Structure-based design and parallel synthesis of N-benzyl isatin oximes as JNK3 MAP kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.03.043

A series of N-benzylated isatin oximes were developed as inhibitors of the mitogen-activated kinase, JNK3. X-ray crystallographic structures aided in the design and synthesis of novel, selective compounds, that inhibit JNK3, but not p38 MAP kinase and provided key insights into understanding the behavior of gatekeeper residue methionine-146 in determining target selectivity for this series.

Full text of DOI:10.1016/j.bmcl.2009.03.043

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2891–2895
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure-based design and parallel synthesis of N-benzyl isatin oximes
as JNK3 MAP kinase inhibitors
Jingrong Cao, Huai Gao, Guy Bemis, Francesco Salituro, Mark Ledeboer, Edmund Harrington, Susanne Wilke,
*
Paul Taslimi, S. Pazhanisamy, Xiaoling Xie, Marc Jacobs, Jeremy Green
Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of N-benzylated isatin oximes were developed as inhibitors of the mitogen-activated kinase,
JNK3. X-ray crystallographic structures aided in the design and synthesis of novel, selective compounds,
that inhibit JNK3, but not p38 MAP kinase and provided key insights into understanding the behavior of
gatekeeper residue methionine-146 in determining target selectivity for this series.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 18 February 2009
Revised 4 March 2009
Accepted 9 March 2009
Available online 17 March 2009
Keywords:
JNK3
JNK3 inhibitors
MAP kinase
Isatin
The c-Jun N-terminal kinases (JNKs, also known as stress acti-
vated protein kinases, SAPKs) are members of the mitogen acti-
vated protein (MAP) kinase family.1 The MAP kinases are a
family of structurally-related serine/threonine kinases that also in-
cludes p38 and the extracellular-signal regulated kinases (ERKs).
The JNK subfamily consists of ten known isoforms encoded by
three genes, jnk-1, jnk-2, and jnk-3, the latter being expressed pri-
marily in the brain and at low levels in the testes and kidney. JNK3
knockout mice were developmentally normal, yet show decreased
neuronal death in response to kainic acid2 and MPTP induced cell
death,3 as well as resistance to hypoxic ischemia.4 Thus inhibition
of JNK3 offers potential for the treatment of neurodegenerative dis-
eases, such as Alzheimer’s disease, Parkinson’s disease, epilepsy
and seizures, as well as for the treatment of ischemic brain injury.
A number of JNK3 inhibitors have been reported in the litera-
ture, notably including SP-600125,5 and CEP-1347,6 the first JNK
pathway inhibitor to enter clinical development. Recently a num-
ber of publications have described a variety of molecules that exhi-
bit different levels of JNK inhibition and selectivities7–13 (Fig. 1).
In this Letter, we present optimization of an isatin oxime
screening hit through application of a combination of parallel syn-
thesis and X-ray crystallography to develop potent and selective
JNK3 inhibitors.
compound 1 as an ATP-competitive JNK3 inhibitor, with moderate
potency for JNK3 (Ki = 2.7 M) and clear selectivity over the MAP
kinase family members ERK2 (>30
l
lM) and p38
a
(>100 lM).
NOH
O
NOH
Me
N
N
O
CF3
1
2
It was quickly established that O-methylation and N-dealkyla-
tion abolished activity, indicating the importance of the free hydro-
xyl and the N-benzyl groups for enzyme inhibition. In addition, the
N-phenyl compound 2 was also significantly less active (JNK3
Ki > 30 lM), than compound 1.
H
N
O
H
N
NH
S
S
N
N
O
O
To identify novel inhibitors of JNK3 we performed a screen of
our corporate compound collection and identified isatin oxime
O
SP600125
HO
O
CEP-1347
* Corresponding author. Tel.: +1 617 444 6315.
E-mail address: jeremy_green@vrtx.com (J. Green).
Figure 1. JNK inhibitors SP600125 and CEP-1347.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.043

