Aryl sulfonamido tetralin inhibitors of the Kv1.5 ion channel

Article abstract of DOI:10.1016/j.bmcl.2009.04.002

Aryl sulfonamido tetralins based on lead compound 2a were synthesized and evaluated for Kv1.5 inhibitory activity. Several compounds having IC₅₀ values less then 0.1 μM were identified. Kv1.5 inhibitors have the potential to be atrium-selective agents for the treatment of atrial fibrillation.

Full text of DOI:10.1016/j.bmcl.2009.04.002

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3063–3066
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Bioorganic & Medicinal Chemistry Letters
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Aryl sulfonamido tetralin inhibitors of the Kv1.5 ion channel
*
Michael F. Gross, Neil A. Castle , Anruo Zou, Alan D. Wickenden, Weifeng Yu, Kerry L. Spear
Icagen Inc., PO Box 14487, Research Triangle Park, NC 27709, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Aryl sulfonamido tetralins based on lead compound 2a were synthesized and evaluated for Kv1.5 inhib-
Received 29 January 2009
Revised 1 April 2009
Accepted 3 April 2009
Available online 8 April 2009
itory activity. Several compounds having IC50 values less then 0.1
have the potential to be atrium-selective agents for the treatment of atrial fibrillation.
Ó 2009 Elsevier Ltd. All rights reserved.
lM were identified. Kv1.5 inhibitors
Keywords:
Voltage-gated potassium channel
Kv1.5
Atrial fibrillation
The need for safe and effective drugs to treat atrial fibrillation
(AF) is growing. AF is a common cardiac rhythm abnormality that
affects millions of people, particularly the elderly.1 Projections sug-
gest that as many as 5.6 million adults in the United States will be
affected by AF by 2050.2 AF can reduce cardiac performance and is
a serious risk factor for stroke.3
Voltage-gated potassium channel blockers hold promise as
therapeutic agents for the treatment of atrial AF. Several potassium
channels including IKr, IKs and IKur play prominent roles in cardiac
action potential repolarization.4 Existing treatment options for at-
rial stabilization typically inhibit more then one of these potassium
currents and inevitably influence atrial as well as ventricular
refractoriness.1a IKur is not detected in ventricular cells which
makes it is a particularly attractive molecular target for the treat-
ment of AF.5 In humans, the IKur current is conducted by the volt-
age-gated potassium channel encoded by Kv1.5.6 Thus, selective
blockade of Kv1.5 should prevent and/or terminate AF without
the threat of ventricular side effects.
Our search for Kv1.5 inhibitors led to the identification of aryl
sulfonamido indane 1, a potent, selective potassium channel block-
er.7 Initial structure–activity relationship (SAR) discoveries estab-
lished that Kv1.5 inhibitory activity was maintained upon
expansion of the five-membered saturated ring (indane scaffold)
to the six-membered ring (tetralin scaffold). In this communication
we would like to report our SAR studies designed to optimize the
Kv1.5 inhibitory activity of aryl sulfonamido tetralin 2a (Fig. 1).8
A series of tetralins having substituent variations in the sulfon-
amido fragment was synthesized as shown in Scheme 1. Ketone
reduction of 7-nitro-1-tetralone (3), dehydration, epoxidation with
m-CPBA and ring opening with ammonium hydroxide gave the
trans-amino alcohol 4. Amine protection, nitro reduction and cou-
pling with m-anisoyl chloride provided 5. Deprotection followed
by sulfonylation afforded analogs 2a–r.
Aryl sulfonamido tetralins having substituent variations in ami-
do fragment were prepared as described in Scheme 2. Certain
amide bioisosteres were also synthesized. Sulfonylation of amino
alcohol 4 with 4-ethylphenylsulfonyl chloride followed by nitro
reduction provided aniline 6. Coupling of 6 with carboxylic acids
or acid chlorides gave the amido analogs 7a–n.9 The carbamate
7o and urea 7p were prepared by reacting 6 with benzyl chlorofor-
mate and benzyl isocyanate, respectively.
In order to determine if the 2-hydroxyl group interacted with
the channel protein, aryl sulfonamido tetralins lacking this func-
tionality were prepared (Scheme 3). Reductive amination of 7-ni-
tro-1-indanone (3), sulfonylation and nitro reduction gave aniline
8. Coupling of 8 with m-anisoyl chloride or hydrocinnamoyl chlo-
ride provided the des-hydroxy analogs 9a and 9b, respectively.
Aryl sulfonamido tetralins having more elaborate amido modi-
fications were synthesized. These efforts were designed to incorpo-
rate an ionizable center into the molecule in an attempt to improve
Et
OMe
OMe
O
O
Et
S
S
O
HN
HN
H
N
H
N
O
OH
OH
O
O
1
2a
Kv1.5 IC50 0.44 µM
Kv1.5 IC50 0.16 µM
* Corresponding author.
E-mail address: ncastle@icagen.com (N.A. Castle).
Figure 1. Structure of Kv1.5 inhibitors indane 1 and tetralin 2a.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.002

