Pseudosaccharin amines as potent and selective KV1.5 blockers

Article abstract of DOI:10.1016/j.bmcl.2015.02.066

Phenethyl aminoheterocycles like compound 1 were known to be potent I_Kur blockers although they lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin amines. Compounds such as 14, 17d and 21c were found to be potent K_V1.5 blockers and selective over other cardiac ion channels. These compounds had potent pharmacodynamic activity, however, they also showed off-target activities such as hemodynamic effects.

Full text of DOI:10.1016/j.bmcl.2015.02.066

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pseudosaccharin amines as potent and selective KV1.5 blockers
⇑
John Lloyd , Heather J. Finlay, Alexander Kover, James Johnson, Zulan Pi, Ji Jiang, James Neels,
Cullen Cavallaro, Ruth Wexler, Mary Lee Conder, Hong Shi, Danshi Li, Huabin Sun,
Anjaneya Chimalakonda, Christine Huang, Mark Salvati, Paul Levesque
Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Phenethyl aminoheterocycles like compound 1 were known to be potent IKur blockers although they
lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin
amines. Compounds such as 14, 17d and 21c were found to be potent KV1.5 blockers and selective over
other cardiac ion channels. These compounds had potent pharmacodynamic activity, however, they also
showed off-target activities such as hemodynamic effects.
Received 20 January 2015
Accepted 26 February 2015
Available online xxxx
Keywords:
KV1.5
Ó 2015 Elsevier Ltd. All rights reserved.
IKur
Atrial fibrillation
Phenethylamine
AERP
Atrial fibrillation (AF) is the most common cardiac arrhythmia
seen in clinical practice and effects over 2.2 million patients in
the United States.1 The prevalence of AF increases with age and
with an aging population it is estimated by 2050 there will be
5.6 million cases of AF in the US.2 Although some AF is asymp-
tomatic, many patients suffer from fatigue, syncope, palpitations
and decreased quality of life. In addition to these symptoms, AF
is associated with a 5-fold increase in the incidence of strokes
and a 2-fold increase in overall mortality.3 One approach to drug
treatment has been to restore and maintain normal sinus rhythm.
This could be achieved by prolongation of the refractory period in
cardiac myocytes by blocking the ion currents responsible for
repolarization. Existing drug treatments such as sodium channel
blockers (flecainide and propafenone) and IKr potassium channel
blockers (sotalol and dofetilide) are effective at prolonging refrac-
tory period but have proven to be pro-arrhythmic because they
affect repolarizing currents in both the atrium and ventricle.
Prolongation of refractory period in the ventricle has been shown
to increase the incidence of the potentially life threatening
arrhythmia torsades de points.4 More recently, targets for drug
therapy that are specific to the atrium have been sought as a
potentially safer and more effective way to treat AF.5 The ultra-
rapid potassium current (IKur) is a current conducted by the
KV1.5 potassium channel that in humans is expressed only in the
atrium.6 Therefore, block of IKur could potentially provide a way
to treat AF without the risk of ventricular arrhythmia.
In our previous publication, we disclosed KV1.5 blockers based
on an aminoheterocycle with a phenethyl substituent.7 Among
those, the aminobenzisoxazole (1) and aminobenzoisothiazole (2)
showed significant block of KV1.5 in isolated cells, however, they
did not show any increase of atrial effective refractory period
(AERP) in rabbits. The isoindolone (3) showed short lived effects
on AERP and chemical instability. This Letter will describe our
efforts to extend the SAR to other heterocyclic structures, specifi-
cally for pseudosaccharin amines (A = SO2), and to further optimize
these compounds with regard to chemical stability, pharmacoki-
netic properties and pharmacodynamic effects (Fig. 1).
