Evaluation of the anti-hepatitis C virus effect of novel potent, selective, and orally bioavailable JNK and VEGFR kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.01.046

Screening of a focused library of TGF beta kinase inhibitors in the cellular HCV replicon model with luciferase read out yielded a number of low micromolar HCV inhibitors. Medicinal chemistry driven optimization resulted in the discovery of 4-[2-(5-bromo-

Full text of DOI:10.1016/j.bmcl.2007.01.046

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1843–1849
Evaluation of the anti-hepatitis C virus effect of novel potent,
selective, and orally bioavailable JNK
and VEGFR kinase inhibitors
Pierre Raboisson,a,* Oliver Lenz,a Tse-I Lin,a Dominique Surleraux,a
Sarvajit Chakravarty,b Annick Scholliers,a Katrien Vermeiren,a Frederic Delouvroy,a
Thierry Verbinnena and Kenneth Simmena
aTibotec BVBA, Gen. De Wittelaan L11 B3, B-2800 Mechelen, Belgium
bScios Inc., 820 West Maude Avenue, Sunnyvale, CA 94086, USA
Received 1 December 2006; revised 12 January 2007; accepted 13 January 2007
Available online 24 January 2007
Abstract—Screening of a focused library of TGF beta kinase inhibitors in the cellular HCV replicon model with luciferase read out
yielded a number of low micromolar HCV inhibitors. Medicinal chemistry driven optimization resulted in the discovery of 4-[2-(5-
bromo-2-fluoro-phenyl)pteridin-4-ylamino]-N-[3-(2- oxopyrrolidin-1-yl)propyl]nicotinamide 36 with a replicon EC50 of 64 nM,
associated with a selective kinase inhibitory profile for human JNK kinases 2 and 3 as well as VEGFR-1, 2, and 3 kinases. More-
over, 36 showed an advantageous PK profile in mice. Experiments performed using different replicon constructs suggest that this
series of kinase inhibitors might mediate their effect through the HCV non-structural protein 5A (NS5A).
Ó 2007 Elsevier Ltd. All rights reserved.
Hepatitis C virus (HCV) is a positive-strand RNA virus
with a genome of approximately 9600 nt belonging to
the Flaviviridae family.1 The World Health Organization
has estimated that 120–130 million people are infected
worldwide with HCV.2 Although acute infection is often
asymptomatic, around 80% of infected individuals
develop persistent HCV infection which is associated
with risk of severe chronic liver disease such as chronic
hepatitis, liver cirrhosis, and hepatocellular carcinoma.3
patient compliance.7 There is an urgent need to develop
more effective and better tolerated drugs for the treat-
ment of HCV infected patients. New antiviral agents
in clinical development include inhibitors of key HCV
enzymes, such as NS3 protease and NS5B RNA-depen-
dent RNA polymerase (RdRp).8 However, the success
of these novel antiviral therapies may be hindered by
the challenge of drug resistance. For this reason, the
development of drugs with novel modes of action, ame-
nable to combination therapies, is of interest.8
At present, no vaccine is available for the prevention of
HCV. Interferon (IFN)-a, a cytokine with immunomod-
ulatory and antiviral activity,5 has been widely used for
treatment of persistent HCV infection. However,
approximately 50% of patients with chronic hepatitis
C caused by genotype 1 virus have no sustained virolog-
ical response (SVR) even after treatment with the most
effective combination therapy to date, pegylated inter-
feron-a-2a with synthetic guanosine nucleoside ribavi-
rin.6 In addition, considerable side effects are
associated with these treatments, resulting in limited
The development of the HCV replicon as a cellular sur-
rogate model for HCV replication has enabled cellular
compound screening campaigns to find novel direct
and indirect antivirals active against HCV.9
Given the pivotal role of TGFb in liver morphogenesis
and fibrosis, as well as reports of kinase inhibitors mod-
ulating HCV replication, we investigated the antiviral
potential of compounds known to alter TGFb
signaling.10,11
We used a Huh7-Rep cell line containing the subgenom-
ic bicistronic replicon clone ET with a luciferase read
out12 to screen a focused library of TGFb Receptor
Keywords: JNK; VEGFR; HCV; Hepatitis C; Kinase.
