Isoindolinone compounds active as Kv1.5 blockers identified using a multicomponent reaction approach

Article abstract of DOI:10.1016/j.bmcl.2016.02.081

A series of isoindolinone compounds have been developed showing good in vitro potency on the Kv1.5 ion channel. By modification of two side chains on the isoindolinone scaffold, metabolically stable compounds with good in vivo PK profile could be obtained

Full text of DOI:10.1016/j.bmcl.2016.02.081

Accepted Manuscript
Isoindolinone compounds active as Kv1.5 blockers identified using a multi-
component reaction approach
Johan Kajanus, Ingemar Jacobson, Annika Åstrand, Roine I. Olsson, Ulrik Gran,
Annika Björe, Ola Fjellström, Öjvind Davidsson, Hans Emtenäs, Anders
Dahlén, Boel Löfberg, Zhong-Qing Yuan, Johan Sundell, Johan Cassel, Jonna
Gyll, Tommy Iliefski, Ågot Högberg, Emma Lindhardt, Jesper Malmberg
PII:
S0960-894X(16)30205-0
DOI:
Reference:
http://dx.doi.org/10.1016/j.bmcl.2016.02.081
BMCL 23635
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 December 2015
26 February 2016
27 February 2016
Please cite this article as: Kajanus, J., Jacobson, I., Åstrand, A., Olsson, R.I., Gran, U., Björe, A., Fjellström, O.,
Davidsson, O., Emtenäs, H., Dahlén, A., Löfberg, B., Yuan, Z-Q., Sundell, J., Cassel, J., Gyll, J., Iliefski, T.,
Högberg, a., Lindhardt, E., Malmberg, J., Isoindolinone compounds active as Kv1.5 blockers identified using a
multicomponent reaction approach, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/
10.1016/j.bmcl.2016.02.081
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Isoindolinone compounds active on the Kv1.5
channel identified using a multicomponent reaction
approach
Johan Kajanus, Ingemar Jacobson, Annika Åstrand, Roine I. Olsson, Ulrik Gran, Annika Björe, Ola Fjellström,
Öjvind Davidsson, Hans Emtenäs, Anders Dahlén, Boel Löfberg, Zhong-Qing Yuan, Johan Sundell, Johan
Cassel, Jonna Gyll, Tommy Iliefski, Ågot Högberg, Emma Lindhardt, Jesper Malmberg

Bioorganic & Medicinal Chemistry Letters
Isoindolinone compounds active as Kv1.5 blockers identified using a
multicomponent reaction approach
Johan Kajanusa,*, Ingemar Jacobsona, Annika Åstrandb, Roine I. Olssonb, Ulrik Grana, Annika Björea, Ola
Fjellströma, Öjvind Davidssona, Hans Emtenäsa, Anders Dahléna, Boel Löfberga, Zhong-Qing Yuana, Johan
Sundella, Johan Cassela, Jonna Gylla, Tommy Iliefskia, Ågot Högberga, Emma Lindhardta, Jesper
Malmbergb
a Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, SE
b Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, SE
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of isoindolinone compounds have been developed showing good in vitro potency on the
Kv1.5 ion channel. By modification of two side chains on the isoindolinone scaffold,
metabolically stable compounds with good in vivo PK profile could be obtained leaving the core
structure unsubstituted. In this way, low microsomal intrinsic clearance (CLint) could be
achieved despite a relatively high logD. The compounds were synthesized using the Ugi
reaction, in some cases followed by Suzuki and Diels-Alder reactions, giving a diverse set of
compounds in a small number of reaction steps.
Keywords:
Atrial fibrillation
Kv1.5
IKur
Isoindolinones
Multicomponent reactions
Structure activity relationship (SAR)
Atrial fibrillation (AF), a cardiac arrhythmia in which the cardiac
atrium operates in an irregular fashion, is the most common
cardiac arrhythmia and a major cause of morbidity and
mortality.1 AF is the most common single factor involved in
stroke in the elderly and as the proportion of elderly individuals
within the population increases, AF is emerging as a major public
health concern. At present there is no effective medical treatment
for AF, thus, there is an increasing need to develop a safe and
effective agent for the management of AF. The performance of
the heart can be modified by modulation of ion channel proteins
in the heart tissue and we have previously reported on the
development of selective blockers of the cardiac ion channel
Kv1.5 as promising agents for the potential treatment of AF.2,3
The Kv1.5 ion channel is only functional in human cardiac atrial
tissue thus giving the possibility to develop an atrial selective
agent. There has been a considerable interest in the development
of selective Kv1.5 channel blockers in the last decade,1b two
recent examples being reports on Kv1.5 inhibitors based on
indoles and pseudosaccharin amines.4,5 However, data on the
clinical efficacy of Kv1.5 blocking compounds in AF is still
lacking.
We identified isoindolinone isomeric mixtures 1-3 (Figure 1)
as initial hits, from an HTS, that looked promising for further
development of an isoindolinone series with micromolar Kv1.5
activity and selectivity against hERG (Table 1). These
compounds had moderate to high lipophilicity with logD ranging
from 3.5 to 4.7 and suffered from low metabolic stability as
judged from their high microsomal intrinsic clearance (CLint) in
human liver microsomes (HLM). The potency difference of
separated enantiomers was in general small for this type of
compounds and in most cases within the experimental error of
the assay (see for example compounds 1, 1E1 and 1E2).
Figure 1. Lead structures.
We have previously published on the synthesis and activity of
two series of Kv1.5 blocking compounds based on phosphinic
amides and oxides and lactam sulfonamides.2,3 Here we report on
the synthesis and in vitro and in vivo characterization of a series
of isoindolinone compounds active on the Kv1.5 ion channel.
The general structure of the compounds described in this
paper is depicted in Figure 2. Data will only be given for
compounds with a phenyl ring in the isoindole core of the
molecule but a few examples were made with aza ring variations