Synthesis of the pseudosaccharin core structure started with 3-
fluorobenzene sulfonyl chloride (4) that reacted with t-butylamine
to form the t-butyl sulfonamide (5). With the benefit of two direct-
ing groups, the metalation followed by reaction with carbon diox-
ide proceeded regioselectively to provide the benzoic acid (6). The
benzoic acid cyclized to the 4-fluoro saccharine (7) in good yield
under acidic conditions. The fluorine was replaced by methoxy
with microwave heating and the saccharin was converted to the
thioethyl pseudosaccharin (9)8 that was used in the subsequent
syntheses (Scheme 1).
We synthesized several compounds with a phenethylamino
substituent on the pseudosaccharin ring system. The most potent
contained a spirocyclic cyclohexane ring substituent on the ben-
zylic carbon. The compounds with substituents on the cyclohexane
ring that were linked through oxygen at the 4-position were syn-
thesized from 4-cyano-4-phenylcyclohexanone (10) which was
protected as the ethylene glycol ketal (11) followed by reduction
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.bmcl.2015.02.066
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lloyd, J.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.02.066

2
J. Lloyd et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
compd
A
KV1.5 IC50 (uM)
0.043
A
N
1
2
3
O
CN
CN
N
H
0.024
S
NH2
a
b
0.034
CO
O
O
O
O
c, d
O
O
10
12
11
Figure 1. Phenethylamino heterocycle KV1.5 antagonists.
f
O
S
O
N
of the nitrile to the amine (12) (Scheme 2). Reaction with
thioethylpseudosaccharin (9) followed by deprotection provided
the ketone (13). Reduction with sodium borohydride gave a mix-
ture (2:1) of the cis (14) and trans (15) isomers that could be sepa-
rated by column chromatography. The pure cis alcohol (14) could
be synthesized by simultaneous reduction of the ketone and the
nitrile of 10 with Red-AlÒ to provide the cis-amino alcohol (16).
Reaction 16 with the thioethylpseudosaccharin (9) provided the
pure cis-14.
N
H
NH2
g
13
O
MeO
O
S
O
HO
N
e
16
N
H
HO
MeO
14-cis
15-trans
Scheme 2. Reagents and conditions: (a) ethylene glycol, pTSA, benzene, 90 °C, 98%;
(b) LAH, THF, 70 °C, 90%; (c) 9, n-BuOH, 70 °C, 82%; (d) 1.0 M HCl, THF, 60 °C, 95%;
(e) NaBH4, MeOH, 25 °C, 86% (2:1 mixture of 14 and 15); (f) Red-AlÒ, toluene,
100 °C, 3 h, 50%; g. 9, n-BuOH, 70 °C, 69%.
Reaction of the alcohol intermediate (14) with isocyanates or
activation as the p-nitrophenyl carbonate and reaction with ami-
nes provided a variety of analogs (17a–i) (Scheme 3).
Compounds with substituents on the cyclohexane ring that
were linked through nitrogen at the 4-position were synthesized
stereoselectively in the cis configuration from 4-cyano-4-
phenylcyclohexanone (10) (Scheme 4). Formation of the imine
with (s)-t-butylsulfinamine followed by reduction with LAH at
low temperature provided the cis-4-amino-1-cyanocyclohexane
(18). Removal of the sulfinamine and reprotection with a t-buty-
loxycarbonyl group followed by reduction of the nitrile provided
the cis-aminomethylcyclohexane (19). Reaction of this amine with
the thioethylpseudosaccharin (9) followed by removal of the BOC
group provided the aminocyclohexane (20). Reaction of this inter-
mediate with chloroformates, isocyanates and sulfonyl chlorides
was used to synthesize a variety of analogs (21a–g).
We were also interested in compounds with a heterocycle sub-
stituent at the 4 position of the cyclohexane ring. The synthesis of
the pyrimidine compound (22) was accomplished through palla-
dium catalyzed coupling of the amine (20) with 2-chloropyrimidine.
The tetrazole (23) was synthesized from the amine (20) using
sodium azide and trimethylorthoformate in acetic acid. (Scheme 5).
