Potassium channel blocking 1,2-bis(aryl)ethane-1,2-diamines active as antiarrhythmic agents

Article abstract of DOI:10.1016/j.bmcl.2019.03.006

Atrial fibrillation (AF) is a major cause of stroke, heart failure, sudden death and cardiovascular morbidity. The Kv1.5 potassium channel conducts the IKur current and has been demonstrated to be predominantly expressed in atrial versus ventricular tissu

Full text of DOI:10.1016/j.bmcl.2019.03.006

Accepted Manuscript
Potassium Channel Blocking 1,2-Bis(aryl)ethane-1,2-diamines Active as Anti-
arrhythmic Agents
Johan Kajanus, Thomas Antonsson, Leif Carlsson, Ulrik Jurva, Anna Pettersen,
Johan Sundell, Tord Inghardt
PII:
S0960-894X(19)30136-2
https://doi.org/10.1016/j.bmcl.2019.03.006
BMCL 26320
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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Revised Date:
Accepted Date:
17 December 2018
19 February 2019
5 March 2019
Please cite this article as: Kajanus, J., Antonsson, T., Carlsson, L., Jurva, U., Pettersen, A., Sundell, J., Inghardt, T.,
Potassium Channel Blocking 1,2-Bis(aryl)ethane-1,2-diamines Active as Antiarrhythmic Agents, Bioorganic &
Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.03.006
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Graphical Abstract
Potassium Channel Blocking 1,2-
Bis(aryl)ethane-1,2-diamines Active as
Antiarrhythmic Agents
Leave this area blank for abstract info.
Johan Kajanus, Thomas Antonsson, Leif Carlsson, Ulrik Jurva, Anna Pettersen, Johan Sundell and Tord Inghardt

Bioorganic & Medicinal Chemistry Letters
Potassium Channel Blocking 1,2-Bis(aryl)ethane-1,2-diamines Active as
Antiarrhythmic Agents
Johan Kajanusa, Thomas Antonssona, Leif Carlssona, Ulrik Jurvaa, Anna Pettersenb, Johan Sundella and
Tord Inghardta
a Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
b Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
ARTICLE INFO
ABSTRACT
Atrial fibrillation (AF) is a major cause of stroke, heart failure, sudden death and cardiovascular
morbidity. The Kv1.5 potassium channel conducts the IKur current and has been demonstrated
to be predominantly expressed in atrial versus ventricular tissue. Blockade of Kv1.5 has been
proven to be an effective approach to restoring and maintaining sinus rhythm in preclinical
models of AF. In the clinical setting, however, the therapeutic value of this approach remains an
open question. Herein, we present synthesis and optimization of a novel series of 1,2-
bis(aryl)ethane-1,2-diamines with selectivity for Kv1.5 over other potassium ion channels. The
effective refractory period in the right atrium (RAERP) in a rabbit PD model was investigated
for a selection of potent and selective compounds with balanced DMPK properties. The most
advanced compound (10) showed nanomolar potency in blocking Kv1.5 in human atrial
myocytes and based on the PD data, the estimated dose to man is 700 mg/day. As previously
reported, 10 efficiently converted AF to sinus rhythm in a dog disease model.
Article history:
Received
Revised
Accepted
Available online
Keywords:
Kv1.5
IKur
Atrial fibrillation
Antiarrhythmic agents
Potassium channel blocker
1,2-Bis(aryl)ethane-1,2-diamines
2018 Elsevier Ltd. All rights reserved.
———
 Johan Kajanus. Tel.: +46-31-7762812; e-mail: johan.kajanus@astrazeneca.com
 Tord Inghardt. Tel.: +46-31-7761954; e-mail: tord.inghardt@astrazeneca.com