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J. Cao et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2891–2895
O
O
N
X
X
X
OH
(a)
(b)
N
H
O
N
O
N
O
Y
Y
Scheme 1. Preparation of N-benzylisatin oximes. Reagents and conditions: (a) ArCH2Cl or ArCH2Br (1.1 equiv), K2CO3 (4 equiv), DMF, 60 °C, 4 h; (b) 1 M NH2OHÁHCl in DMF
(4 equiv), rt, 1 h (95% over two steps, where X = F, Y = H).
O
N
X
X
(b)
(a)
O
O
NH2
+
N
H
O
N
H
O
NOH
O
X
N
X
O
(c)
N
N
O
Ar
Ar
Scheme 2. Solid-phase synthesis of isatin oximes. Reagents and conditions: (a) DMF, pyridine, 16 h; (b) ArCH2Cl or ArCH2Br, DBU, DMF, 35 °C, 48–72 h; (c) TFA, CH2Cl2, 1 h.
Yields 12–77% overall from hydroxylamine resin.
These discoveries led us to investigate further the synthesis and
inhibitory activities of N-benzyl isatin oximes. Initial work to de-
velop SAR employed two synthetic approaches, starting with the
commercially available isatins. In the first approach (Scheme 1) a
solution-phase method was developed that was amenable to par-
allel synthesis. In this scheme the reaction conditions were se-
lected such that the isatin in DMF was added to excess K2CO3,
followed by addition of benzyl bromides or chlorides and the reac-
tions left to mix at 60 °C for 6 h. Addition of excess hydroxylamine
hydrochloride converted the isatin to the corresponding oxime,
and any remaining alkylating agent was sequestered by the
hydroxylamine to produce a more water-soluble benzyl hydroxyl-
amine, thereby facilitating a simple aqueous work-up.
that revealed the key structural elements needed for binding.17
The isatin carbonyl oxygen is H-bonded to the NH of Met149 in
the hinge region that links the two kinase subdomains, with the
oxime hydroxyl H-bonded to the backbone carbonyl of residue
Table 1
JNK3 inhibition data for 5-substituted isatin derivatives
N
X
OH
N
O
Y
In the second approach (Scheme 2) a solid-phase method was
developed using the TFA-cleavable hydroxylamine resin described
by Richter and Desai.14 O-p-Alkoxybenzyl hydroxylamine resin was
treated with substituted isatins in a mixture of DMF and pyridine
and shaken at ambient temperature overnight. Thorough washing
of the resin (DMF Â2, MeOH Â2, CH2Cl2 until no color was observed),
followed by cleavage of a small sample with 50% TFA in CH2Cl2 re-
leased the isatin oxime together with a small amount of byproduct
arising from cleavage of the linker from the resin. This side reaction
has been previously noted with this hydroxylamine Wang resin.15
The resin-bound isatin oxime was N-alkylated by treatment with al-
kyl chloride or bromide (2 equiv) in DMF in the presence of DBU
(2 equiv). After 48–72 h at 35 °C the resin was washed with DMF,
MeOH, and CH2Cl2. Alkylation at elevated temperatures (e.g., 80 °C)
resulted in shorter reaction times, but poorer quality product. N-
Alkylated isatin oximes were released from the resin with 50% TFA
in CH2Cl2 and products were purified by preparative HPLC.
Table 1 illustrates data for the N-benzylated isatin oxime deriv-
atives prepared from commercially available isatins. It is evident
that the SAR for the isatin substituents (X) was relatively flat. How-
ever the commercially available isatins represent very limited
structural diversity. More significant variation in enzyme potency
was observed from the N-substituent. In particular the 3,5-dime-
thoxybenzyl (compounds 15, 24) and the 6-fluoro-4H-benzo[1,3]-
dioxin-8-ylmethyl (compounds 25–27) substituents conferred the
most potency.
Compd
X
Y
JNK3 Ki (l
M)16
3
4
5
6
7
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
F
H
>10
8.5
8.1
2-F
3-F
4-F
2-NO2
3-NO2
4-NO2
3-Cl
8.3
>10
0.94
7.0
5
6.7
6.8
9.9
5.2
0.99
0.51
>10
>10
12
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
4-Cl
3-Me
4-Me
3-CF3
3,5-(OMe)2
a
H
H
H
H
Cl
Br
Me
Me
F
2.5
2.7
3-CF3
3-Me
4-OMe
>10
1.6
0.79
0.44
0.74
1.7
F
F
3,5-(OMe)2
a
a
a
Cl
OCF3
a
N-substituent is 6-fluoro-4H-benzo[d][1,3]dioxin-8-ylmethyl
O
At this point we were able to obtain an X-ray crystallographic
structure of compound 25 bound to the ATP-site of JNK3 (Fig. 2)
O
F

