Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine

Article abstract of DOI:10.1016/j.bmcl.2016.03.101

We started with a medium throughput screen of heterocyclic compounds without basic amine groups to avoid hERG and β-blocker activity and identified [1,2,4]triazolo[4,3-a]pyridine as an early lead. Optimization of substituents for Late I_Na curre

Full text of DOI:10.1016/j.bmcl.2016.03.101

Accepted Manuscript
Discovery of triazolopyridine GS-458967, a Late Sodium Current Inhibitor
(
Late I i) of the Cardiac Na 1.5 Channel with Improved Efficacy and Potency
Na
V
Relative to Ranolazine
Dmitry O. Koltun, Eric Q. Parkhill, Elfatih Elzein, Tetsuya Kobayashi, Gregory
T. Notte, Robert H. Jiang, Xiaofen Li, Thao D. Perry, Belem Avila, Wei-Qun
Wang, Catherine Smith-Maxwell, Arvinder K. Dhalla, Sridharan Rajamani,
Brian Stafford, Jennifer Tang, Nevena Mollova, Luiz Belardinelli, Jeff A.
Zablocki
PII:
S0960-894X(16)30331-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.03.101
BMCL 23744
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
4 February 2016
25 March 2016
26 March 2016
Please cite this article as: Koltun, D.O., Parkhill, E.Q., Elzein, E., Kobayashi, T., Notte, G.T., Jiang, R.H., Li, X.,
Perry, T.D., Avila, B., Wang, W-Q., Smith-Maxwell, C., Dhalla, A.K., Rajamani, S., Stafford, B., Tang, J., Mollova,
N., Belardinelli, L., Zablocki, J.A., Discovery of triazolopyridine GS-458967, a Late Sodium Current Inhibitor (Late
I i) of the Cardiac Na 1.5 Channel with Improved Efficacy and Potency Relative to Ranolazine, Bioorganic &
Na
V
Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.03.101
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Bioorganic & Medicinal Chemistry Letters
Discovery of triazolopyridine GS-458967, a Late Sodium Current Inhibitor (Late
I i ) of the Cardiac Na 1.5 Channel with Improved Efficacy and Potency
Na
V
Relative to Ranolazine
a
a
a
a
a
Dmitry O. Koltun* , Eric Q. Parkhill , Elfatih Elzein , Tetsuya Kobayashi , Gregory T. Notte , Robert H.
a
a
a
a
b
b
Jiang , Xiaofen Li , Thao D. Perry , Belem Avila , Wei-Qun Wang, Catherine Smith-Maxwell, Arvinder
K. Dhalla, Sridharan Rajamani, Brian Stafford, Jennifer Tang, Nevena Mollova, Luiz Belardinelli,
b
b
c
c
c
b
a
Jeff A. Zablocki.
a
Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA
Department of Biological Sciences, Gilead Sciences Inc., 333 , Fremont, CA, 94555, USA
b
c
Department of Drug Metabolism, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA
ARTICLE INFO
ABSTRACT
We started with a medium throughput screen of heterocyclic compounds without basic amine groups
to avoid hERG and -blocker activity and identified [1,2,4]triazolo[4,3-a]pyridine as an early lead.
Optimization of substituents for Late INa current inhibition and lack of Peak INa inhibition led to the
discovery of 4h (GS-458967) with improved anti-arrhythmic activity relative to ranolazine.
Unfortunately, 4h demonstrated use dependent block across the sodium isoforms including the central
and peripheral nervous system isoforms that is consistent with its low therapeutic index
Article history:
Received
nd
(approximately 5-fold in rat, 3-fold in dog). Compound 4h represents our initial foray into a 2
Revised
Accepted
generation Late INa inhibitor program and is an important proof-of-concept compound. We will
provide additional reports on addressing the CNS challenge in a follow-up communication.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords: Late INa current inhibitor; GS-
4
58967; anti-arrhythmic; ranolazine;
ventyricular arrhythmia.
6
Introduction
blood pressure. Ranolazine has been shown to eliminate early
after depolarizations (EADs) and reduce the increase in
transmural dispersion of repolarization (TDR), thus lowering the
Ischemic heart disease (IHD) is a result of atherosclerotic
narrowing of coronary vessels and has a high prevalence (7%)
within the United States. IHD progresses from silent ischemia
6
potential for arrhythmias to occur. Late INa current is enhanced
in patients with genetic mutations in SCN5A leading to a Long
QT-3 syndrome (LQT-3) that can lead to sudden cardiac death by
1
that often goes undetected to more severe ischemia that causes
7
chest pain (angina), a condition that affects 9 million people in
potentially fatal Torsades des Pointes.
2
the US. Ranolazine 1 is approved for the treatment of chronic
3
Late INa current (Figure 1) can be generated in vitro by the
addition of toxins ATX-II or tefluthrin that bind to an external
binding site that does not overlap with the lidocaine binding site.
In a manual single-patch clamp experiment, ranolazine (1, Figure
angina. Although the mechanism of ranolazine’s antianginal
effect has not been determined, it inhibits cardiac late (also
known as persistent) sodium channel current (Late INa current, or
simply Late INa) at therapeutic levels. Late INa (Figure 1) is
enhanced in an ischemic state due to reactive oxygen species
8
2