Chart 1. Representative examples of Kv1.5 blockers from different chemical
series.
Although the management of patients with atrial fibrillation
(AF) has advanced in recent years, this arrhythmia remains one
of the major causes of stroke, heart failure, sudden death, and
cardiovascular morbidity in the world. It affects approximately
2% of the general population, increasing to more than 10% at
ages above 80.1 Two major treatment strategies prevail:
prevention of stroke through the use of anticoagulants; and
antiarrhythmic approaches which strive towards restoring sinus
rhythm or controlling heart rate. Atrial fibrillation is a
progressive disease resulting in atrial electrophysiological change
and structural remodeling which promotes AF itself and
eventually results with AF being permanent.2,3 The presently
available pharmacological options for AF management have
limited efficacy and are associated with considerable risks,
particularly proarrhythmia.2 Attractive prospects for improved
AF management include drugs that selectively target ion
channels such as the ultra-rapidly activating outward potassium
current (IKur), the acetylcholine-activated inwardly directed
potassium current (IKAch), and the small conductance Ca2+-
activated (SK) potassium channels engaged in atrial
repolarization.2-4 Such atrial repolarization-delaying agents
would, at least theoretically, increase atrial refractoriness and
consequently restore and maintain normal sinus rhythm without
the undesired effects of impulse propagation and cardiac
contractility and circumvent ventricular proarrhythmia liability.
However, few such agents are currently in clinical use or under
clinical investigation. Vernakalant is approved for conversion of
recent onset AF and is considered to block atrial early
repolarizing currents including IKur. AZD2929 and NTC-801
(BMS-914392) are investigational agents which selectively block
IKAch though they failed to demonstrate anticipated
electrophysiological action and antiarrhythmic efficacy in early
clinical studies.3,5
We have previously reported on our efforts to develop Kv1.5
inhibitors based on diphenylphospine amides and oxides
(resembling the diphenylphosphine oxide DPO-111),12 lactam
sulfonamides,13 and isoindolinones14 (Chart 2). In this report, we
present our work on a series of 1,2-bis(aryl)ethane-1,2-diamines.
Compd
Kv1.5
IC50
hERG
IC50
IKs
IC50
(M)
CYP2D6
IC50
LogDc
CLint HLM
(l/min/mg)
b
b
(µM)a
(M)
>33
>33
6.3
(M)
0.13
>20
>20
5.4
1
2
3
4
0.41
2.2
1.4
4.0
2.2
4.6
3.3
14
<5
58b
23
17
0.22b
>33b
60
3.2
>33
*
* R or S
Chart 2. Examples of Kv1.5 blockers from previous AstraZeneca series.
The present series originated from a focused screen of the
AstraZeneca corporate compound collection in which a virtual
screen was performed with both in-house and competitor
compounds as seeds. A hit from this screen was the symmetrical
diamine 1 (Table 1), which docked very nicely into a homology
model of Kv1.5, and was a promising starting point for further
optimisation.15 The compound was potent in vitro and showed
excellent potency in an initial in vivo mouse PD model which
utilized the QT interval as a surrogate marker for blockade of the
Kv1.5 channel, thus giving low predicted doses to man.
However, the compound was a strong CYP2D6 inhibitor, gave
rise to reactive metabolites (tested by cyanide trapping of
iminium ions) and was found to be a blocker of the IKs current.
Of the potentially atrial-selective currents, IKur has been the
target for the most intensive research efforts and the first to raise
attention.3 The Kv1.5 potassium channel conducts the human
IKur and has been demonstrated to be predominantly expressed
in human atrial versus ventricular tissue. This observation is
supported by the absence of the IKur current in human
ventricular cardiomyocytes and the failure of potent, selective
IKur blockers to prolong ventricular action potential duration in
vitro and delay ventricular repolarization in vivo.3,6 Taken
together, these experimental findings provide compelling
evidence of IKur as an atrial-selective target. Considerable
resources have been invested in identifying and developing
efficacious and safe IKur blockers of various chemical classes
(Chart 1).7-9 However, despite convincing experimental data,
whether the Kv1.5 channel is an effective target for
antiarrhythmic therapy in the clinical setting is still an open
question. That XEN-D0103, a selective Kv1.5 blocker in early
clinical testing, failed to reduce AF burden in patients with
paroxysmal AF adds to the uncertainty.10
Replacing the phenyl rings in 1 with 2-substituted pyridyl
rings, giving 2, markedly lowered the CYP2D6 and IKs
inhibition, which partly may be explained by the lowering of
logD. However, with N-alkyl chain analogs like 3, CYP2D6 and
IKs inhibition was still maintained at a low level despite a higher
logD. Furthermore, the issue with reactive metabolites, caused by
iminium ion formation, was decreased when cyclic amines were
replaced with acyclic N-alkyl groups. Finally, compound 4, the
acyclic analog of 2, was found to be potent on Kv1.5 and
gratifyingly also selective against hERG and IKs. The compound
was also found to be reasonably metabolically stable in human
liver microsomes and did not give rise to any reactive metabolites
(e.g. imminium ion formation).
Table 1. From hit to a selective lead compound
BMS-394136
BMS-919373
MK-1832
1
4
3
2