*
Corresponding author. Tel.: +32 15 44 42 62; fax: +32 1540 1257;
e-mail addresses: praboiss@tibbe.jnj.com; PierreRaboisson@aol.com
1
kinase (TGFb-R1) inhibitors.9 We found that
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.01.046

1844
P. Raboisson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1843–1849
of the 4-(4-pyridylamino) moiety from an in-house
N
kinase library yielded a number of low micromolar
HCV inhibitors reported in Table 1. Interestingly, the
nature of the amide of the pyridyl ring is known to
modulate the kinase profile and potency of the pyrimi-
dine derivatives.4 Amongst the compounds tested (2–13),
only the 2-oxopyrrolidin-1-ylpropylaminocarbonyl
derivative 8 was found significantly more potent than
the initial hit 1 (EC50 = 84 and 890 nM, respectively).
It is noteworthy that a number of compounds tested
(e.g., 8, CC50-(MT4-LTR-Luc) = 5.86 lM, CC50-(Huh7-
CMV-Luc) = 17.7 lM) exhibited micromolar cytotoxic-
ity toward both MT4 and Huh7 cell lines. Since the
pteridine 1 exhibited no cytotoxicity up to 25 lM, we
decided to explore further SAR within the pteridine series.
HN
N
N
N
N
F
Cl
1
(SCI-208)
Chart 1. TGFb-R1 kinase inhibitor.4
[2-(5-chloro-2-fluoro-phenyl)pteridin-4-yl]pyridin-4-yl-
amine 1 (Chart 1),4 a previously reported potent
TGFb-R1 inhibitor (IC50 = 53 nM), is also inhibiting
HCV RNA replication with an EC50 of 0.89 lM with
no associated cytotoxicity in MT4 and Huh7 cells engi-
neered to constitutively express luciferase (CC50 > 25 lM).
The target pteridines 18–32 were synthesized as shown
in Scheme 1. Attempts to acylate 3-amino-pyrazine-2-
carboxylic acid ethyl ester 14 with 1 equivalent of ben-
zoylchlorides, using different reaction conditions, failed
to provide the monoacylated product in good yields.
The selection of a subset of structurally related pyrimi-
dines13 bearing a variety of carboxamides in position 3
Table 1. Inhibition of HCV replication in Huh-7-Rep cells (luciferase assay) for methoxypyrimidine 2–1313 measured by 50% effective concentration
(EC50) versus cytotoxicity in (a) Huh7-Luc and (b) MT4-LTR-Luc cell lines measured as CC50
O
R
N
N
H
HN
O
N
F
Cl
N
Compound
R
Huh7-Rep EC50 (lM)
ToxCC50(lM)
MT4
Huh7
2
3
NH2CH2CH2-
CF3CH2-
O
3.6
1.2
4.7
>32
5.5
>32
4
5
4.6
2.5
>32
15.4
>32
17.1
O
O
N
O
6
7
8
2.6
>32
5.0
>32
15.8
17.7
N
0.59
0.084
O
N
5.8
N
N
9
0.92
0.55
8.1
3.3
15.3
3.6
10
N
OH
H
11
12
9.6
>32
>32
>32
>32
N
OH
H
0.85
N
O
13
1.0
3.9
4.0
O
N

P. Raboisson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1843–1849
1845
COOEt
O
Moreover, introduction of a 2-methyl group resulted in
a 10-fold drop of activity (compare 32 to 23) and a high-
er cytotoxicity. The endocyclic nitrogen of the pyridyl
moiety was found to be important since its removal also
resulted in a 10-fold dropped activity (compare 23 to 24
and 26 to 31). Furthermore, substitution of the exocyclic
nitrogen of 23 with alkyl and aralkyl led in all cases to
less active compounds (27–30). To our satisfaction, the
introduction of the 2-oxopyrrolidin-1-ylpropylamino-
N
N
CONH2
NH
N
N
R2
O
N
R3
N
N
R3
OEt
ii
i
iii
O
O
R3
15a-e
R1
R2
R2
NH2
OH
14
16a-e
N
N
N
R2
N
R2
iv
N
N
N
N
carbonyl
moiety
identified
in
the
former
2-methoxypyrimidine series produced the same benefi-
cial effect in the pteridine series, leading to the identifica-
tion of 36, the most active derivative of this series
(EC50 = 64 nM).
17a-e
R3
R3
18-32
(Table 2)
16a, 17a R2 = H, R3 = Cl
16b, 17b R2 = H, R3 = CF3
16c, 17c R2 = F, R3 = H
16d, 17d R2 = F, R3 = Cl
16e, 17e R2 = F, R3 = Br
Unlike 8, no cytotoxicity was observed with the pteri-
dine analog 36 even at the highest concentrations tested
(CC50 > 32 lM). This lack of cytotoxicity was confirmed
by a 4 day proliferation assay and by measurement of
cellular RPL13A transcript levels. In both cases, the
CC50 was found to be over 32 lM. In addition 36 had
no effect on cell cycle and on intracellular ATP concen-
tration up to 50 lM. Moreover, 36 was found to be inac-
tive on BVDV up to 100 lM. Therefore, 36 was chosen
as the lead compound of this series and was further pro-
filed for its in vitro and in vivo characteristics.