) displayed inhibition of ATX-II enhanced Late INa with IC50 6.9
6
M.
(
ROS) that chemically modify the -subunit protein (SCN5A)
resulting in incomplete inactivation that occurs late in the action
potential. Late INa leads to intracellular Na overload and
Unlike Late INa that is strictly pathological, Peak INa current’s
physiological role is essential to the propagation of the action
potential from the pacemaker sinoatrial (SA) node through the
atria and ventricles. Peak INa is triggered by change of
extracellular voltage during each heartbeat. Ranolazine does not
inhibit Peak INa c6urrent at therapeutic levels with a selectivity
index of >50 fold.
4
+
+2
+2
subsequent Ca overload through activity of Na-Ca exchanger
operating in the reverse mode. Ranolazine inhibits this process
by lowering the ischemic burden (calcium imbalance and
5
sequelae). At its therapeutic range (2 – 8 M in plasma),
6
ranolazine inhibits a number of cardiac ion currents (e.g. IKr).
Ranolazine provides its antianginal benefit without causing
bradycardia (slowing of heart rate) and/or lowering systemic

Figure 1. Late sodium channel current (Late INa) in a control
experiment (a), or enhanced with aid of 1 nM (b) or 3 nM (c)
ATX-II.
Figure 3. Synthesis of analogs via Suzuki coupling.
Figure 4. General core synthesis.
Herein, we describe our initial efforts to discover a
potent Late INa current blocker selective against peak current, and
demonstrate the anti-ischemic and anti-arrhythmic effects of our
lead molecule 4h in isolated heart and in vivo models,
respectively. Rather than starting with ranolazine (1), we
screened a number of in-house heterocyclic compounds without a
basic group, to decrease the likelihood of hERG and -blockade,
for their Late INa inhibitory activity using automatic patch clamp
Figure 5. Dimroth rearrangement.
9
system (hNav 1.5 -subunit HEK-293). We discovered a more
potent compound 2 (81% inhibition at 10 M), and used it as a
9
starting point for our hit-to-lead effort.
3
In our initial design, we relied on CF O-phenyl group as
Results and Discussion
a bioisostere for the phenoxyphenyl group to enhance metabolic
stability. We were seeking to eliminate the para-amino-biphenyl
motif as well, fearing the potential oxidation into a quinone
methide. We envisioned a [6,5] system being a potential
bioisostere for para-amino-biphenyl group by virtue of cyclizing
To begin our hit-to-lead effort, we performed initial
screening of our synthetic analogs for Late INa inhibition at 10
M concentration. With a few exceptions, compounds exhibiting
70% or greater inhibition at 10 M were subsequently tested to
determine an IC value. Selected compounds were then counter-
1
0
the sulfonamide group into a fused 5-member ring.
The
50
proposed changes are summarized as 3 in Figure 2.
screened against Peak INa inhibition at concentration close to their
0% block of Late INa – typically 1 M or 0.1 M. The
screening for Peak Na inhibition was performed at
5
Figure 2. Ranolazine (1), in-house compound (2), and the
design for hit-to-lead effort (3).
I
physiologically relevant pacing frequencies of 1 Hz and 3 Hz,
corresponding to 60 and 180 beats per minute, respectively.
Initially, we evaluated a number of fused bicyclic
bridge-head nitrogen [6,5] systems for their effectiveness as
para-amino-biphenyl group bioisosteres keeping the para-
trifluoromethoxyphenyl substituent constant. The results of our
study are shown in Table 1. As a first example of generic
structure 3, we evaluated [1, 2, 4]triazolo[4,3-a]pyridine system 4
for its ability to replace para-amino-biphenyl group while
10
retaining Late INa inhibition properties of 2. We examined a
number of groups ranging from polar (NH , 4a) to lipophilic
2
Chemistry
(CF , 4h) at the 3-position, the lone position on ring B available
3
for substitution. Lipophilicity is clearly preferred as seen from
In general, the compounds were prepared via Suzuki coupling
using a palladium catalyst, a bromo-core molecule, and an
appropriately substituted boronic acid or ester in the presence of
relatively high activity of 4e-h (Me, i-Pr, CHF
polar groups 4a-b. The most potent compound from this series,
CF analog 4h, was found to have an IC50 of 333 nM for Late INa
2 3
, CF ) relative to
3
a mild base (e.g. NaHCO ) at a temperature of 120 – 170C for
3
inhibition while exhibiting < 15% block of Peak INa at the same
concentration under 1 and 3 Hz pacing frequencies. Next, we
examined isomeric [1,2,4]triazolo[1,5-a]pyridine scaffold 5.
Unsubstituted analog 5a had an IC50 of 941 nM and was less
10
1
0 min to 1 h (Figure 3). Cores 4, 6, 7, and 10 were prepared
from the corresponding hydrazine through reaction with the
appropriate substituted anhydride followed by in situ
condensation to form the core (Figure 4). Core 8 was prepared
from the corresponding pyridylmethylamine through reaction
with the appropriate substituted anhydride followed by
phosphorous oxychloride induced condensation to form the core
3
active than 4h. Substitution at the position 2 with a CF group
proved detrimental to activity, especially in 5b compared to 4h.
In subsequent series 6 and 7, we explored the introduction of an
additional nitrogen atom in ring A of the bicyclic fused system,
10
(
Figure 4). Core 5 was prepared by taking the corresponding
3
while keeping optimal CF substituent in the 3-position. In the
core 4 and treating with cesium carbonate at high temperature to
invoke a Dimroth rearrangement as shown in Figure 5.
case of 6a, the compound retained Late INa inhibition, but had
unacceptable Peak INa inhibition, more than 4h. Compound 7a
proved inferior to 4h, supporting the conclusion that ring A does