Values represent average of 2 measurements unless otherwise noted.
a Assayed using IonWorksTM HT technology in CHO cells.16
b n=1
Table 2. Importance of relative stereochemistry
c Lipophilicity measured by chromatography.17
A feature that was found among the symmetrically substituted
molecules like 1-4 was that the meso compound (S,R) displayed
much higher lipophilicity then the two enantiomers (R,R) and
(S,S). Compounds 2 (S,S-isomer), 5 (meso) and 6 (R,R-isomer)
illustrate this point with measured logD values (Table 2) of 2.2,
4.6 and 2.2, respectively, a consequence of the differences in pKa
(10.4 for the enantiomers and 8.7 for the meso compound). There
is also a large difference in metabolic stability of these
compounds, where 2 and 6 are metabolically stable and 5 is
highly cleared. We hypothesize that the difference in pKa and
other properties relate to the ability of the compounds to bind a
proton using both amine nitrogens. In the chiral compounds, this
can be accomplished with the two amine nitrogens in the same,
or nearly the same plane, without steric clash of the two
neighbouring aryl groups (Table 2). The same way of binding is
less favorable in the meso compound 5 where the two aryl groups
are eclipsed, which results in a sterically unfavorable interaction,
hence, basicity is significantly reduced.
2
5
6
Compound
Kv1.5
IC50
LogDc
CLint
HLM
(l/min/mg)
pKa
(µM)a
2
5
6
2.2
1.4b
4.8
2.2
4.6
2.2
<5
412
<5
10.4
8.7
10.4
Values represent average of 2 measurements unless otherwise noted.
a Assayed using IonWorksTM HT technology in CHO cells.16
b n=1
c Lipophilicity measured by chromatography.17