Scheme 1. Reactions and conditions: (i) 2-(R2)-5-(R3) benzoylchloride,
pyridine; (ii) NH3; (iii) NaOH; (iv) PyBOP, R1-H.
Indeed, the diacylated derivatives 15a–e were always
obtained as the major products. Therefore, 14 was acyl-
ated in the presence of an excess of 2-R2-5-R3 benzoyl
chloride affording the N,N-disubstituted intermediates
15 in almost quantitative yields.
To better understand the mechanism by which 36 is
inhibiting the HCV replication in the replicon system,
a series of in vitro experiments was conducted. Enzy-
matic experiments showed that 36 does not significantly
inhibit either HCV NS5B polymerase or HCV NS3/4A
protease (IC50 > 30 lM for both).
Treatment of esters 15 with ammonia in refluxing etha-
nol led to the monoacetylated amides 16a–e, which were
readily cyclized to the corresponding pteridinones 17a-e
by reaction with NaOH. Eventually, intermediates 17
were activated by treatment with benzotriazole-1-yl-
oxy-tris-pyrrolidino-phosphonium hexafluorophosphate
(PyBOP), leading to a very reactive O-benzotriazole imi-
noether (structure not shown) in quantitative yield,
which after subsequent treatment with the appropriate
anilines resulted in the final products 18–32 (Table 2).
Since the initial hit 1 had been reported to inhibit the
TGFb R1 kinase with an IC50 of 54 nM in a biochemical
assay, we evaluated a subset of pteridines against this
target. In this assay, 36 was found to be a weaker inhib-
itor of TGFb R1 kinase (IC50 = 3.2 lM, representing a
60-fold loss of activity) compared to 1 (IC50 = 53 nM).
Moreover, as shown in Figure 1a, no overall correlation
between the inhibition of TGFb R1 kinase and inhibi-
tion of Huh7-replicon could be established for this ser-
ies, suggesting that 36 is inhibiting HCV replication
through another mechanism. To further assess the
kinase profile of this novel series of HCV inhibitors,
pteridines 1 and 36 were evaluated against a panel of
171 kinases. Pteridine 36 exhibits a selective inhibition
profile against human JNK 2 and 3 as well as against
human VEGFR kinases 1–3 (JNK2 IC50 = 37 nM;
JNK3 IC50 = 59 nM; VEGFR-1 IC50 = 47 nM, VEG-
FR-2 IC50 = 140 nM and VEGFR-3 IC50 = 123 nM)
compared to the initial hit 1, which in addition to its
TGFb R1 activity, inhibited 15 different kinases over
85% at a concentration of 10 lM. Interestingly, 36
showed no significant inhibitory effect on closely related
JNK1 (IC50 = 10.5 lM) and inhibits less than 70% at
10 lM all the other 165 kinases tested. To further
explore if these pteridine derivatives exert their anti-
HCV activity through the inhibition of JNK and/or
VEGFR kinases, an additional subset of compounds
was evaluated on these two kinase families. Interestingly,
only VEGFR-3 inhibition seems to correlate with
The synthesis of 4-[2-(5-bromo-2-fluoro-phenyl)pteri-
din-4-ylamino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]nico-
tinamide 36 is reported in Scheme 2. The pteridinone 17e
was converted in 99% yield to the iminochloride 33 by
reaction with thionylchloride and dimethylformamide.
Treatment of 33 with aminonicotinic methyl ester in
presence of triethylamine provided the ester 34 (75%
yield), which was readily hydrolyzed to the correspond-
ing acid by treatment with sodium hydroxide. The
subsequent coupling reaction of 35 with 3-(2-oxopyrroli-
din-1-yl)propylamine provided the target compound 36
in 30% yield.
The substitution of the phenyl ring in position 2 was
found to modulate the anti-HCV activity of this series.
Indeed, although the removal of the chlorine or the flu-
oro atoms in position R2 and R3, respectively, led to
compounds 2–10 times less potent (compare 19 and 20
to 1), the replacement of the chlorine with a bromine
resulted in a 3-fold increase of activity (compare 23 to
1 and 31 to 21). The introduction of a methyl group in
the position 3 of the pyridyl moiety decreases the activity
by half (compare 21 with 1 and 31 with 23). Surprising-
ly, the ethyl derivative 22 was found equally potent to 1.