not tolerate nitrogen in this position. Having examined a number
of systems with 3-nitrogen in ring B, we switched to a 2-nitrogen
imidazo[1,5-a]pyridine scaffold 8. Keeping CF substituent in the
3
position 3, we explored the additional position 1 available for
substitution. Unsubstituted analog 8a exhibited an IC50 of 102
nM. Unfortunately, the inhibition of Peak INa by 8a was high
Late Na IC50 block
at 10
Peak Na
1 Hz
v
1.5 block, % (M)
4
R
IC50
,
3 Hz
(
41.1% at 1 M, 1 Hz). 1-Methyl-substituted analog 8b was

M
nM
much less active. In the next 2-nitrogen scaffold 9, positions 3
1
2
h
i
j
k
l
m
n
o
p
q
r
4-OCF
3-OCF
4-CF
4-F
3
333
13.7 (0.1)
46.0 (1)
11.1 (0.1)
33.3 (1)
(R ) and 2 (R ) are available for substitution. In a head-to-head
3
52.9%
comparison, position 3 has once again proven to be advantageous
3
211
7915
887
1
2
1
for substitution (9b, R = CF
3
, R = H, IC50 of 353 nM vs. 9c, R
2
=
H, R = CF
3
, IC50 of 3345 nM). For 9b, the inhibition of Peak
4-OCHF
4-OCH CF
4-NHCH CF
2
2
3
281
INa was high (49.0% at 1 M, 1 Hz). Finally, we explored
2
3
23.5%
49.8%
56.8%
scaffolds 10 and 11 that represent an alternative position of the
bridge-head nitrogen with respect to 4-trifluoromethoxyphenyl
substituent (para vs. meta in 4-9). Based on the SAR across all
scaffolds the bulk at the 3-position did not yield improvement
over the hydrogen substituent. Between the two scaffolds,
compound 11b was the most potent, but inhibition of Peak INa
was high (40.4% at 1 M, 1 Hz).
t
4-O Bu
4-OEt
4-OMe
2221
182
59
t
4- Bu
64.4 (1)
30.6 (0.1)
52.0 (1)
57.2 (1)
24.0 (0.1)
76.0 (1)
s
t
4-SiMe
4-SF
4-CN
4-NO
2-Me-4-OCF
3-Me-4-OCF
3
5
397
u
v
w
x
y
12
28.5%
22.5%
2
3
123
166
37.9 (1)
30.8 (1)
49.6 (1)
36.8 (1)
Table 1. Sodium channel blocking properties of fused [6,5]
heterobiaryl compounds [Ar = 4-(trifluoromethoxy)phenyl] and
the Structure-Activity Relationships in the central core.
3
2,4-Cl
4-OCF3
2
53.5%
1.9%
1
3
a
Me
67.5%
20.4 (1)
13.9 (1)
b
OMe
1647
Having performed a “nitrogen scan” among scaffolds 4-11, we
settled on scaffold 4 and its most potent 3-trifluoromethyl analog
4h as a starting point for the SAR studies in rings A and C. We
synthesized analogs 4i-y with the goal of evaluating steric and
electronic effects of substituents on ring C (Table 2). We found
that the substituent in 4-position is essential, while 2- or 3-
substited C rings retain potency, but reduce the selectivity against
peak current. Potency of substituents in 4-position correlates
more with steric than electronic effects with the best compounds
Late Na
at 10
v
1.5 block
Peak
Na
1 Hz
v
1.5 block, % (M)
1
2
4
R
R
IC50
nM
3 Hz

