values were obtained from Essen Instruments
Inc. c pH 7.4 buffer, direct UV method. d Human liver microsomal.15
e Fluorescent method.16
2.2
1.2
2412
Tmax (h)
t1/2 (h)
AUC (ng h/mL)
1.7
1989
82
AUC (ng h/mL)
3
3
bioavailability F (%)
a DMAC/PEG200, 10/90, 1 mL/kg. b 2% Tween/0.5% MC, 3 mL/kg.
Table 4. In Vitro Pharmacology of 4g
IW IC50 (nM)a
Kv1.5 hERG Nav1.5 Cav1.3 Cav1.2 Kv1.1 Kv1.3 Kv4.3
480 15100 >30 23.4 >30 2.66 1.41 3.87
EP IC50 (μM)b
a Kv1.5 IC50 determined on an IonWorks platform with CHO-
hKv1.5. hERG IC50 values were obtained from Essen Instruments
Inc. b EP IC50 values were determined with the following stably trans-
fected cell lines: CHO-Nav1.5, HEK-Cav1.3, HEK-Cav1.2, CHO-
Kv1.1, CHO-Kv1.3, CHO-Kv4.3.
Figure 4. Compound 4g reduced the average number of successful
AF/AFL inductions per dog that lasted between 5 and 10 min (1.1 (
0.3 vs 0.4 ( 0.2; p = 0.047, n = 8; 3 mg/kg).
Figure 3. Single crystal X-ray structure of KVI-020, 4g.
and a short elimination half-life (1.2 h). Oral pharmacokinetics
were characterized by a bioavailability of 82%, a half-life of
1.7 h, and a systemic exposure (AUC) of 1989 ng h/mL.
(R)-1-(Methylsulfonylamino)-3-[2-(4-methoxyphenyl)ethyl]-
4-(4-methoxyphenyl)-2-imidazolidinone (4g) was chosen for
further evaluation because of its Kv1.5 potency (IC50 =
480 nM), hERG selectivity (31 fold), and pharmaceutical
properties. Compound 4g was selective against hERG,
Nav1.5, Cav1.2, and Cav1.3 but was less selective for homo-
logous channels Kv1.1, Kv1.3, and Kv4.3 (Table 4). The
structure of 4g was confirmed by single crystal X-ray analysis
(Figure 3).
The druglike properties of 4g were examined (Table 5). Dog
microsomal stability was lower than human (t1/2 of 11 vs 30
min), and the reversible inhibition of Cyp450s 3A4, 2D6, and
2C9 in human liver microsomes was >37 μM. Caco-2 perme-
ability was high (A-B and B-A = 40 and 39 ꢀ 10-6 cm/s),
and substrate efflux was not observed. Beagle and human
protein binding were moderate.
The pharmacokinetics of 4g were evaluated in male beagles
at 3 mg/kg iv and 3 mg/kg po (Table 6). A single 30 min iv
infusion of 4g (3 mg/kg) demonstrated moderate clearance
(23 (mL/min)/kg), moderate volume of distribution (2.2 L/kg),
3
The in vivo efficacy of 4g was then evaluated in several
animal models. Prolongation of the atrial effective refractory
period (AERP) is a marker of antiarrhythmic activity, while
prolongation of the ventricular effective refractory period
(VERP) is an indicator of hERG liability.17 Compound 4g
was evaluated in a beagle model of AERP, and 12% and 17%
AERP prolongations were observed at 4.6 and 23 μM steady
state plasma concentrations (1.9 and 6.3 mg/kg, iv infusion).
VERP remained unchanged in both models, consistent with
the desired atrial selectivity. Overall cardiac function, includ-
ing HR, BP, and dp/dt, was not statistically different between
treatment groups and vehicle control.
4g was also evaluated in a canine model of AF, designed to
measure incidence of AF in a more clinically relevant setting.
In the canine atrial/ventricular tachypacing model,18 surgical
implantation of a pacemaker was followed by 2 weeks of high
atrial and ventricular pacing (220 bpm). This induced remo-
deling of the heart resulted in heart failure characterized as

6534 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 21
Blass et al.
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Figure 5. Compound 4g reduced mean AF/AFL duration per dog
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clinically relevant to the human condition. AF was induced
via burst pacing (10 s, 600 bpm). Following oral administra-
tion of 4g (n = 8, 3 mg/kg), the success rate of inducing AF for
5-10 min intervals decreased 63% (Figure 4), average AF
duration decreased 55% (Figure 5), and total AF burden
(total time in AF) decreased 52%.
In summary, 4g is a potent, selective blocker of the atrial
potassium channel Kv1.5. It demonstrated efficacy in clini-
cally relevant models of AF and mechanistic models of the
cardiac action potential. In addition, its pharmacokinetic and
pharmaceutical properties were acceptable for late stage pre-
clinical development, and KVI-020/WYE-160020 (4g) has
been advanced into development for the treatment of AF.
Acknowledgment. The authors thank the Department of
Analytical Chemistry group at Wyeth Research for support of
the studies described.
Supporting Information Available: Details of the synthesis
and characterization of 4a-q: protocols for in vitro and in vivo
experiments. This material is available free of charge via the
Internet at http://pubs.acs.org.
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