of the isoindolinone ring structure. Introducing nitrogens in the
scaffold gave the desired lowering of logD, as measured by
chromatography,6 but generally gave a decrease in Kv1.5
potency. Instead, we aimed at improving the metabolic stability
of these compounds by introducing polar groups in the side
chains R1 or R2 or in the central motif to lower logD.
Alternatively, we tried to inhibit metabolism by blocking labile
positions, i.e. by substituting benzylic positions or by making
fluorinated analogs of metabolically unstable compounds.
case for the azaindole variations, a general decrease in Kv1.5
potency was observed (Table 1).
Figure 3. A few selected examples of replacements with polar side chains
Figure 2. General structure of the isoindolinone derivatives.
leading to decreased Kv1.5 potency.
The synthesis of these compounds relies on the Ugi reaction
starting from 2-formylbenzoic acids, an amine, and a isocyanide
(Scheme 1).7 The Ugi step was performed in methanol at room
temperature giving these pharmacologically interesting racemic
molecules in a single step. Racemic mixtures that were
interesting for further profiling were separated using chiral
chromatography. Isocyanide starting materials that were not
commercially available were synthesized from the corresponding
amines by treatment with excess ethyl formate to give the formyl
amides,8 that were then dehydrated to the isocyanide using
Burgess reagent.9 The solution of crude isocyanide in acetonitrile
was used directly in the following Ugi reaction.
Table 1. Preliminary SAR of substituted isoindolinones.
Cmpd
hKv1.5 IC50 (M)a
Log Dd CLint HLM
hERG
IC50
(l/min/mg)
(M)e
Rb+-fluxb
Qpatchc
0.9
3.3 (n=2)
4.7
> 100
62
1
3.4 (n=2)
10.4 (n=2)
6.0
1.0
3.0
1.5
1.1
-
4.7
4.7
3.5
4.5
-
> 100
> 100
> 100
> 100
> 100
> 33
> 33
> 33
32
1E1
1E2
2
0.7 (n=2)
13
3
> 33
4
> 32
> 32
> 32
> 10 (n=3)
-
3.6
-
34
> 33
> 33
-
5
6
7
-
-
> 100
62
3.2
1.1
17
2
4.4
4.4
4.4
4.0
4.3
4.0
4.6
5.6
5.9
5.6
5.1
4.9
4.7
< 12
20
46
9a
1.3
> 32
26
9aE1
9aE2
9b
3.4
24
8.4
31
6.9 (n=3)
> 100
88
45
4.5 (n=2)
> 33
15
9c
17
7.6 (n=5)
59
9d
3
2.1 (n=4)
> 100
> 100
> 100
> 100
> 100
> 100
> 100
28
10
2.2
1.2
1.7
10.5
11.3
2.4
0.8
24
11a
11b
11c
11d
11e
13a
-
22
1.3
27
-
> 32
30
-
Scheme 1. Reagents and conditions: (a) neat, 100-120 °C microwave heating,
20-30 min, 57-99%; (b) Burgess reagent, CH3CN, 50 °C, 4 h, quant.; (c)
MeOH, r.t., overnight, 4-64%; (d) chiral separation.
3.3 (n=3)
> 33
37
-
4.7
> 100
> 33
13b
a n=1 unless otherwise noted in parenthesis.
b Assayed with Rb+-flux.10
c
Assayed with QPatchTM technology.11
The Ugi chemistry allowed for high throughput synthesis and
several analogs of the initial hits were evaluated in which the side
chains were replaced with polar substituents, representative
examples are compounds 4-7 (Figure 3). We did not, however,
find any polar replacements that retained potency, but as was the
d
Lipophilicity measured by chromatography.6
Values are means of 2-6 experiments.
e