1846
P. Raboisson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1843–1849
Table 2. Inhibition of HCV replication in Huh-7-Rep cells (luciferase assay) for pteridines 1, 17d, 18–32, 34, and 36 measured by 50% effective
concentration (EC50) versus cytotoxicity in HUH7-CMV-Luc and MT4-LTR-Luc cell lines measured as CC50
R1
N
N
R3
N
N
R2
Compound
R1
R2
R3
Huh7-RepEC50(lM)
ToxCC50(lM)
MT4
Huh7
>25
17d
1
HO-
F
F
Cl
Cl
>50
0.89
>25
N
>25
>25
>25
>25
>32
NH
NH
NH
NH
N
N
N
18
19
20
H
F
CF3
H
1.91
9.95
1.67
>25
>25
>32
H
Cl
N
21
F
Cl
2.0
>32
>32
NH
N
N
22
23
24
25
F
F
F
F
Cl
Br
Br
Br
0.71
0.35
4.0
>32
>32
>32
>32
>32
>32
>32
>32
NH
NH
NH
N
1.98
26
27
28
29
F
F
F
F
Br
Br
Br
Br
6.4
>32
>32
>32
>32
>32
>32
>32
>32
NH
N
N
N
3.65
2.2
N
N
N
0.99
N
N
30
31
F
F
Br
Br
1.96
0.80
11.0
>32
22.2
>32
N
NH

P. Raboisson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1843–1849
1847
Table 2 (continued )
Compound
R1
R2
R3
Huh7-RepEC50(lM)
ToxCC50(lM)
MT4 Huh7
N
32
34
F
F
Br
Br
3.60
4.95
13.2
>32
12.9
>32
NH
COOCH3
N
N
O
O
NH
NH
N
36
F
Br
0.064
>32
>32
HCV-replicon inhibition, suggesting that the anti-HCV
activity of 36 might be linked to VEGFR-3 inhibition
(Fig. 1d) (squared correlation coefficient r2 = 0.480).
However, additional experiments are required to vali-
date this hypothesis.
N
OMe
NH
Cl
N
N
N
N
N
F
N
F
i
iii
ii
17e
N
N
The antiviral activity of 36 was further analyzed in a
panel of full length and subgenomic 1a and b repli-
cons. Although 36 is a potent inhibitor of the ET rep-
licon clone (harboring E1202G, T1280I adaptive
mutations in NS3 and K1846T in NS4B), the com-
pound was found inactive up to 32 lM in other geno-
type 1b and 1a derived replicons (harboring S2204I or
S2197P adaptive mutation in NS5A). Since one
remarkable difference between the ET clone and the
other replicons tested is the lack of adaptive mutation
within NS5A of the ET clone, it can be hypothesized
that 36 is directly or indirectly interfering with NS5A.
This hypothesis was supported by the introduction of
the NS5A adaptive mutation S2204I in a replicon
backbone devoid of adaptive mutation resulting in a
significant loss of activity of 36 in a transient HCV
34
33
O
O
Br
Br
O
N
OH
NH
N
N
N
H
NH
N
N
N
iv
N
F
N
F
N
N
N
35
36
Scheme 2. Reactions and Conditions: (i) SOCl2, DMF; (ii) 4-amino-
O
pyridine-3-carboxylic acid methyl ester; (iii) NaOH; (iv)
PyBOP.
,
H2N
N
100000
100000
c
100000
10000
1000
100
a
b
10000
10000
*
1000
100
10
1000
100
*
*
*
10
10
10
100
1000
10000
10
10
100
1000
10000
100000
100
1000
10000
100000
HUH7 -Replicon EC50 (nM )
HUH7-Replicon EC50 (nM)
HUH7-Replicon EC50 (nM)
100000
10000
1000
100
100000
100000
10000
1000
e
d
f
10000
1000
100
100
10
*
*
10
10
10
100
1000
10000
100000
10
100
1000
10000
100000
10
100
1000
10000
100000
HUH7-Replicon EC50 (nM)
HUH7-Replicon EC50 (nM)
HUH7-Replicon EC50 (nM)
Figure 1. Inhibition of HCV replication in Huh-7 Rep cells (luciferase assay) for a subset of pteridines measured by 50% effective concentration
(EC50) versus inhibition of different kinases measured by 50% inhibitory concentration (IC50): (a) TGFb-R1; (b) VEGFR-1(h); (c) VEGFR-2 (h); (d)
VEGFR-3 (h); (e) JNK2; (f) JNK3. Compound 36 is highlighted in the graphs with the symbol ( ).