3064
M. F. Gross et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3063–3066
NH2
Et
O
e-g
a-d
O2N
OH
O
O2N
a-c
S
HN
6
H
N
O
OH
4
N
3
OMe
R5
O
OMe
R1
O
S
NHBoc
OH
h, i
HN
H
O
OH
H
N
11a-l
N
O
O
Scheme 5. Reagents and conditions: (a) (S)-(À)-N-(trifluoroacetyl)prolyl chloride,
5
2r-a
NEt3, DMF, 59%; (b) K2CO3, H2O, MeOH, 65%; (c) R5-PhCH2Br, K2CO3, MeCN, 70% for
11a.
Scheme 1. Reagents and conditions: (a) NaBH4, MeOH, 99%; (b) catalytic TsOH-
H2O, toluene, 100 °C, 100%; (c) m-CPBA, CH2Cl2, 100%; (d) NH4OH, THF/EtOH, 50 °C,
89%; (e) Boc2O, NEt3, THF, 71%; (f) NaBH4, catalytic NiCl2, THF/MeOH, 89%; (g)
m-anisoyl chloride, NEt3, CH2Cl2, 81%; (h) 4 N HCl, dioxane, 86%; (i) R1-PhSO2Cl,
catalytic DMAP, NEt3, THF, 52% for 2d.
presented in Table 1. In order to rapidly establish a SAR, the amido
fragment was held as m-anisoyl. Kv1.5 activity tended to improve
as the size of the alkyl substituent in the 4-position increased from
ethyl to n-pentyl (2a–f). Unfortunately, the improvement in
potency achieved by adding more lipophilicity was offset by a cor-
responding reduction in aqueous solubility (see 2a vs 2e, Table 2).
Replacing the ethyl of 2a with a methoxy (2j) resulted in a consid-
erable loss in activity. Methyl (2h), trifluoromethyl (2i), nitro (2k),
halo (2l–n) and hydrogen (2g) substitution in the 4-position also
resulted in compounds having diminished Kv1.5 activity relative
to 2a. Likewise, methyl (2o) or halo (2p–r) substitution in the 2-
or 3-position was not tolerated.
Et
Et
O
O
S
S
a, b
c, d
or e
HN
HN
4
O
OH
O
OH
H
N
H2N
R2
O
7a-p
6
Turning our attention to the amido portion of the molecule, the
sulfonamide fragment was held as 4-ethylphenyl (Table 3). In the
benzamido series, the 2- and 4-OMe analogs (7b and 7c, respec-
Scheme 2. Reagents and conditions: (a) 4-Et-PhSO2Cl, catalytic DMAP, NEt3, THF,
67%; (b) NaBH4, catalytic NiCl2, THF/MeOH, 89%; (c) R2COCl, NEt3, DMF, 66% for 7l;
(d) R2CO2H, (EtO)2P(O)–OBt, NEt3 DMF, 18% for 7m; (d) BnNCO, THF for 7p, 48%.
Table 1
Kv1.5 activity of tetralins having sulfonamido variations
Et
Et
O
O
HN
OMe
R1
O
S
S
a-c
d
HN
3
O
O
S
O
H
N
H2N
R3
HN
H
N
OH
O
O
9a, b
8
2a-r
Scheme 3. Reagents and conditions: (a) NH4OAc, Na(CN)BH3, MeOH, 77%; (b) 4-Et-
PhSO2Cl, NEt3, THF, 58%; (c) NaBH4, catalytic NiCl2, THF/MeOH, 97% (d) R3COCl,
NEt3, THF, 78% for 9a.
Compound
R1
IC50 (lM) or inhibition at 1 l
Ma
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
4-Et
4-n-Pr
4-i-Pr
4-n-Bu
4-t-Bu
4-n-Pent
H
2-Me
4-CF3
4-OMe
4-NO2
4-Br
4-Cl
4-F
3-Me
3-Cl
0.44
0.09
0.43
0.14
0.16
0.07
14 2%
30 2%
21 6%
3.0
the aqueous solubility of these Kv1.5 inhibitors. Reaction of 6 with
bromoacetyl bromide provided an
a-bromoacetamido intermedi-
ate that participated in displacement reactions with aryl- or al-
kyl-amines to give glycinamido analogs 10a–h (Scheme 4).
Reaction of
6
with (S)-(À)-N-(trifluoroacetyl)prolyl chloride,
deprotection and reaction with benzyl bromides gave the proli-
namido analogs 11a–l as a mixture of diastereomers (Scheme 5).
Compounds were tested for inhibition of potassium current in
LtkÀ or mouse fibroblast L929 cells expressing human Kv1.5 using
patch-clamp electrophysiological (EP) techniques.10 Inhibition of
the hERG current was also measured using EP. In this study, com-
pounds were synthesized and tested as racemic mixtures.
6
2%
14 12%
11 1%
5
7
2
2
3
1%
1%
2%
2%
2%
3-F
2-F
We began this investigation by preparing aryl sulfonamido tet-
ralins having substituent variations in the sulfonamide fragment as
a
Inhibition values are means of at least two experiments SEM.
Table 2
Et
Aqueous solubility of Kv1.5 inhibitors11
O
a, b
S
HN
6
Compound
l
g/mL
H
N
O
R4
OH
N
H
2a
2e
7j
7l
9a
9b
5
0.3
2
0.6
0.2
<0.1
O
10a-h
Scheme 4. Reagents and conditions: (a) bromoacetyl bromide; NEt3, DMF, 75%; (b)
R4NH2, K2CO3, MeCN, 60% for 10a.