To investigate the structure activity relationship (SAR) of
substituents in the isoindolinone core, derivatives of compound 1
were synthesized (Schemes 2-4). Phenols 9a and 9b were
synthesized via a sequential Ugi/Diels-Alder reaction in which
intermediates 8a and 8b were obtained in high yields using the
Ugi reaction (Scheme 2) and the Ugi products were then ring-
closed by a Diels-Alder reaction. When catalyzed by Yb(OTf)3 as
Lewis acid, cyclization was followed by a ring opening-
elimination to give the hydroxy substituted iosindolinones after
tautomerization.12,13 The methyl sulfonamide substituted
isoindolinones 9c and 9d were synthesized using a similar
Ugi/Diels-Alder approach.14
Measured log D of these compounds is high > 4, and
correspondingly CLint was high except for compound 9a and its
enantiomers 9aE1 and 9aE2. We hypothesize that the apparent
high metabolic stability of these latter compounds is an artifact
due to time dependent CYP inhibition15 caused by formation of
reactive ortho-quinone methides that can bind covalently to
cytochrome P450 enzyme(s) (CYP). Formation of ortho-quinone
methides have been observed in similar systems, e.g. for
antidiabetic agent Troglitazone, for which inhibition of CYP3A4
activity was observed in vitro in human liver microsomes.16
Scheme 3. (a) CH3I, K2CO3, CH3CN, 60 °C, 1.5 h, 56%; (b) CHClF2,
Bu4NHSO4, DCM, r.t., 2 h, 36%; (c) CH2BrF, K2CO3, CH3CN, microwave
140 °C, 10 min, 63%, (d) MsCl, triethylamine, DCM, r.t., 2 h, 50%; (e) chiral
separation on Reprosil 20x250 mm chiral column using 40% isopropyl
alcohol in heptane; (f) MeOH, r.t., overnight, 31%.
Scheme 2. Reagents and conditions: (a) MeOH, r.t., overnight, 97% (8a),
97% (8b), 76% (8c), 60% (8d); (b) 8a, Yb(OTf)3 (10 mol%), xylene, reflux,
1.5 h, 46%; (c) 8b, Yb(OTf)3 (50 mol%), BMIM-PF6 (4 equiv.), dioxane,
microwave, 200 °C, 40 min, 16% (9b), 6% (10); (d) 8c or 8d, BMIM-PF6 (10
equiv.), dioxane, microwave 200 °C, 30 min, 56% (9c), 10% (9d).
Analogs of 9a were synthesized (Scheme 3) in which the phenol
was alkylated using different electrophiles giving compounds
11a-d. Compound 11e, the des-methyl analog of 11a, was
synthesized in a single step using Ugi chemistry. Compound 9a
was separated into its enantiomers using chiral chromatography.
Two cyano analogs (13a and b) were synthesized from the
corresponding bromides using Pd chemistry (Scheme 4).
Scheme 4. Reagents and conditions: (a) MeOH, r.t., overnight, 32% (12a),
52% (12b); (b) Pd(PPh3)4, Zn(CN)2, DMF, microwave, 200 °C, 45 min, 85%
(13a), 150 °C, 15 min, 70% (13b).
The ion channel-blocking potency on the Kv1.5 channel and
hERG was assessed as described in previous publications.2,3
A
preliminary SAR was established using Rb+-flux and Qpatch
assays (Table 1).10,11 The Qpatch assay was the main assay to
develop SAR in the present work. In comparison with
unsubstituted compound 1, the introduction of hydroxy-, methyl-
and ether groups in the central core did in most cases have a
minor effect on Kv1.5 potency, whereas a methylsulfonamide
(9c and d) or mesylate (11d) had a slightly lower potency. A
nitrile group in the 5-position of the isoindolinone (13a) ring had
a neutral effect on the Kv1.5 potency, whereas in the 6-position
(13b) it gave a lower potency. As shown in Table 1, several of
these compounds met our design criteria where we were aiming
for Kv1.5 potency ≤ 1 µM, at least 25 times selectivity against
hERG, and hERG potency > 20 µM.
To investigate whether the biphenyl moiety was contributing to
low metabolic stability in analogs of compound 1, a series of
fluorine substituted biphenyls (14-19, 21, 22) were prepared, in
which potential sites of oxidative metabolism were blocked. The
compounds were synthesized by sequential Suzuki/Ugi (Scheme
5) and Ugi/Diels-Alder/Suzuki reactions (Scheme 5 and 6). The
Kv1.5 potency of these fluorinated analogs were in most cases
comparable to 1 (Table 2) and CLint was somewhat reduced
although metabolically stable compounds were not generally
obtained. The metabolic stability of compound 9 encouraged us
to further explore the same structural motif in compounds 21 and