*

1848
P. Raboisson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1843–1849
genotype 1b replicon assay.12 It is interesting to note
that the adaptive mutation S2204I is known to reduce
hyperphosphorylation of NS5A. In addition, a recent
report showed that kinase inhibitors, which change
the hyperphosphorylation status of NS5A, modulate
HCV replication.14 Therefore it is intriguing to specu-
late that this series of pteridines is inhibiting HCV
RNA replication by an indirect mechanism that would
modulate the phosphorylation state of NS5A.
Table 3. Mean plasma and tissue levels (n = 3) together with some
basic pharmacokinetic parameters of pteridine 36 after a single oral
administration of 20 mg base-equiv/kg in the male Swiss SPF (CD1)-
mice
Concentrations (ng/mL)
Plasma
Heart
Liver
0.5 h
1 h
220 ( 100)
166 ( 160)
21.7 ( 6.7)
20.3 ( 5.1)
5.52 ( 1.2)
678 ( 258)
557 ( 403)
4057 ( 1730)
2937 ( 1852)
2 h
4 h
92.9 ( 49.9) 611 ( 131)
83.6 ( 35.9) 627 ( 189)
Interestingly, the introduction of Y2065H, a previously
reported resistance mutation in the N-terminal domain
of NS5A, had no effect on susceptibility to 36.15
8 h
24 h
29.1 ( 6.0)
BQLa BQLa BQLa
201 ( 59)
Cmax (ng/ml)
Tmax (h)
t1/2(2–8 h) (h)
220
0.5
2.9
678
0.5
4057
0.5
3.4
3.5
Before investigating further the mechanism by which
these pteridines inhibit HCV replication, we deter-
mined if the lead compound 36 displayed DMPK
properties which are compatible with in vivo efficacy
testing.
AUC(0–8 h) (ng h/mL) 309
1119
1262
3.8b 24b
6965
7973
AUC0Àinf (ng h/mL)
Ratio tissue/plasma
332
—
a BQL, below the limit of quantification. LLOQ was 0.500 ng/ml for
plasma and ranged between 5.00 and 13.16 ng/g for tissue.
b Value based upon the AUCinf
.
The plasma kinetics, oral bioavailability together with
heart and liver-plasma tissue distribution in male
Swiss SPF (CD1)-mice were determined after a single
oral administration of 20 mg/kg of 36 using 50%
PEG-400 in water as vehicle. The compound levels
were quantifiable up to 8 h post administration. As
shown in Figure 2 and Table 3, time profile of the
heart, liver, and plasma concentration is similar, indi-
cating distribution equilibrium between plasma and
these tissues. The mean maximum concentrations
(Cmax) in the plasma, heart, and liver were all
achieved at 0.5 h post-dose (Tmax), indicating a rapid
absorption of 36. Given that viral replication of
HCV is reported to occur primarily in hepatocytes,
achieving high drug concentrations in the liver is
believed to be critical for the clinical success of
HCV inhibitors. In this respect, 36 was found to be
well distributed with the highest concentration ob-
served in the liver (4057 ng/g), followed by heart
(678 ng/g) and plasma (220 ng/mL). Furthermore, the
mean half-life of 36 in the plasma (t1/2 (2À8 h)) is
2.9 h, which is comparable with those of liver
(3.5 h), and heart (3.4 h) and the AUC0Àinf is equal
to 332 ng.h/mL. Interestingly, the tissue levels decline
in a pattern similar to plasma and, no evidence of
retention was found during this study.
In conclusion, we have reported here a novel series of
potent and non-cytotoxic HCV inhibitors, which exhib-
its selective nanomolar activity toward both JNK and
VEGFR kinase families. Among the compounds ana-
lyzed, 4-[2-(5-bromo-2-fluoro-phenyl)pteridin-4-ylami-
no]-N-[3-(2- oxopyrrolidin-1-yl)propyl]nicotinamide 36
was found to be the most potent HCV-replicon inhibitor
(EC50 = 64 nM). Experiments performed on other repli-
con constructs suggest that 36 mediates its effect through
NS5A. Moreover, 36 exhibits advantageous DMPK
properties in mice. Additional studies are underway to
further elucidate the mechanism by which this series of
pteridines inhibits HCV replication.
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1
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