Evolution of thiazolidine-based blockers of human Kv1.5 for the treatment of atrial arrhythmias

Article abstract of DOI:10.1016/j.bmcl.2006.07.007

Blockade of the Kv1.5 ion channel is a potentially atrial-selective avenue for the treatment of atrial fibrillation and atrial flutter. The development and biological evaluation of a series of thiazolidine-based blockers of Kv1.5 is described.

Full text of DOI:10.1016/j.bmcl.2006.07.007

Bioorganic & Medicinal Chemistry Letters 17 (2007) 282–284
Evolution of thiazolidine-based blockers of human Kv1.5
for the treatment of atrial arrhythmias
Chris M. Jackson, Benjamin Blass, Keith Coburn, Laurent Djandjighian,
Gina Fadayel, Andrew J. Fluxe, Steven J. Hodson, John M. Janusz,*
Michael Murawsky, James M. Ridgeway, Ronald E. White and Shengde Wu
Procter and Gamble Pharmaceuticals, The Mason Business Center, 8700 Mason-Montgomery Road, Mason, OH 45040, USA
Received 25 May 2006; revised 26 June 2006; accepted 5 July 2006
Available online 13 November 2006
Abstract—Blockade of the Kv1.5 ion channel is a potentially atrial-selective avenue for the treatment of atrial fibrillation and atrial
flutter. The development and biological evaluation of a series of thiazolidine-based blockers of Kv1.5 is described.
Ó 2006 Elsevier Ltd. All rights reserved.
Atrial flutter and atrial fibrillation are the most common
cardiac arrhythmias and they are associated with an in-
crease in heart failure, stroke, and mortality.1–3 Atrial
fibrillation affects three million Americans and leads to
80,000 strokes each year. Irregular propagation of the
cardiac impulse leads to fibrillation. One approach to
prevent fibrillation involves increasing myocardial
refractoriness by blockade of repolarizing currents car-
ried by potassium ion (K+) channels. Most currently
marketed antiarrhythmic agents block the hERG chan-
nel and the associated IKr repolarizing current which is
present in both the atria and the ventricles. While block-
ade of hERG in the atria can reduce atrial arrhythmias,
blockade of hERG in the ventricles leads to a prolonga-
tion of the QT interval and an increased propensity for
life-threatening ventricular arrhythmias. Blockade of
atrial-selective K+ channels could provide an approach
for control of atrial arrhythmias that is devoid of ad-
verse ventricular effects. One such atrial-selective chan-
nel is Kv1.5 which carries the ultrarapid delayed
rectifier current IKur.4–6 The IKur current functions
selectively in human atrial cells so blockade of Kv1.5
may provide a promising approach for the development
of safe and effective drugs for prevention of atrial
arrhythmias.7,8 Several companies have pursued Kv1.5
inhibitors and much of this work has been summarized
in recent reviews.9,10
O
O
N
S
I
We began our search for novel Kv1.5 blockers with the
vicinally-substituted thiazolidinone class first reported
by Icagen.11 Our goal was to determine the scope of vic-
inally-substituted heterocycles as Kv1.5 blockers start-
ing from the thiazolidinone class as a prototype.
Thiazolidinones 4 were synthesized (Scheme 1) in a 3-
R1
Core Heterocycle
and Linker
NH2
1
O
Upper
Ring
O
N
SH
R1
HO
S
2
R3
O
R2
4
R3
Keywords: Atrial fibrillation; Potassium channel; Human Kv1.5; Thi-
azolidine; Atrial-selective.
Lower ring
R2
Scheme 1. Conditions: THF reflux.
3
*
Corresponding author. Tel.: +1 513 622 2146; fax: +1 513 622
0086; e-mail: janusz.jm@pg.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.07.007