M
a
b
c
d
e
NH
NHSO Me
2
NMe
H
2
8.4%
2.0%
containing bulky, mildly electron-donating groups like OCF
3
, t-
2
7541
8935
Bu, Me Si, as well as electron-withdrawing CF analog with a
3
3
Me
Pr
CHF
57.2%
48.5%
number of these having Late INa IC50’s <500 nM. However, none
of the analogs in this follow-on study matched the combination
of potency and selectivity that initial OCF analog (4h) provides.
3
i
f
g
h
5
a
b
6
2
351
333
25.7 (1)
13.7 (0.1)
22.5 (1)
11.1 (0.1)
CF
3
Next, we evaluated the effect of the substituents in 7-position
of ring A on Late INa inhibition. We hypothesized that relocating
the (4-trifluoromethoxy)phenyl group from 6- to 7-position will
retain the molecule’s overall linear topology and allow binding in
a similar fashion, but analog 12 was completely inactive.
H
941
223
CF
3
27.1%
52.5%
CF
3
3
18.3 (1)
41.1 (1)
49.0 (1)
30.8 (1)
13.0 (1)
20.3 (1)
7
CF
Inserting
a
substituent in 7-position along with 6-(4-
8
a
b
9
a
b
c
trifluoromethoxy)phenyl group (Me, 13a; and OMe, 13b) was
intended to force the C ring out of plane of ring A. We learned
that this conformational change reduces both activity and
selectivity.
CF
CF
3
H
Me
102
3
42.5%
67.9%
H
CF
H
H
H
3
353
3345
CF
3
1
0
a
b
c
H
Me
CF
1512
5052
901
41.4 (10)
22.5 (1)
1.4 (10)
5.0 (1)
3
1
1
a
b
H
CF
3
425
417
34.9 (1)
40.4 (1)
4.6 (10)
8.1 (1)
Table 2. Sodium channel blocking properties of 3-
trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridines.
(

Table 3. In vitro ADME and in vivo pharmacokinetic properties
of compound 4h.
Figure 5. Reversal of ATX-II increase in MAPD90 by 4h and
ranolazine.
In vitro
0
20
40
60
80
Ran
MW
Measured LogD
347.22
3.38
6.0 / 4.7
(n=6)
-
-
-
-
Aqueous solubility, M (HCl, pH 2.2 / PBS, pH 7.6)
Microsomal stability, t1/2, min (human/dog/rat)
Caco-2 permeabilty, A  B, ×10 cm/s (1 / 10 M)
B  A, ×10 cm/s (1 / 10 M)
In vivo, PO
AUC(0 ∞), nM h (rat/cyno. monkey)
max, nM (rat/cyno. monkey)
max, h (rat/cyno. monkey)
In vivo, PO
ss, L (rat/cyno. monkey)
CL, L/h/kg (rat/cyno. monkey)
max, h (rat/cyno. monkey)
F, % (rat/cyno. monkey)
>395 / 70 / 229
41.25 / 27.85
43.95 / 35.20
-
6
-
6
Emax
458967
.
5703 / 76094
397 / 1480
2.7 / 6.0
(n=4)