22 that also appear to be metabolically stable, but probably for
the same reasons as discussed above for compound 9. The
selectivity against hERG was acceptable for most of these
analogs.
infusions were followed by a wash-out period of 15 minutes and
measurements for QT and plasma concentration taken twice per
period, giving a total of 6 data sets. A cumulative dose of 20
µmol/kg was given. PK/PD modeling using link models18 on
effect-plasma concentration data was applied to estimate the
unbound steady-state plasma concentration (Ceu30) giving a 30%
increase of the QT-interval. In vivo efficacy could be
demonstrated for several of these compounds in the mouse model
(see Table 2 and 3).
Table 2. SAR of fluorinated analogs of biphenyl 1.
Cmpd
hKv1.5
IC50
Log Dc
CLint HLM
(l/min/mg)
hERG
Ceu30
mouse
(M)
(M)d
(M)a,b
0.8
1.7
2.0
0.9
1.5
1.1
1.4
1.6
1.4
5.2
5.2
5.3
5.3
5.0
5.0
5.2
5.2
5.0
58
62
> 33
> 32
> 33
> 33
> 33
> 31
> 33
> 33
> 33
0.054
-
14E1
14E2
15E1
15E2
16E1
16E2
17E1
17E2
18
49
0.055
0.28
0.066
-
41
38
103
102
96
0.079
-
34
0.90
6.0
2.7
3.5
4.8
4.5
4.6
53
56
> 32
27
-
-
-
19
21
22
< 12
< 12
a Assayed with QPatchTM technology.11
b Values are means of 2-6 experiments.
c Lipophilicity measured by chromatography.6
d Values are means of 2-4 experiments.
Scheme 5. Reagents and conditions: (a) Pd(PPh3)4, Cs2CO3, degassed
DME/water 5:1, microwave 130 °C; (b) HCl (sat.) EtOAc; (c) 2-
formylbenzoic acid, tert-butyl isocyanide, MeOH, r.t., overnight, 45-79%.
Attempts to optimize compound 2 gave compounds with low
Kv1.5 activity or compounds prone to formation of reactive
intermediates as detected by glutathione trapping experiments in
vitro.
Finally, analogs of compound 3 (23-29) were investigated in
which the isoindoline core was kept unsubstituted, whereas the
side chains R1 and R2 had variations in substitution and chain
length (Table 3). Keeping R1 as a p-halo substituted phenethyl
and introducing dimethyl substitution adjacent to the phenyl ring
in combination with fluorinated alkanes as R2 gave 23 and 24
with favorable Kv1.5 inhibition potency and complete stability in
human liver microsomes.
In the search for analogs to compound 3 to evaluate in vivo in
PD efficacy models, the most promising single stereoisomers
based on Kv1.5 potency and metabolic stability, 23E1 and
28I119, were selected for further profiling. We found that 23E1
and 28I1 had desirable in vivo PK properties (Figure 4), despite a
measured logD at 4.2 for both compounds. Whilst efficacy in an
in vivo mouse model could be demonstrated for both these
Scheme 6. Reagents and conditions: (a) MeOH, r.t., overnight, 97%; (b)
Yb(OTf)3 (10 mol%), xylene, reflux, 1.5 h, 57%; (c) Pd(PPh3)4, Cs2CO3,
degassed DME/water 5:1, microwave 130 °C, 97% (21), 73% (22).
analogs, disappointingly we were unable to establish
a
correlation between human in vitro and mouse in vivo potency
among the isoindolinone compounds. Moreover, the dog in vivo
PK experiments indicated tolerance issues for some of these
compounds and therefore our continued work in the Kv1.5 area
was focused on other lead series. The results of these
investigations will be presented in due course.
The pharmacodynamic (PD) effect of the compounds was
investigated in an in vivo screening model measuring QT
prolongation in anaesthetized BALBc male mice as a biomarker
of efficacy; Kv1.5 being present also in rodent ventricles.17 Two
increasing doses given as consecutive 15-minute intravenous

Table 3. SAR of analogs of compound 3.
Acknowledgments
We thank the Separation Science Laboratory at AstraZeneca
Mölndal for help with compound purification and separation.
Professor Neal Castagnoli is acknowledged for fruitful
discussions and Dr. Mark Furber is acknowledged for useful
comments on this manuscript.
Cmpd
R1
R2
hKv1.5 Log Dc
IC50
Clint
HLM
(l/min/
mg)
Ceu30
mouse
(M)
(M)a,b
References and notes
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23
0.5
0.7
1
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23E2
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4.1
180
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a Assayed with QPatchTM technology.11
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Figure 4. In vitro data and in vivo PK data on pure stereoisomers of
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F=absolute bioavailability after oral dosing.