The compounds 14, 15, 17a–i, 21a–g, 22 and 23 were tested for
block of potassium current in mouse fibroblast L929 cells expressing
human KV1.5.9 We also evaluated these compounds for in vitro
metabolic stability in liver microsomes to select the more metaboli-
cally stable analogs for progression to additional ion channel selec-
tivity assays, in vivo pharmacokinetic and pharmacodynamic
studies. Our hypothesis was that replacement of the carbonyl in
compound 3 with a sulfonyl would lead to compounds that were
more chemically stable. We also replaced the dimethyl substituents
on the phenethyl chain with a spirocyclohexane which we knew
from previous work was tolerant of a wide range of substitution
and was associated with greater pharmacodynamic potency.7 The
O
S
O
S
O
O
N
N
a
b
17a, c, e, g
N
H
N
H
17b, d, f, h, i
R1
O
HO
MeO
MeO
14
Compd
R1
Compd
R1
O
O
HO
17a
17b
17c
17d
17e
17f
N
N
H
H
O
O
P
O
17g
17h
17i
N
H
(EtO)2
N
H
Me2N
O
O
F3C
N
H
N
H
O
N
N
O
N
N
S
N
H
O
S
O
Ph
N
H
O
Scheme 3. Reagents and conditions: (a) RNCO, dibutyl tin diluarate (0.1 equiv),
toluene, MeCN, 85 °C, 60–87%; (b) (i) p-nitrophenylchloroformate, Et3N, CH2Cl2,
16 h, 25 °C, 71%; (ii) RNH2, Et3N, CH2Cl2, 16 h, 25 °C, 40–77%.
initial compound (14) contained a 4-cis-hydroxycyclohexane sub-
stituent on the phenethyl chain and was very potent in blocking
KV1.5 and was chemically stable during purification and handling.
We compared the cis (14) to the trans (15) analogs and found the
cis compound to be greater than 10-fold more potent. Therefore,
in subsequent studies we synthesized and tested only the cis
isomers.
We explored elaboration of the hydroxyl group to carbamates
and found that a wide range of small non-polar alkyl groups were
well tolerated (Table 1). We were particularly interested in
branched or fluorinated groups as a way to potentially block oxida-
tive metabolism. Unfortunately this was not the case. Although the
alkyl carbamates (17a–c) were potent they were also readily
degraded in our liver microsome assay. However, the carbamate
with the aminothiadiazole substituent (17d) showed good potency
and metabolic stability. We also synthesized carbamates that con-
tained small polar substituents such as hydroxyl, amino, acyl sul-
fonamide and acyl phosphoramide in an effort to improve the
O
S
O
S
H
N
O
S
H
N
O
Cl
O
O
O
F
b
a
HO
d
F
F
6
5
4
c
O
O
O
O
S
O
O
e
N
HN
HN
S
S
S
O
O
MeO
MeO
F
8
9
7
Scheme 1. Reagents and conditions: (a) t-BuNH2, CHCl3, 0 °C, 20 h, 89%; (b) n-BuLi,
CO2, THF, 0 °C, 86%; (c) H2SO4, 25 °C, 18 h then 55 °C, 3 h, 73%; (d) NaOMe, MeOH,
150 °C, 20 min, 86%; (e) (EtO)2P(S)SH, 150 °C, 1 h, 71%.
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J. Lloyd et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
Table 1
Inhibition of KV1.5 of 4-hydroxycyclohexane analogs
KV1.5 inhibitiona
IC50
Metabolic stabilityb
(% remaining in human, rat, mouse)
a, b
CN
c, d, e
CN
Compd
O
S
O
NH2
,
lM
N
H
O
O
N
H
19
f, g
18
1
2
3
14
0.043
0.024
0.034
0.034
>0.3 (14% inh)
0.065
0.17
0.089
0.092
>>10 (1% inh)
>10 (27% inh)
>10 (13% inh)
0.030
7, 13, 11
13, ND, NDc
99, 43, ND
90, 68, 53
98, 73, 73
2, <1, <1
9, 5, <1
<1, <1, 3
75, 70, 66
NTd
10
O
S
O
S
O
O
N
N
15
N
N
H
17a
17b
17c
17d
17e
17f
17g
17h
17i
H
R1
H2N
N
H
MeO
MeO
20
h
i
21a, c
21b
NT
NT
2, <1, <1
NT
j
21d
21e
>10 (4% inh)
k
a
Values are means of 2–4 experiments.
