Benzopyran sulfonamides as KV1.5 potassium channel blockers

Article abstract of DOI:10.1016/j.bmcl.2007.04.020

K_V1.5 blockers have the potential to be atrium-selective agents for treatment of atrial fibrillation. The benzopyrans provide a template for the synthesis of potent and selective K_V1.5 blockers.

Full text of DOI:10.1016/j.bmcl.2007.04.020

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3271–3275
Benzopyran sulfonamides as KV1.5 potassium channel blockers
John Lloyd,* Karnail S. Atwal, Heather J. Finlay, Michael Nyman, Tram Huynh,
Rao Bhandaru, Alexander Kover, Joan Schmidt, Wayne Vaccaro, Mary Lee Conder,
Tonya Jenkins-West and Paul Levesque
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA
Received 2 February 2007; revised 2 April 2007; accepted 4 April 2007
Available online 10 April 2007
Abstract—KV1.5 blockers have the potential to be atrium-selective agents for treatment of atrial fibrillation. The benzopyrans
provide a template for the synthesis of potent and selective KV1.5 blockers.
Ó 2007 Elsevier Ltd. All rights reserved.
Atrial fibrillation (AF) is a cardiac arrhythmia that af-
fects a large and growing population. Over 2 million
cases were reported in the US in 1999 and that number
has increased 2- to 3-fold over that last 15 years.1 Inci-
dence of AF increases with age so that the number of
cases will likely increase in the future.2 Although AF is
not a fatal condition, the inefficient emptying of the
atrium can lead to thrombus formation. The primary
mortality risk in AF is from stroke.3
mias.4 Unfortunately, prolongation of repolarization
in the ventricle at normal heart rates has been shown
to also cause arrhythmia. The polymorphic ventricular
tachycardia torsades de pointes can be caused by block
of repolarization in the ventricle and can lead to fatal
ventricular fibrillation.5
The ultrarapid potassium current (IKur) is an important
repolarizing current that in humans is expressed in the
atrium but not ventricle.6 Therefore, selective block of
this current may lead to a method of treating atrial
arrhythmia without the risk of ventricular effects. IKur
is conducted by the voltage gated potassium channel
encoded by KV1.5.7 Drugs that block this channel have
the potential to increase atrial action potential duration
and prevent and/or terminate atrial fibrillation with
increased safety.
Cardiac rhythm is regulated by the cyclic changes in
membrane potential of the cardiac myocytes. Changes
in membrane potential are regulated by the opening
and closing of ion channels. Together, ionic currents
contribute to the shape of the membrane potential ver-
sus time relationship known as the action potential.
After excitation and depolarization caused by the influx
of sodium and then calcium ions, the myocytes return to
their resting potential following the efflux of potassium
ions. This final repolarization phase is necessary for an-
other excitation and contraction to occur. The net
potassium current is conducted through several different
potassium channels, including the rapid (IKr) and slow
(IKs) delayed rectifier potassium currents. Block of the
IKr with class III antiarrhythmic drugs (e.g., dofetilide)
results in delayed repolarization and has been shown
to effectively treat both atrial and ventricular arrhyth-
Researchers at Icagen discovered an indane compound
(1) that blocked KV1.5 (Fig. 1).8 We proposed that the
indane template could be replaced by the benzopyran
template and we wished to test this hypothesis with
the synthesis of KV1.5 blockers based on a benzopyran.
O
S
HN
H
N
O
Keywords: KV1.5; IKur; Ultra rapid potassium current; Potassium ion
channel; Ion channel blocker; Antiarrhythmic; Atrial arrhythmia;
Atrial fibrillation.
MeO
OH
1
O
*
Corresponding author. Tel.: +1 609 818 5327; fax: +1 609 818
3331; e-mail: john.lloyd@bms.com
Figure 1. Indane KV1.5 blocker.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.04.020