We found that compounds 1-6 were nearly exclusively
metabolized by CYP3A4 and would therefore be very sensitive
to drug-drug interactions (DDI), i.e. that co-administration
with a potent inhibitor of CYP3A4 could increase circulating
levels of compounds 1-6 and decrease margins to safety related
findings, or that co-administration with a strong inducer of
CYP3A4 could reduce exposure below the desired therapeutic
level.18 With a view to mitigate this risk, we decided next to
investigate introduction of functional groups with the potential
to undergo Phase II metabolism, e.g. glucuronic acid
conjugation. We also hypothesized that reduced lipophilicity
and larger polar surface (PSA) area would promote renal
elimination which would further reduce the risk of DDI. SAR
exploration (briefly summarized in Figure 1) revealed that
introduction of one or two hydroxy groups in the amine side
chains was well tolerated with respect to Kv1.5 potency (and
with retained high selectivity vs. hERG and IKs).
predictions which are summarized in Table 4. Based on these
data, two compounds, 10 and 1220, were selected as candidates
for studies in a dog disease model.
We have previously reported6 that 10 (AZ13395438) caused
a concentration dependent and selective increase in atrial
refractoriness, with little or no effect on ventricular
refractoriness and repolarization or on hemodynamics in the
dog. In a rapid atrial pacing (RAP) dog model of AF, 10
converted AF to sinus rhythm in all animals tested (n=12) at an
unbound plasma concentration of 0.48 ± 0.076 µM.
Guided by these data, 10 emerged as a promising candidate
for investigation in the clinical setting. Unfortunately,
compound 10, which can best be characterized as a mixed
potassium channel agent, blocking not only Kv1.5
(IC50=1.7µM but also Kir3.1/Kir3.44 (IKACh) (IC50=4.1µM) and
Kv4.3 (IC50=11 µM),21 showed proconvulsant effects in the
pentylenetetrazole (PTZ) rat model and produced significant
findings in behavioral scoring in the Irwin Screen in the rat.
While the mechanisms underlying the observed CNS side
effect is not well understood,22 evaluation of additional analogs
in the PTZ rat model revealed that the safety margin to
predicted human therapeutic exposure was inherently modest
(<10 fold) and we therefore stopped working on this lead series
and turned our attention to alternative chemical starting points.
The symmetrically substituted chiral compounds 1-4 in
Table 1 could be synthesized from the commercially available
chiral diamines 15 and 16 using simple alkylation methods
(Scheme 1). Whilst compounds 1-3 could by synthesized in
one step using 1,5-dibromopentane or propionaldehyde,
alkylation of 16 with 1-bromopropane gave selectively the
dialkylated compound 17. A second substituent could then be
introduced using reductive amination as exemplified in the
synthesis of 4 which is produced via aminal 18. Product
formation from the aminal was driven by using excess (> 10
eq) of acetaldehyde and reducing agent that were added in
portions during the course of the reaction. Further development
leading to a 100 g scale synthesis of enantiomerically pure
building block 17 has previously been reported.23
Figure 1. Structure activity relationship (SAR) overview.
As shown in Table 3, glucuronic acid conjugation was
indeed observed for compounds 7-10 but disappointingly it
represented less than 1.5% of the total metabolism in human
hepatocytes (CYP3A4 oxidation still the dominant route).
However, the decreased lipophilicity and increased polar
surface area, as compared to compound 4, gave a substantially
increased renal elimination in dog, i.e. larger fraction in urine
for several compounds (9, 11-14) and this would contribute to
reducing the impact of DDI for patients without renal disease.
In addition to the chiral compounds 1-4, their meso forms
were also investigated. In this case, the synthesis was
performed from trans epoxide 19 as described for compound 5
(Scheme 2). The epoxide was synthesized from
picolinaldehyde using hexaethylphosphorous triamide, and
obtained as a mixture of cis and trans isomers that was
separated using chiral chromatography. Ring opening of trans
epoxide 19 with piperidine gave amino alcohol 20, which
could be used to introduce a second amine substituent after
activation with methane sulfonic anhydride.
As indicated in Table 3, a few compounds were also tested
in human atrial myocytes, wherein potency of blockade of the
IKur current was significantly higher than in the CHO cells
used for screening. It should be noted here that under our
primary assay conditions, the previously mentioned literature
compounds BMS-394136 and BMS-919173 showed potency
in the same range as our compounds (IC50 = 0.30 µM and 3.6
µM respectively, n=2).
By comparing the outcome of the reactions from the cis and
trans epoxides with the products from alkylation of the chiral
diamines it became evident that after mesylation of 20
neighboring group participation gives the aziridinium ion 21 as
an intermediate. From the epoxide stage to the final product
there are therefore three consecutive inversion substitution
reactions taking place giving a net inversion of configuration
so that the meso products are obtained from the trans epoxide.
Based on an overall assessment of desired properties
(potency, dog plasma and renal clearance and alternative routes
of elimination), four compounds were chosen for studies of
electrophysiological effects in anesthetized rabbits (Table 4).
Briefly, increasing doses of test compound were infused
intravenously and after 20 minutes, the effective refractory
period in the right atrium (RAERP) was measured. The
unbound compound plasma exposure which prolonged the
RAERP by 20 milliseconds (Ceu20) was predicted by PKPD
modelling. An increase of RAERP to such an extent has been
suggested to translate into antiarrhythmic efficacy in man19 and
this average exposure was used for early dose to man (eD2M)

Table 3. Representative compounds illustrating the impact of substitution on potency and PK properties
Compound
Structure
Kv1.5
IC50
Human atrial
myocytes, IKur
IC50 (µM)b
LogD
PSA
Phase II
metabolism
(glucuronidation)
(%)c
Dog plasma
CL
(ml/min/kg)
Dog renal
CL
(µM)a
(ml/min/kg)d
3.2 ± 0.2
(n=3)
4
Nd
3.3
2.3
23
63
0%
16
44
0.7 (6.9%)
2.1 (4.4%)
7e
4.8
7.3
0.39 ± 0.06
1.5%
8e
0.26 ± 0.05
2.4
63
0.5%
37
1.8 (4.7%)
2.7 ± 0.5
(n=4)
9
Nd
0.06 ± 0.02
Nd
2.7
2.6
1.8
54
68
54
1%
0.5%
0%
21
6.1
25
2.5 (11%)
0.19 (5.1%)
2.7 (11%)
10f
11
1.7
10
12
13
14
3.4
Nd
Nd
Nd
2.8
2.5
2.3
45
68
63
0%
0%
0%
3.0
16
25
0.3 (12%)
5.5 (19%)
7.1 (28%)
2.1 ± 0.3
(n=4)
5.6
a n=2 unless otherwise indicated
b n=3 (cells from 1 donor)
c Fraction of the total metabolism that undergoes phase II metabolism (glucuronidation) in human hepatocytes
d Fraction of the dose excreted in urine given in parentheses
e Compounds 7 and 8 are enantiomers. The absolute stereochemistry of the 1,2-diamine has been arbitrarily assigned
f Experimental details including NMR, HRMS and X-ray are summarized in Supplementary material