C. M. Jackson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 282–284
283
component 1-pot reaction, with mercaptoacetic acid, a
phenethylamine, and an arylaldehyde. We chose to be-
gin our work by exploring the Kv1.5 blocking ability
of compounds with two key structural changes: (1) ke-
tone rather than aldehyde-derived thiazolidinones and
(2) incorporation of the carbonyl group in the linker
rather than the heterocyclic ring in the form of
acylthiazolidines.
ation with substituted or unsubstituted benzyl bromides
using DBU as a base provided the target blockers 6
(Scheme 2).
We began this investigation with an unsubstituted phen-
yl for the upper ring. From our previous work, we ob-
served that three lower ring substitutions consistently
provided active blockers; namely 4-Cl, 3,4-di-Cl, and
3,4-di-CH3. As expected, compounds 6a–c (Table 2)
were effective blockers of Kv1.5 with the 3,4-dimethyl
compound 6c being the most potent. Next, we prepared
four compounds with a p-methoxy R1 group in the
upper ring (6d–g). Compound 6d, where there is no sub-
stitution on the lower aryl ring (R2 = H), gave an IC50
more than five times greater than the others in this set.
The remaining three compounds (6e–g) were about
two- to fivefold more potent than the corresponding
des-methoxy compounds (6a–c), reinforcing the obser-
vation that a methoxy in the upper ring increases poten-
cy. Next, the effect of varying the position of the
methoxy group on the upper ring was examined. The
3-methoxy compounds (6h–i) and the 2-methoxy com-
pounds (6k–m) had similar potencies and each of these
compounds was about twofold less potent than the cor-
responding 4-methoxy analog.
At the outset, several benchmark thiazolidinones were
prepared and we soon discovered that a methoxy group
was preferred in the upper ring and that both electron
donating and electron withdrawing groups were allowed
in the lower ring (Table 1). Compound I, with a p-meth-
oxy in the upper ring and a 3,4-dimethyl arrangement in
the lower ring, was a potent Kv1.5 blocker with an IC50
value of 137 nM, in good agreement with the value
reported by Icagen.
The ketone-derived thiazolidinones 4a–d were prepared
from a series of substituted indanones and acetophenon-
es. The data in Table 1 show that compounds in both
series are sub-micromolar blockers of Kv1.5. The most
potent compound, 4d, derived from 3,4-dimethylace-
tophenone has an IC50 value of 69 nM, about twice
the potency of the Icagen compound I.
We next turned to changes in the thiazolidinone scaffold
to determine if the intact thiazolidinone was an essential
part of the pharmacophore or if it might serve primarily
as a scaffold for display of the upper and lower rings.
Thus, we moved the carbonyl group outside of the ring,
giving rise to thiazolidine amides and carbamates. The
chemistry (Scheme 3) began with reaction of an alde-
hyde 3 and cysteamine hydrochloride 7 to provide the
2-arylthiazolidine 8 which was then acylated with an
Both the Icagen compound and the ketone-derived thia-
zolidinones had low aqueous solubility ranging from ꢀ5
to 50 lg/mL. As an approach to improve solubility, we
replaced one of the carbons in the linker with oxygen
to provide N-alkoxythiazolidinones. The N-hydroxy
intermediate 5 was prepared using the same synthetic
methodology used for the thiazolidinones but employing
hydroxylamine in place of the phenylalkylamine. Alkyl-
Table 1. Blockade of Kv1.5 by ketone-derived thiazolidinones
O
O
N
R1
R1
O
O
Br
HO
a
O
N
+
+ HONH HCl
3
N
2
2
R1
b
S
S
S
R2
5
R2
6
R2
Compound
R1
R2
H
% Block
at 1 lM
Kv 1.5
IC50 (lM)
Scheme 2. Conditions: (a) THF reflux and (b) DBU, DMF.
Table 2. Blockade of Kv1.5 by N-alkoxythiazolidinones
I
0.137
0.812
0.487
0.390
0.069
Compound
R1
R2
%Block
at 1 lm
Kv 1.5
IC50 (lM)
6a
6b
6c
6d
6e
6f
H
4-Cl
35
77
0.997
0.463
0.207
0.924
0.187
0.113
0.095
0.380
0.179
0.269
NT
4a
4b
4c
4d
66
61
88
96
H
3, 4-di-Cl
3, 4-di-CH3
H
Cl
H
92
4-OMe
4-OMe
4-OMe
4-OMe
3-OMe
3-OMe
3-OMe
2-OMe
2-OMe
2-OMe
NT
NT
92
4-Cl
3, 4-di-Cl
3, 4-di-CH3
4-Cl
6g
6h
6i
NT
NT
NT
75
CH3
CH3
3, 4-di-Cl
3, 4-di-CH3
4-Cl
6j
6k
6l
25
3, 4-di-Cl
3, 4-di-CH3
NT
92
0.204
0.177
6m