3272
J. Lloyd et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3271–3275
O
NH2
O
O
e
a, b, c, d
S
OH
2
NH2
O
HN
O
N
H
O
NC
OH
HO2C
OH
O
S
a, b
R
6
O
HN
O
O
O
S
3
2
OH
N
H
HN
7a-h
O
H
c, d, e
N
OH
MeO
O
compd
R
compd
R
O
4
7a
7b
7c
7d
H
7e
7f
2-OCF3
4-F
Scheme 1. Reagents and condition: (a) HCl, H2O, 100 °C (99%); (b) 4-
EtPhSO2Cl, NaOH (1 M aq), THF (27%); (c) Ph2PON3, t-BuOH,
dioxane, Et3N (46%); (d) TFA, CH2Cl2 (65%); (e) 3-MeO–Ph–COCl,
Et3N, CH2Cl2 (75%).
4-CF3
4-CH3
3-CH3
7g
7h
4-OCH3
4-NO2
Scheme 3. Reagents and condition: (a) HCl, H2O, 100 °C (99%);
(b) BOC2O, NaOH (1 M aq), THF (24%); (c) PhCH2CH2NH2, EDC,
HOBt, NMM, CH2Cl2, (99%); (d) TFA, CH2Cl2 (77%); (e)
R-PhSO2Cl, Et3N, CH2Cl2 (60–84%).
The benzopyran template was available from the known
3S,4R-aminoalcohol (2).9 Hydrolysis of the nitrile
followed by sulfonylation of the amine provided the acid
3 (Scheme 1). The 6-aminobenzopyran analog of the
indane was synthesized from the acid using the Arndt–
Eistert synthesis to form the amine which was coupled
with 3-methoxybenzoyl chloride to provide the amide 4.
Analogs with variation in the sulfonamide fragment
were synthesized from 2 by hydrolysis of the nitrile
and BOC protection of the amine followed by amide
formation with phenethylamine. Deprotection and sub-
sequent sulfonylation provided the analogs 7a–h
(Scheme 3).
The reversed amide analog (5a) of amide 4 and addi-
tional amide analogs 5b–m were synthesized from acid
3 using standard coupling procedures (Scheme 2).
The tertiary sulfonamides 9a–f were synthesized from
the amine 6 by reductive amination followed by sulfony-
lation (Scheme 4).
O
S
O
S
O
HN
O
HN
O
O
O
OH
HO2C
OH
R
R
Compounds with the opposite stereochemistry of the
amino alcohol were synthesized from the known
3R,4S-benzopyran10 by methods described (Schemes 1
and 2). Thus we synthesized analogs of 5e and 5g–j with
3R,4S-configuration (10a–e).
a or b,c
5a-m
3
compd
compd
5g
R
H
N
The des-hydroxy compound 11 was synthesized from
the amino alcohol 2 by sulfonylation followed by thio-
5a
5b
5c
5d
5e
5f
MeO
N
H
N
N
H
N
R
O
NH
O
5h
5i
N
H
a
6
OH
N
H
O
S
N
N
8
N
b
F
R
N
H
O
N
O
O
OH
N
H
9a-f
5j
N
N
H
compd
9a
compd
9d
R
R
5k
N
H
N
N
N
n-Bu
NH2
H
N
N
N
N
5l
9b
9c
9e
9f
N
H
HN
N
N
5m
N
H
HN
Scheme 2. Reagents: (a) amine, EDC, HOAt, CH2Cl2 (40–90%);
(b) TFFH, Et3N, CH2Cl2 (90%); (c) amine, Et3N, MeCN (30–85%).
Scheme 4. Reagents: (a) R-CHO, NaBH(OAc)3, HOAc (22–58%);
(b) 4-EtPhSO2Cl, Et3N, CH2Cl2 (9–71%).