We focused our efforts on the compounds obtained from the
cis epoxide 22 since those products generally exhibited favorable
physicochemical properties in line with what was discussed
previously for the symmetrically substituted compounds. As an
illustration of the synthetic chemistry used to make non-
symmetrically substituted compounds, the synthesis of 10 is
described in Scheme 2. The synthetic sequence started from cis
epoxide 22 that was opened by reaction with the appropriate
amine, in this case dipropylamine giving the racemic compound
23. In the next step, a second amine was introduced by activating
the amino alcohol 23 with methanesulfonic anhydride giving rise
to the intermediate aziridinium ion 24 in analogy with what was
previously described. Formation of the aziridinium ion could be
monitored by 1H NMR and when formation was complete, (S)-3-
(propylamino)propane-1,2-diol 25 was added giving the
diastereomeric mixture 26 which was separated by chiral
chromatography. Crystallization and X-ray diffraction revealed
that 10 has the (S,S,S)-configuration as shown in Figure 2.24
Table 4.
RAERP Ceu20
(µM)a
eD2M
Compound
(mg/day)b
9
0.220
0.150
0.057
0.290
800
700
300
2100
10
12
13
a Free compound plasma exposure which prolongs the right atrial effective
refractory period (RAERP) by 20 ms
in the rabbit
b Estimated dose to man which will give an average free plasma exposure
equal to Ceu20
HCl
HCl
e
d
15
16
17
c
18
a
b
Figure 2. X-ray structure of (S)-3-(((1S,2S)-2-(dipropylamino)-1,2-
di(pyridin-2-yl)ethyl)(propyl)amino)propane-1,2-diol (10).
1
2
3
4
Acknowledgements
Scheme 1. Reagents and conditions: (a) 1,5-dibromopentane, K2CO3,
CH3CN, rt, 2 days, 85%; (b) 1,5-dibromopentane, Et3N, DMF, 60 °C,
overnight, 63%; (c) propionaldehyde, NaBH(OAc)3, DCE, rt, 2 days, 29%;
The authors would like to acknowledge important scientific
contributions from AstraZeneca coworkers Ingemar Jacobsson,
Annika Björe, Yantao Chen, Boel Löfgren and Ola Fjellström.
(d) 1-bromopropane, Et3N, DMF, rt,
NaBH(OAc)3, DCE, rt, 3 days, 48%.
2
days, 62%; (e) acetaldehyde,
c
d
19
20
5
21
a,b
e
f
h
22
24
23
10
26
27
g
25
Scheme 2. Reagents and conditions: (a) hexaethylphosphorous triamide,
toluene, -5 °C to rt; (b) chromatography, 32% (19), 23% (22); (c) piperidine,
microwave heating, 180 °C, 20 min, used crude; (d) methanesulfonic
anhydride, DCM, 0 °C, 30 min, piperidine, rt, 27% (two steps); (e)
dipropylamine, IPA, 85 °C, 70 h, 98%; (f) methanesulfonic anhydride, DCM,
0 °C, 4 h, 25, rt, 98% ; (g) propan-1-amine, IPA, 70 °C, 2 h, 96%; (h) chiral
chromatography separation, 47% (10). The single crystal X-ray structure of
compound 10 is shown (data in Supplementary material).

22. For 10, the free brain exposure in rat was ca 4% of the free plasma
exposure as determined by measurements of total concentrations
in brain and plasma at steady state following a continuous
intravenous infusion of 10 at 2µmol/kg/h for a duration of 4h. Free
concentrations were then calculated from measured unbound
fractions in brain and plasma. Secondary pharmacology profiling
offered no clear explanation of the observed effects, but we did
observe weak binding to the NMDA receptor (13% and 14%
inhibition @ 10µM at the glycine and phencyclidine sites,
respectively).
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20. In high dose PK experiments in dog, 12 showed unwanted ECG
effects which may be attributed to stronger blockade of sodium
channels as compared to other analogs in the series. No further
experiments were carried out with 12.
21. Additional ion channel IC50 data (µM) for 10: hERG>33µM
(37%@33µM); IKs>33µM; NaV1.5=19µM; CaV1.2>33µM.