M. F. Gross et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3063–3066
3065
Table 3
Table 5
Kv1.5 activity of tetralins having amido variations
Kv1.5 inhibition of glycinamido analogs
Et
Et
O
O
S
O
S
O
HN
HN
H
N
R4
OH
H
N
R2
OH
N
H
O
O
10a-h
7a-p
R2
IC50 (lM) or inhibition at 1 l
Ma
Compound
R4
1
l
Ma (%)
Compound
10a
10b
10c
10d
10e
10f
Ph
10
13
25
39
15
18
31
34
1
1
4
5
2
3
5
3
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7
7l
7m
7n
7o
7p
Ph
19 4%
0.45
0.45
28 2%
0.71
0.34
2-Me-Ph
3-Me-Ph
3-OMe-Ph
4-Et-Ph
4-OMe
2-OMe-Ph
4-OMe-Ph
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
3,5-Di-OMe-Ph
PhCH2
3-MeO-PhCH2
PhCH2CH2
PhOCH2
trans-PhCH@CH
PhCC
trans-Ph-cprop
PhCH2O
10g
10h
PhCH2
PhCH2CH2
0.64
22 4%
28 4%
0.25
22 3%
0.20
0.43
0.35
0.23
0.61
a
Inhibition values are means of at least two experiments SEM.
Prompted by our desire to incorporate more polarity into these
molecules in an attempt to improve the aqueous solubility, we pre-
pared a series of glycinamido analogs (10a–h). Compound 10a was
a weak Kv1.5 inhibitor. As presented in Table 5, neither substitu-
tion on the phenyl ring (10b–f) nor chain extension to give the
benzyl 10g or phenethyl 10h derivatives significantly improved
activity.
We continued to search for opportunities to incorporate a basic
center into the amido side chain and discovered that the diastereo-
meric prolinamido analogs 11a–l were potent Kv1.5 blockers. A
variety of phenyl substitution patterns were equally well tolerated
(Table 6). It is noteworthy that 11a is considerably more active
than the isosteric glycinamido analog 10g. The conformational
constraint imposed by the pyrrolidine ring may be responsible
for the increase in potency.
Selected compounds were tested for their ability to inhibit the
hERG potassium channel. These data are presented in Table 7. Inhi-
bition of this cardiac current is problematic due to the potential
induction of unwanted ventricular side effects.12 We were satisfied
with the selectivity of 2b that we estimated to be >100-fold (Kv1.5
IC50 0.09 lM; hERG <50% inhibition at 10 lM). Unfortunately,
prolinamido analogs 11c and 11f did not display this level of selec-
tivity and our interest in this chemical series was diminished.
PhCH2N(H)
a
Inhibition values are means of at least two experiments SEM.
tively) were about the same potency as the 3-OMe analog 2a. A
decrease in activity was observed with 3,5-di-OMe substitution
(7g). Potency was improved slightly upon 4-Cl substitution (7f),
but diminished with 2- and 3-Cl substitution (7d and 7e, respec-
tively). Albeit limited in scope, no firm SAR deductions could be
made from this study. Other opportunities to increase Kv1.5 inhib-
itory activity with amido modifications were explored.
Phenacetamido analogs 7h and 7i were weak Kv1.5 inhibitors.
Extending the methylene spacer to provide hydrocinnamamido
derivative 7j afforded a Kv1.5 inhibitor having improved potency
relative to 2a. Follow-up chemistry on this observation identified
other compounds having good activity including the trans-cinna-
mamido 7l, phenylpropynamido 7m and trans-phenylcyclopropa-
namido 7n analogs. A drop off in activity was observed with
phenoxyacetamido 7k. The benzyl carbamate 7o and benzyl urea
7p derivatives retain Kv1.5 potency indicating amido bioisosteres
are tolerated. Once again, the aqueous solubility of at least two
of these more lipophilic aryl sulfonamido tetralins (7j and 7l) is
diminished relative to 2a (Table 2).
Table 6
As we anticipated from previous studies with aryl sulfonamido
indanes, the hydroxyl group on the tetralin scaffold was not a crit-
ical element of the Kv1.5 pharmacophore.7 The des-hydroxy ana-
logs 9a and 9b retained Kv1.5 inhibitory activity (Table 4).
However, removing the hydroxyl group was problematic since
the des-hydroxy analogs were at least 20-fold less soluble (see
2a vs 9a, and 7j vs 9b, Table 2).
Kv1.5 activity of prolinamido analogs
Et
O
S
O
HN
H
N
OH
N
R5
O
11a-l
Compound
R5
H
2-Cl
3-Cl
3-CF3
3-OCF3
3-OMe
3-Me
4-Cl
4-CF3
4-OCF3
4-Me
4-t-Bu
IC50 (lM) or inhibition at 1 l
Ma
Table 4
Kv1.5 activity of des-hydroxy tetralins
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11
77 2%
87 2%
0.22
89 3%
0.29
Et
O
S
O
HN
H
N
R3
0.30
78 2%
92 1%
89 1%
86 1%
75 1%
80 6%
O
9a,b
Compound
R3
IC50 (lM)
11l
9a
9b
3-OMe-Ph
PhCH2CH2
0.59
0.28
a
Inhibition values are means of at least two experiments SEM.