J. Lloyd et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3271–3275
Table 1. Indane and benzopyran anaolgs
3273
O
S
Compound
KV1.5 inhibition IC50a(lM)
1
0.033
0.29
>10
HN
a, b, c, d, e
O
HN
O
4
5a
5b
5c
5d
5e
5f
5g
5h
5i
N
2
11
>1.0
0.28
0.17
0.26
0.077
0.12
0.13
0.17
0.21
0.079
>1.0
>10
O
Scheme 5. Reagents: (a) 4-EtPhSO2Cl, Et3N, CH2Cl2 (85%); (b)
Im2CS, C2H4Cl2 (85%); (c) n-Bu3SnH, AIBN, MePh; (d) KOH,
HOC2H4OH; (e) pyrrolidine, EDC, HOAt, DMF (31% 3 steps).
carbonylimidazolide formation then reduction.10
Hydrolysis of the nitrile to the acid followed by amide
formation provided 11 (Scheme 5).
5j
5k
5l
5m
a Values are means of 2–4 experiments.
The analog with replacement of the amide functionality
at the 6-position with an isosteric amine 12 was synthe-
sized by reduction of the amide 5e. The amidine 13 was
synthesized by sulfonylation of the nitrile 2 followed by
formation of the imidate and reaction with phenethyl-
amine. The sulfonamide 15 was made from the sulfonyl-
chloride 1411 by formation of the sulfonamide followed
by epoxide formation, ring opening with ammonia, and
sulfonylation (Scheme 6).
contained combinations of aryl and alkyl substituents
(5b–e).
We were interested in the tolerance for basic functional-
ity. Amides with both anilines (5f–h) and alkyl amines
(5i–j) showed potency in the range of 0.08–0.2 lM (Ta-
ble 1). The amide of 5-phenyl-3-aminopyrazole (5k) was
among the most potent compounds we discovered.
However, not all basic functionality was tolerated. Pyr-
idine and imidazole replacements of the phenyl ring in
5e resulted in compounds (5l and 5m) that showed little
KV1.5 block.
All the compounds were tested for block of potassium
current in mouse fibroblast L929 cells expressing human
KV1.5.12 The initial compounds were direct analogs of 1
where we retained the 4-ethylphenylsulfonamide but
modified the substituent at the 6-position of the benzo-
pyran (Table 1). The direct benzopyran analog 4 showed
a 10-fold decrease in potency from the indane, however,
it still retained significant potency. Although the re-
versed amide analog 5a lost additional potency, we felt
we could re-optimize this chemotype using automated
synthesis. This proved to be the case and we quickly
identified alternate substituents that significantly
improved potency over 5a. In many cases, these
Our investigation then turned to the sulfonamide substi-
tuent. We first modified substituents on the benzenesulf-
onamide while the 6-position substituent was held as
the 2-phenylethylamide. The unsubstituted benzenesulf-
onamide (7a) was much less potent than the 4-ethyl
compound (5e). The compounds containing either
4-trifluoromethyl (7b), 4-methyl (7c), 3-methyl (7d) or
2-trifluoromethoxy (7e) groups had about the same
potency as the 4-ethylbenzenesulfonamide (5e). How-
ever, the 4-fluoro (7f), 4-methoxy (7g), and 4-nitro (7h)
substituents were significantly less potent (Table 2).
O
S
HN
O
OH
Additional substitution on the sulfonamide nitrogen
appeared to be well tolerated and enhanced potency in
some cases (Table 3). The simple butyl substituent
provided one of our most potent compounds (9a).
Compounds 9b and 9c with branched alkyl groups were
N
H
a
5e
O
12
O
S
NH
HN
O
O
OH
N
H
b, c, d
Table 2. Sulfonamide substituents
2
13
Compound
KV1.5 inhibition IC50a(lM)
O
5b
7a
7b
7c
7d
7e
7f
0.26
>1.0
0.20
0.40
0.34
0.15
>1.0
>1.0
>1.0
S
O
S
HN
O
O
ClO2S
14
OH
N
H
O
e, f, g, b
O
15
Scheme 6. Reagents and condition: (a) LiAlH4, THF, 67 °C (13%); (b)
4-EtPhSO2Cl, Et2N, CH2Cl2 (80%); (c) HCl, EtOH; (d)
PhCH2CH2NH2 (47% 2 steps); (e) PhCH2CH2NH2, Et3N, CH2Cl2
(87%); (f) mCPBA, CH2Cl2; (g) NH4OH, THF, EtOH (71% 2 steps).
7g
7h
a Values are means of 2–4 experiments.

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J. Lloyd et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3271–3275
Table 3. Amide benzopyran analogs
Table 5. Amide replacements
KV1.5 inhibition IC50a(lM)
Compound
KV1.5 inhibition IC50a(lM)
Compound
9a
9b
9c
9d
9e
9f
0.057
0.32
0.12
0.13
0.12
0.28
5e
13
12
15
0.26
>10
0.24
0.51
a Values are means of 2–4 experiments.
a Values are means of 2–4 experiments.
Table 6. Block of hERG
Compound
% Inhibition at 10 lMa
Table 4. Amino alcohol modifications
1
21%
40%
7%
Compound
KV1.5 inhibition IC50a(lM)
4
5e
5g
0.26
0.12
0.13
0.17
0.21
0.19
>1
5d
5f
39%
9%
5h
5i
5g
5k
9a
9d
10d
11
47%
35%
61%
80%
51%
5j
5g
10a
10b
10c
10d
10e
11
0.26
0.089
0.20
0.22
0.11
a Values are means of 2–4 experiments.
a Values are means of 2–4 experiments.
In conclusion, we have established that the benzopy-
ran core is an acceptable scaffold for potent IKur
blockers. We have explored modifications of this scaf-
fold including the amide at the 6-position, the substi-
tuent on the phenyl ring of the benzenesulfonamide,
and modifications of the amino alcohol template.
We have discovered several compounds with good
potency for block of IKur and good selectivity over
block of hERG. In subsequent publications we will
discuss further modification of the benzopyran core
structure.
less potent than 9a. Some basic substituents were toler-
ated. The pyridylmethyl compounds 9d and 9e were
about 2-fold less potent than the n-butyl compound
9a, however, the imidazomethyl compound 9f suffered
significant loss of potency.
We were also interested in investigating some modifi-
cations of the amino alcohol template. We reversed
the stereochemistry of the amino alcohol in 5e and
5g–i to give the 3R,4S analogs 10a–e. This modifica-
tion was not well tolerated in the neutral phenethyl
compound 10a but was tolerated in the analogs
containing a basic amine (10b–e). Among these basic
analogs, stereochemistry of either the amide or the
benzopyran makes little difference in blocking potency.
This suggests that the compounds that contain an
amine may bind differently from the neutral com-
pounds. The des-hydroxy compound (11) was as
potent as the hydroxy compound (5g) indicating that
the alcohol is not important for interaction with the
channel protein (Table 4).
Acknowledgment
This paper is dedicated to the memory of Karnail S.
Atwal.
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