284
C. M. Jackson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 282–284
R1
Table 4. Blockade of Kv1.5 by thiazolidine amides (R2 = 3,4-di-Me)
R1
O
O
Compound
X
R1
% Block
at 1 lm
Kv1.5
IC50 (lM)
X
Y
HN
NH2
a
N
X
HS
+
3
S
b
7
S
9h
9i
OCH2
CH2CH2
CH2
H
18
87
77
89
92
68
8
9
R2
H
R2
9j
OMe
OMe
OMe
OMe
0.537
0.150
9k
9l
CH2CH2
CH=CH
CH2CH2CH2
Scheme 3. Conditions: (a) TEA, DMF and (b) TEA, CH2Cl2.
9m
Table 3. Blockade of Kv1.5 by thiazolidine carbamates (R1 = H,
X=CH2O)
and sulfone metabolites 10b and 10c, and they were
compared by LCMS with the isolate from the S9 assay.
Compound R2
%Block at 1 lm Kv1.5 IC50 (lM)
9a
9b
9c
9d
9e
9f
4-Me
4-OMe
4-c-Pr
80
72
64
55
O
O
4-N(Me)2
3, 4-di-CH3
3, 4-di-Cl
95
93
0.162
N
S
9g
4-OMe, 3-Cl 35
O
n
Cl
Cl
10a n=0
10b n=1
10c n=2
appropriate acid, acid chloride or chloroformate, giving
the target compounds 9.
The result confirmed that the sulfur was the main site
for metabolic oxidation. This prompted us to aban-
don the thiazolidinone scaffold and to explore isoster-
ic alternatives that might provide more metabolically
stable compounds. These efforts will be reported
separately.
A series of compounds (9a–g) was made using benzyl
chloroformate for the acylating agent (R1 = H) and sev-
en different substitutions (R2) in the lower ring (Table
3). These were screened at 1 lM concentration for block
of Kv1.5. All the compounds except for 9g produced at
least 50% inhibition of current. The 3,4-d-CH3 and 3,4-
di-Cl, compounds 9e and9f, were the most active, with
the 3,4-di-CH3 compound 9e giving an IC50 similar to
the corresponding N-alkoxythiazolidinone 6c (Table
2). These results demonstrate that the carbonyl group
does not need to be part of the heterocyclic ring and pro-
vided the first data to suggest that the heterocyclic ring
might serve primarily as a scaffold for appropriate orien-
tation of the vicinal side chains.
Acknowledgments
The authors would like to acknowledge: David Ackley,
Timothy Baker, Charlie Cruze, David Foltz, Michael
Karb, Mike Quijano, Pam Riley, Amy Walter, and
Ken Wehmeyer for their work in the areas of compound
metabolic stability, metabolite identification, and
bioavailability.
We then changed our focus to amides (Table 4) 9h–m. The
first amide that we made, 9h, reversed the CH2O orienta-
tion in the linker versus the corresponding carbamate 9e
which resulted in a dramatic loss in activity. Next, we
examined a series of homologous compounds with all car-
bon linkers 9i–m. All the compounds showed good block-
ade with the two carbon linker, compound 9k, the most
active in the saturated series. IC50 determinations con-
firmed that the two carbon linker provided a more potent
compound than the one carbon linker (9k vs 9j). Adding
rigidity to the two carbon linker in the form of an alkene
provides compound (9l) that retained good activity.
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