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M. F. Gross et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3063–3066
Table 7
hERG inhibiton of tetralins
References and notes
1. (a) Page, R. L.; Roden, D. M. Nat. Rev. Drug Disc. 2005, 4, 889; (b) Lloyd-Jones, D.
M.; Wang, T. J.; Leip, E. P.; Larson, M. G.; Levy, D.; Vasan, R. S.; D’Agostino, R. B.;
Massaro, J. M.; Beiser, A.; Wolf, P. A.; Benjamin, E. J. Circulation 2004, 110, 1042.
2. Go, A. S.; Hylek, E. M.; Phillips, K. A.; Chang, Y.; Henault, L. E.; Selby, J. V.; Singer,
D. E. JAMA 2001, 285, 2370.
Compd
10
l
Ma (%)
2b
11c
11f
39
77
50
2
5
6
3. Crystal, E.; Connolly, S. J. Heart 2004, 90, 813.
4. Nerbonne, J. M.; Kass, R. S. Physiol. Rev. 2005, 85, 1205.
a
Inhibition values are means of at least two experiments SEM.
5. Li, G.-R.; Feng, J.; Yue, L.; Carrier, M.; Nattel, S. Circ. Res. 1996, 78, 689.
6. Fedida, D.; Wible, B.; Wang, Z.; Fermini, B.; Faust, F.; Nattel, S.; Browm, A. M.
Circ. Res. 1993, 73, 210.
7. Gross, M. F.; Beaudoin, S.; McNaughton-Smith, G.; Amato, G. S.; Castle, N. A.;
Huang, C.; Yu, W. Bioorg. Med. Chem. Lett. 2006, 17, 2849.
8. The compounds in this letter were first disclosed in patent application
WO9937607.
9. Benzotriazol-1-yl diethyl phosphate was used as the coupling reagent. See:
Kim, S. et al. Tetrahedron Lett. 1985, 26, 1341.
10. Synders, D. J.; Tamkun, M. M.; Bennett, P. B. J. Gen. Physiol. 1993, 101, 513.
11. Aqueous solubility of the crystalline solids were determined in 50 mM phosphate
buffered saline at pH 6.8 using the shake-flask method and LC/MS/MS detection.
12. (a) Recanatini, M.; Poluzzi, E.; Masetti, M.; Cavalli, A.; De Ponti, F. Med. Res. Rev.
2005, 25, 133; (b) Clancy, E. E.; Kurokawa, J.; Tateyama, M.; Wehrens, X. H. T.;
Kass, R. S. Annu. Rev. Pharmacol. Toxicol. 2003, 43, 441; (c) Yang, T.; Snyders, D.;
Roden, D. M. J. Cardiovasc. Pharm. 2001, 38, 737.
In summary, we have discovered that aryl sulfonamido tetralins
are Kv1.5 inhibitors. Investigation of the sulfonamido fragment re-
vealed a tight SAR with strong preference for para-alkyl substitu-
tion on the phenyl ring. In contrast, a more diverse set of
variations was tolerated on the amido portion of the molecule.
hERG selectivity became a concern when a basic nitrogen was
introduced. In subsequent publications we will discuss our efforts
to design aryl sulfonamido tetralin Kv1.5 inhibitors having im-
proved potency and selectivity coupled with more desirable phys-
iochemical properties.