-100
-120
C
t
0
10
100 1,000 10,000 100,000
V
3.4 / 0.6
0.193 / 0.013
14.1 / 32.9
105 / 83
Drug Concentration (nM)
t
Then, we determined the anti-arrhythmic effect of 4h in an in
vivo model of chemically induced ventricular arrhythmia (Figure
6
). In anesthitized rabbits we slowed the heart rate through the
We proceeded to study in vitro and in vivo pharmacokinetic
properties of 4h (Table 3). Compound 4h has proven to be
highly metabolically stable in rat and human liver microsomes
addition of an -blocker (methoxyamine) followed by the
addition of a hERG blocker (clofilium) that induced 80% of the
control animals to have torsade des pointes (TdP). Compound 4h
completely protected against Tdp at 300 nM concentration.
Ranolazine was only partially protective at much higher
concentrations (14 uM) with 40% of the animals having Tdp.
(dog was an outlier species) which translated into low in vivo
clearance in both rat and cynomolgus monkeys. Its low
molecular weight and moderate LogD values along with high
Caco-2 permeability and the absence of net efflux translated into
high oral bioavailability and exposure in both species.
Figure 6. Protection from hERG induced ventricular
arrhythmias by 4h in anesthetized rabbits.
We also tested the activity of 4h in manual patch clamp assays
determining the IC50 for Late INa inhibition, the peak sodium
inhibition against sodium isoforms, use dependent block at 10
2
Hz, and the hERG inhibition. The IC50 for Late INa inhibition by
4
h was found to be 130 nM affording a good separation (>10x)
from peak sodium inhibition against the various isoforms (Table
) based on % inhibition at 1 uM. Unfortunately, 4h
4
demonstrated high use dependent block at 10 Hz across the
various sodium channel isoforms. Our plan in identifying leads
without basic groups paid off with regards to low hERG
inhibition for 4h with 17% inhibition at 10 uM.
Conclusion
Next, we proceeded to study the efficacy of 4h in
Langendorff isolated heart model (Figure 5). We added ATX-II
We started the Late INa program with a medium throughput
screen that afforded 2 as our initial hit that was subsequently
modified to a fused [6,5] heterocyclic system. We settled on a
(3 nM) to prolong the mean action potential duration (MAPD90)
by 68 + 11% from 181 + 7 (control) to 306 + 28 ms (n = 6).
Compound 4h completely reversed the ATX-II increase in
MAPD90 with an IC50 of 0.21 uM consistent with its cellular
inhibition of Late INa. Ranolazine only partially (60%) reversed
the effects of ATX-II increase in MAPD90 with an IC50 of 16 uM
[1,2,4]triazolo[4,3-a]pyridine system that was further optimized
to obtain 4h as a potent Late INa inhibitor that had a good
separation of Late INa inhibition from Peak INa and hERG.
Compound 4h was found to reverse the effects of ATX-II in
isolated hearts, and it was found to protect against chemically
induced ventricular arrhythmias in vivo at concentrations
consistent with its IC50 for Late INa inhibition. Unfortunately, 4h
demonstrated use dependent block across the sodium isoforms
including the brain and peripheral nervous system isoforms that
is consistent with its low therapeutic index (approximately 5-fold
in rat and 3-fold in dog). Compound 4h represents our initial
(Figure 4).
Table 4. Peak and use dependent block across sodium channel
isoforms for 4h.
Peak
INa
% Block
(0.1 Hz)
% Block (10 Hz)
Block
1
uM
0.1 uM
1
M
0.1 M
nd
foray into a 2 generation Late INa inhibitor program that we will
provide additional reports on addressing specifically the CNS
hNav1.1
hNav1.2
hNav1.3
hNav1.4
hNav1.5
hNav1.6
hNav1.7
hNav1.8
4.7
4.8
7.8
68
72
34.1
38.8
44.1
43.7
11.1
25
challenges in due course.
14.8
19.0
27.9
24.3
26.8
30.0
47.2
Acknowledgments
0.4
60.3
69.3
35.6
57.8
88.7
64.2
3.1
We would like to thank Manoj Desai and Gerry Rhodes for
their suggestions on executing the Late INa program.
3.4
5.2
References and Notes
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11.1
53.5
29.3
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Discovery of Triazolopyridine GS-458967, a
Late Sodium Current Inhibitor (Late INai ) of
Leave this area blank for abstract info.
the Cardiac Na
V
1.5 Channel with Improved
Efficacy and Potency Relative to Ranolazine
Dmitry O. Koltun*, Eric Q. Parkhill, Elfatih Elzein, Tetsuya Kobayashi, Gregory T. Notte, Robert H. Jiang, Xiaofen Li, Thao D. Perry, Belem Avila,
Wei-Qun Wang, Catherine Smith-Maxwell, Arvinder K Dhalla, Sridharan Rajamani, Brian Stafford, Jennifer Tang, Nevena Mollova, Luiz Belardinelli,
Jeff A. Zablocki.