Percent of parent compound (3 lM) remaining following a 10 min incubation in
l
b
21f
liver microsomes containing appropriate co-factors was determined.
m, n
c
21g
ND = not determines.
d
NT = not tested.
Compd
R1
Compd
R1
O
O
O
Table 2
S
21a
21e
Inhibition of KV1.5 of 4-aminocyclohexane analogs
O
O
O
S
Compd
KV1.5 inhibitiona
IC50
Metabolic stabilityb
(% remaining in human, rat, mouse)
,
l
M
H
21b
21c
21d
21f
N
H
N
H
O
20
>10 (5% inh)
0.055
>10 (20% inh)
0.052
0.028
0.060
>10 (18% inh)
0.052
0.047
NT
55, 19, NT
NT
85, 29, <1
95, 57, 48
75, 67, 30
NT
<1, <1, <1
6, <1, <1
56, 19, 56
O
21a
21b
21c
21d
21e
21f
21g
22
O
S
21g
N
O
O
O
F3C
O
Scheme 4. Reagents and conditions: (a) (S)-tBuSONH2, |Ti(OEt)4, THF, rt, 4 h, 65%;
(b) LAH, THF, À78 °C, 0.2 h; (c) 4.0 M HCl, dioxane, rt, 0.5 h, 50% over 2 steps; (d)
BOC2O, NaOH, THF, rt, 1 h, 100%; (e) NaBH4, CoCl2Á6H2O, MeOH, 0 °C to rt, 14 h, 74%;
(f) 9, n-BuOH, 70 °C, 81%; (g) TFA, CH2Cl2, 25 °C, 1 h, 92%; (h) ROCOCl, Et3N, CH2Cl2,
25 °C, 3 h, 58–67%; (i) EtNCO, CH2Cl2, 25 °C, 16 h, 81%; (j) (i) triphosgene, CH2Cl2,
25 °C, 2 h, 95%; (ii) CF3CH2OH, dibutyl tin diluarate (0.1 equiv), toluene, 25 °C, 48 h,
40%; (k) EtSO2Cl, Et3N, CH2Cl2, 25 °C, 16 h, 60%; (l) NH2SO2NH2, dioxane, 150 °C,
4 min, 62%; (m) chlorosulfonyl isocyanate, 2-bromothanol, 0 °C, 30 min, then Et3N,
25 °C, 20 h, 35%; (n) Et2NH, MeCN, 160 °C, 6 min, 80%.
23
0.032
a
Values are means of 2–4 experiments.
Percent of parent compound (3 lM) remaining following a 10 min incubation in
b
liver microsomes containing appropriate co-factors was determined.
The 4-amino intermediate (20) gave us access to a range of ana-
logs containing carbamate, amide, urea and heterocycle. Although
the 4-amino compound (20) was not potent, non-basic analogs were
very potent in blocking KV1.5 (Table 2). Similar to the 4-hydroxyl
analogs, carbamates with small alkyl substituents showed good
potency, however, ureas (21b) were less potent. The ethyl carba-
mate (21a), isopropyl carbamate (21c), trifluoroethyl carbamate
(21d) and the ethyl sulfonamide (21e) all showed good potency
and higher levels of metabolic stability. The primary sulfamide
(21f) showed very little potency, however, the diethyl sulfamide
(21g) was quite potent although it lacked metabolic stability.