J. Cao et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2891–2895
2893
shown to be important for kinase inhibitor selectivity. A distinct
difference between JNK3 and p38 is that the hydrophobic pocket
in JNK3 contains a methionine (Met146) residue where the analo-
gous residue in p38 is the less sterically demanding threonine
(Thr106).21 From the isatin 6-position, substituents would point
either toward binding opportunities in the glycine-rich loop or to-
ward solvent which would enable us to add solubilizing groups to
our molecules without penalty. Given the limited commercial
availability of 4 and 6-substituted isatins, we needed to prepare
a selection of key intermediates.
4-Substituted isatins were prepared by the method shown in
Scheme 3, in which 4-substituted indoles are 3,3-dibrominated
and subsequently hydrolyzed to give the desired isatin.22
6-Substituted isatins were prepared from the corresponding p-
substituted o-nitro bromobenzenes (Scheme 4). Substitution of the
bromide using diethylmalonate gave the arylmalonates, which
were reduced, decarboxylated and cyclized in a single step to give
the oxindole. Claisen reaction with ethyl formate gave the enol,
which was O-alkylated with chloromethyl methyl ether and oxida-
tively cleaved to afford the 6-substituted isatins.
Further elaboration of these key intermediates into N-substi-
tuted isatin oximes was performed by the methods shown in
Schemes 1 and 2.
As can be seen in Table 2, results from the 6-substituted isatin
series were similar to those previously observed in the 5-substi-
tuted series, in that no profound effect on binding affinity was ob-
served. Larger substituents, designed to extend into the glycine
rich loop, or out into solvent, exhibited poor binding (data not
shown).
Figure 2. X-ray structure showing compound 25 bound to JNK3 active site.
R
R
R
Br
O
As might be expected from the structure of 25 (Fig. 2) and from
Br
a
b, c
previous reports on the binding of inhibitors to p38a 19
,
substitu-
ents at the isatin 4-position had a more pronounced effect on bind-
ing to both JNK3 and p38 (Table 3). In comparison to the potent
and selective compound 16 (X = H), the larger 4-phenyl compound
41 (Table 3) showed a slightly decreased affinity for JNK3 (1.8 M),
but, for the first time, we observed measurable affinity for p38
(9.5 M). Figure 3 shows the X-ray crystal structure of compound
O
O
N
H
N
N
H
a
Ar
l
Scheme 3. R = Br, CH3, COOMe. Reagents and conditions: (a) NBS, t-BuOH, 2.5 h, rt;
(b) MeOH, H2O, 4 h, reflux, 44% (two steps); (c) ArCH2Br, K2CO3, DMF, 5 h, rt, 60–
70%.
a
l
41 bound to JNK3. It can be seen that the isatin 4-phenyl substitu-
ent points towards the hydrophobic pocket, but the side chain of
the gatekeeper residue Met146 is folded back, effectively closing
the pocket. The isatin oxime is also seen to be in the (Z)-conforma-
tion. With the larger styrenyl substituent at the 4-position of com-
pound 47 the gatekeeper residue Met 146 is forced aside (Fig. 4) to
create the hydrophobic pocket that accommodates the large
hydrophobic 4-styrenyl substituent. Comparison of the unsubsti-
Glu147. The oxime is observed in the E-conformation, consistent
with the small molecule X-ray structure of (E)-N-(2-hydroxy-
ethyl)-isatin oxime.18 To determine the orientation of the oxime,
a ligand lacking the oxime O was refined against the X-ray data.
An electron density difference map was then calculated to show
the correct placement of the oxime O (E- or -conformation). Vec-
tors coming from the isatin 4- and 6-positions appeared to offer
good opportunities for optimization, while those from the 5- and
7-positions present more inter- and intra-molecular steric clashes,
respectively. The structure appeared to be consistent with the ini-
tial SAR of the 5-substituents. Substitution at the isatin 4-position
would direct pendant groups toward a hydrophobic pocket blocked
by Met-146, the gatekeeper residue that we19 and others13,20 have
tuted alkene 49 (JNK3 Ki = 0.14
47 (JNK3 Ki = 0.74 M) suggests that opening and filling the hydro-
phobic pocket with a rigid side chain results in slight loss of po-
tency (Table 3, JNK3 data), whereas filling corresponding
hydrophobic pocket without having to create it first (Table 3, p38
data) results in a significant gain in potency. This loss of JNK3 activ-
lM) with the styrenyl compound
l
a
a
CO2Et
CO2Et
NO2
Br
a
b
c
X
X
NO2
X
N
H
O
X
OMe
O
O
OH
d
e
X
N
H
O
N
H
O
X
N
H
O
Scheme 4. Reagents and conditions (X = Me, Br, NO2): (a) CH2(CO2Et)2, K2CO3, DMF, 80 °C, 78%; (b) Fe (3 equiv), AcOH, 120 °C, 90%; (c) HCO2Et, NaOH, EtOH, 95%; (d)
CH3OCH2Cl, K2CO3, DMF, 80%; (e) NaIO4, KMnO4, K2CO3, t-BuOH, dioxane, 88%. Yields are indicated for X = Br.