Heteroaryl substituents linked through the amine like pyrimidine
(22) or directly attached to the cyclohexane like tetrazole (23) were
very potent but lacked sufficient metabolic stability. Based on these
data, the isopropyl carbamate (21c), trifluoroethyl carbamate (21d)
and sulfonamide (21e) were chosen for further in vitro and in vivo
evaluation.
The compounds which were chosen for additional character-
ization were first assayed for ion channel selectivity. Most of these
compounds showed >100-fold selectivity over block of sodium,
calcium and hERG channels (Table 3).
The pharmacokinetics of selected analogs with a combination of
good potency, selectivity and higher metabolic stability (14, 17d
and 21c) were characterized for pharmacokinetic properties in rats
(Table 4). Compounds 14 and 21c showed good exposure (Cmax and
AUC) and moderate clearance. Compound 17d showed significantly
physical properties of the compounds. Unfortunately, these polar,
acidic or basic substituents were not well tolerated for KV1.5
potency. Only when the amino group was less basic as in the ani-
line (17h) was the potency restored. Unfortunately, this compound
had low metabolic stability. Both compounds 14 and 17d showed
sufficient potency and in vitro metabolic stability that they pro-
gressed to additional in vitro and in vivo characterization.
O
S
O
S
O
O
N
N
a
b
N
N
H
N
H
N
N
H
H2N
MeO
N
MeO
22
23
20
O
S
O
N
H
N
N
MeO
N
N
Scheme 5. Reagents and conditions: (a) 2-chloropyrimidine, i-PrOH, 140 °C,
microwave 5 min then 160 °C, microwave 20 min, 25%; (b) NaN3, trimethylortho-
formate, acetic acid, 0–25 °C over 12 h followed by 100 °C, mw 10 min, 56%.
Please cite this article in press as: Lloyd, J.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.02.066

4
J. Lloyd et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Table 3
3.0 mg/Kg and the plasma concentration to prolong AERP by 20%
Ion channel selectivitya
(EC20) was calculated (Table 6). There was no effect on ventricular
ERP reflecting the selectivity for KV1.5 over ventricular ion chan-
nels. Compounds 14 and 17d showed a robust pharmacodynamic
Compd
IC50
IKur
(lM)
% inhibition at 10 lM
ICa
INa
hERG
effect with 20% prolongation of AERP at less than 1 lM plasma con-
14
0.034
0.092
0.052
0.028
0.060
14
8
41
51
14
27
21
14
23
7
54
17
68
47
59
centration. However, like the rat pharmacodynamic study, signifi-
cant increases in blood pressure were also observed in the rabbits.
In addition, a significant increase in gastrointestinal motility was
observed with compound 14. We attributed these effects to off-tar-
get activity since other K V1.5 blockers have been reported that do
not show these liabilities.12 In an effort to determine the nature of
the off-target activities we screened compounds 14 and 21c at a
17d
21c
21d
21e
a
Values are means of 2–4 experiments.
Table 4
concentration of 10 lM for over 37 receptors and enzymes that
Pharmacokinetic parameters in rats
could potentially cause cardiovascular effects or toxicity
(Supplemental material). Both compounds were inactive against
most of the receptors with only modest activity against the opiate
receptor (64%), acetylcholine esterase (55%) and adenosine A3
receptor (64%). Both 14 and 21c had maximum plasma concentra-
Compd
14a
17da
21ca
Dose inf (mg/kg)b,d
2.0
5.0
1.6
3.6
2.0
5.0
Dose po (mg/kg)c,d
Cmax
AUC po (
Half-life (h)
Cl (mL/min/kg)
Vss (L/kg)
F (%)
(
l
M)
l
1.7 1.6
2.7 2.1
5.1
27 7.3
3.2
0.011 0.006
0.20
2.3 0.8
6.8 1.2
0.9 0.15
1.0
0.93 0.33
1.8 0.5
0.9 0.1
9.4 4.7
0.3 0.2
7.2
M h)
tions less than 10 lM at the highest dose so it seemed unlikely
these activities were the source of the off-target toxicities.
In conclusion, pseudosaccharin amines were discovered as
potent and selective KV1.5 blockers. Variation of the substituent
at the 4-position of the spirocyclohexane ring was shown to modu-
late potency and metabolic stability. Several compounds showed
very high potency, ion channel selectivity, and in vitro metabolic
stability. Compounds 14, 17d and 21c increased AERP in the rabbit
pharmacodynamic model, however, they also showed increases in
blood pressure. This type of off target activity precluded further
advancement of this series.
34
a
b
c
Values are means from 3 animals.
inf = intra-arterial infusion for 10 min.
po = oral gavage.
d
Vehicle 40% PEG 400, 40% water, 20% ethanol for both iv and po doses.
Table 5
Pharmacodynamic effects in ratsa
Compd QT interval (% change) Mean BP (% change) Plasma concn (lM)
Supplementary data
14
17d
21c
66 11
13 11
19
44 11
153 39
72 12
23
68
3
8
4
Supplementary data (Supplemental information includes off-
target liability screening for 14 and 21c, the details of the rat
AERP experiments and experimental details for the synthesis of
21c.) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.bmcl.2015.02.066.
38
4
a
Values are means of 2–4 experiments.
Table 6
Pharmacodynamic effects in rabbits11 of compound 14, 17d, 21c
References and notes
Compd
EC20
(
lM)
Mean BP (%change)
Max plasma conc. (lM)
1. Anter, E.; Jessup, M.; Callans, D. J. Circulation 2009, 119, 2516; Rich, M. W. J.
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Intern. Med. 1995, 155, 469; Go, A. S.; Hylek, E. M.; Phillips, K. A.; Chang, Y.;
Henault, L. E.; Selby, J. V. JAMA 2001, 285, 2370.
14
17d
21c
0.6
23
<0.7
19
6
17
6.1
23 9.6
4.7 1.6
3. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial
Fibrillation: A Report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines and the European Society of
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R. G.; Halperin, J. L. Ann. Intern. Med. 1999, 131, 688.
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suggest other degradation and elimination pathways in addition
to oxidative metabolism.
4. Roden, D. M. Br. J. Pharmacol. 2008, 154, 1502.
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Philipson, L. H.; Tamkun, M. M. J. Clin. Invest. 1995, 96, 282.
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D.; Levesque, P.; Hsueh, M.-M.; Harper, T. W.; Wexler, R. R.; Lloyd, J. Bioorg.
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8. Note that this reaction can be exothermic and care must be used when heating.
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10. See Supplemental information.
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T.; Bhandaru, R.; Caringal, Y.; DiMarco, J.; Gan, J.; Harper, T.; Huang, C.; Conder,
M. L.; Sun, H.; Levesque, P.; Blanar, M.; Atwal, K.; Wexler, R. J. Med. Chem. 2012,
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Bhandaru, R.; Vaccaro, W.; Huynh, T.; Huang, C. S.; Conder, M. L.; Jenkins-West,
T.; Levesque, P. Bioorg. Med. Chem. Lett. 2009, 19, 5469.
The pharmacodynamic activities of the selected compounds
were first evaluated at 3 mg/Kg in rats.10 Since rats express KV1.5
in both the atrium and ventricle, the QT interval in the ECG was
used to evaluate block of IKur. All the compounds tested (14, 17d,
21c) were effective at increasing the QT interval as predicted by
their in vitro activity (Table 5). However, in addition to high level
of activity in prolonging QT, these compounds were also found to
significantly increase blood pressure.
To check if this increase in blood pressure was specific to rats,
the pharmacodynamic activities of 14, 17d, and 21c were also
tested in a rabbit model.11 Like humans, rabbits express the IKur
current in atrium but not ventricle and the effective refractory per-
iod (ERP) was determined in both atrium and ventricle to measure
atrial selectivity. The compounds were dosed at 0.3, 1.0 and
Please cite this article in press as: Lloyd, J.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.02.066