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J. Cao et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2891–2895
Table 2
Data for 6-substituted isatins
NOH
O
X
N
O
F
O
Compd
6-X
JNK3 Ki (l
M)16
16
28
29
30
31
32
33
34
35
36
37
38
39
H
Me
Br
0.51
0.09
0.1
Ph
0.2
OMe
CF3
NH2
MeSO2NH
EtCONH
NO2
COOMe
COOH
CONHEt
0.24
0.33
0.4
0.46
0.61
0.64
0.16
0.3
1.0
Table 3
Data for 4-substituted isatins
Figure 3. X-ray structure showing compound 41 bound to JNK3 active site.
X
N
O
NOH
O
F
O
Compd
4-X
JNK3 Ki (
l
M)
p38a Ki (
lM)
ERK2 Ki (lM)
16
40
41
42
43
44
45
46
47
48
49
50
H
Br
Ph
0.51
0.185
1.8
5.8
13
2.0
30
0.7
0.74
>15
0.14
1.4
>10
9.5
7.4
3.4
>15
25
23
m-F–Ph
p-F–Ph
CN
COOMe
Me
CH@CHPh
CH2CH2Ph
CH@CH2
Et
>15
>15
>15
0.23
0.03
8
>15
>15
>15
ity suggests an approximate 1 kcal net cost involved in moving the
gatekeeper residue aside to create the pocket. Interestingly com-
pound 48, an analog of 47 with a saturated linking group, is devoid
of JNK3 inhibition, yet p38a inhibition is enhanced approximately
10-fold. We attribute this to the superior ability of the rigid styryl
group to shift the JNK3 Met146 side chain out of the way and the
ability of the flexible phenethyl group to conform to the exact
shape of the p38 hydrophobic pocket.
Figure 4. X-ray structure showing compound 47 bound to JNK3 active site.
nases. A clear understanding of the mobility of the JNK3 gatekeeper
Met146 residue and how this affects selectivity for this class of
inhibitor was developed through the application of structure-
based design. These results complement those reported by Swahn
et al.10b for compound 51 (Fig. 5), which also exhibited an induced
fit binding mode similar to that seen for compound 47, yet showed
Compound 28 was identified as the most potent of this class of
compounds and was subject to further evaluation. Selectivity for
JNK family enzymes was excellent, with little or no activity ob-
served against a panel of kinases (Table 4). Compound 28 may
prove to be a useful tool compound for better understanding JNK
pathway biology.
a higher selectivity ratio for JNK3 to p38a. Compound 28 was iden-
tified as a potent selective, JNK-specific MAP kinase inhibitor that
will help explore JNK biology.
In conclusion, we have identified a novel series of JNK-selective
inhibitors that exhibit a very high level of overall kinase selectivity
for JNK over closely related p38 MAP kinases, as well as other ki-

J. Cao et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2891–2895
2895
Table 4
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Kinase selectivity data for compound 28
Kinase
Ki (
l
M)
Kinase
Ki (lM)
JNK3
JNK2
JNK1
AKT3
CDK2
ERK2
Flt3
0.09
0.07
0.45
>30
>30
>50
>4
JAK3
Lck
p38a
PDK1
ROCK1
Src
>30
>30
>20
>30
>30
>30
>30
>10
Syk
Tie2
9. Jiang, R.; Duckett, D.; Chen, W.; Habel, J.; Ling, Y. Y.; LoGrasso, P.; Kamenecka, T.
M. Bioorg. Med. Chem. Lett. 2007, 17, 6378.
GSK3b
>30
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Bioorg. Med. Chem. Lett. 2005, 15, 3459; (b) Swahn, B.-M.; Huerta, F.; Kallin, E.;
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Bioorg. Med. Chem. Lett. 2006, 16, 5723; (b) Liu, M.; Wang, S.; Clampit, J. E.;
Gum, R. J.; Haasch, D. L.; Rondinone, C. M.; Trevillyan, J. M.; Abad-Zapatero, C.;
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Cl
H
N
NH
N
N
O
N
H
OH
O
Figure 5. Compound 51.
Supplementary data
13. Alam, M.; Beevers, R. E.; Ceska, T.; Davenport, R. J.; Dickson, K. M.; Fortunato,
M.; Gowers, L.; Haughan, A. F.; James, L. A.; Jones, M. W.; Kinsella, N.; Lowe, C.;
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14. Richter, L. S.; Desai, M. C. Tetrahedron Lett. 1997, 38, 321.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.03.043.
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