3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3

Article abstract of DOI:10.1016/j.bmcl.2004.03.090

A novel series of acyclic 3-(7-azaindolyl)-4-(aryl/heteroaryl)maleimides was synthesized and evaluated for activity against GSK-3β and selectivity versus PKC-βII, as well as a broad panel of protein kinases. Compounds 14 and 17c potently inhibited GSK-3β (IC₅₀=7 and 26nM, respectively) and exhibited excellent selectivity over PKC-βII (325 and >385-fold, respectively). Compound 17c was also highly selective against 68 other protein kinases. In a cell-based functional assay, both 14 and 17c effectively increased glycogen synthase activity by inhibiting GSK-3β.

Full text of DOI:10.1016/j.bmcl.2004.03.090

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3245–3250
3-(7-Azaindolyl)-4-arylmaleimides as potent, selective
inhibitors of glycogen synthase kinase-3
Han-Cheng Zhang,a,* Hong Ye,a Bruce R. Conway,b Claudia K. Derian,a
Michael F. Addo,a Gee-Hong Kuo,b Leonard R. Hecker,a Diane R. Croll,a
Jian Li,a Lori Westover,b Jun Z. Xu,b Richard Look,b Keith T. Demarest,b
Patricia Andrade-Gordon,a Bruce P. Damianoa and Bruce E. Maryanoffa
aDrug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA
bDrug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ 08869-0602, USA
Received 5 February 2004; revised 26 March 2004; accepted 29 March 2004
Abstract—A novel series of acyclic 3-(7-azaindolyl)-4-(aryl/heteroaryl)maleimides was synthesized and evaluated for activity against
GSK-3b and selectivity versus PKC-bII, as well as a broad panel of protein kinases. Compounds 14 and 17c potently inhibited
GSK-3b (IC50 ¼ 7 and 26 nM, respectively) and exhibited excellent selectivity over PKC-bII (325 and >385-fold, respectively).
Compound 17c was also highly selective against 68 other protein kinases. In a cell-based functional assay, both 14 and 17c effectively
increased glycogen synthase activity by inhibiting GSK-3b.
Ó 2004 Elsevier Ltd. All rights reserved.
1.Introduction
diabetic complications and other disorders,3b;6 we iden-
tified a novel series of macrocyclic bisindolylmaleimides
with potent (single-digit nanomolar IC50) dual inhibition
against both PKC-bII and GSK-3b,7 indicating high
homology (ca. 50%) at their ATP binding sites between
these two enzymes. Replacement of both indole rings
with 7-azaindole led to a series of macrocyclic bis-7-
azaindolylmaleimides as GSK-3b inhibitors.8 The com-
pounds generally showed excellent selectivity against a
broad panel of about 60 protein kinases; however,
achieving high selectivity over PKC-bII proved to be a
challenge. Of the many macrocyclic bis-7-aza-
indolylmaleimides prepared,8 only one compound with a
tetra(ethylene glycol)-linked 22-membered ring exhib-
ited good selectivity for GSK-3b over PKC-bII (>200-
fold).8a We were interested in expanding on this foun-
dation. Herein, we report the synthesis and biological
evaluation of a novel series of acyclic 3-(7-azaindolyl)-4-
(aryl/heteroaryl)maleimides as potent GSK-3b inhibi-
tors with excellent selectivity over PKC-bII (>300-fold),
as well as a broad panel of other kinases.
Glycogen synthase kinase-3 (GSK-3) is a serine/threo-
nine protein kinase composed of two isoforms (a and b)
with high homology (ca. 90%) at the catalytic domain.1
GSK-3b plays a critical role in glucose homeostasis,
CNS function (via the proteins tau and b-catenin), and
cancer (via angiogenesis, apoptosis, and tumorigene-
sis).2 Inhibition of GSK-3-dependent phosphorylation
should activate insulin-dependent glycogen synthesis,
thereby mimicking the action of insulin to lower plasma
glucose. Thus, inhibitors of GSK-3b would afford a
novel mode of treating type II diabetes.3 Additionally,
GSK-3 inhibitors have therapeutic potential for treating
neurodegenerative diseases, bipolar disorder, stroke,
cancer, and chronic inflammatory diseases.4
A number of GSK-3 inhibitors with various degrees of
selectivity against other protein kinases have been re-
ported in the past several years.5 During the search for
PKC-b inhibitors as potential agents for treatment of
2.Synthetic chemistry
Keywords: GSK-3 inhibitors; Kinases; Azaindolylmaleimides.
* Corresponding author. Tel.: +1-215-628-5988; fax: +1-215-628-
4985; e-mail: hzhang@prdus.jnj.com
Methyl 7-azaindole-3-glyoxylate
from commercially available 1 by deprotonation with
2
was prepared
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.03.090

3246
H.-C. Zhang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3245–3250
OMe
O
OMe
O
NH2
O
OMe
O
O
O
b
c
d
a
N
N
H
N
N
N
N
N
N
N
N
H
Et
Et
Et
1
3
5
4
2
H
OMe
O
O
N
O
O
e
5
2
N
f
N
N
N
N
N
Et
t-BuMe2SiO
6
HO
7
Scheme 1. Reagents and conditions: (a) EtMgBr, THF, )65 °C, then MeO2CCOCl, )78 °C, 24%; (b) EtI, Cs2CO3, DMF, 50 °C; (c) Et3SiH, TFA,
55 °C; (d) NH3, MeOH, 90 °C, 34% overall yield from 2; (e) Br(CH2)3OSiMe2–t-Bu, Cs2CO3, DMF, 50 °C, 44%; (f) t-BuOK, THF, 0 °C, then concd
HCl, 39%.
ethylmagnesium bromide followed by acylation with
methyl oxalyl chloride (Scheme 1). N-Alkylation of 2
with iodoethane in the presence of Cs2CO3 in DMF
afforded intermediate 3, which was reduced with Et3SiH
in CF3CO2H (TFA) at 55 °C to provide methyl ester 4.
Aminolysis of ester 4 gave amide 5. Compound 2 was
also N-alkylated with 3-(tert-butyldimethylsilyl-
oxy)propyl bromide to give a-keto ester 6. Maleimide
condensation of 6 and amide 5 proceeded smoothly in
the presence of t-BuOK at 0 °C.9 Treatment with concd
HCl removed the silyl group to yield acyclic bis-7-aza-
indolylmaleimide 7.
mide 13 in the presence of t-BuOK followed by addition
of concd HCl to derive maleimide 14 along with some 15
(Scheme 3). Deprotection of Boc group in 14 with TFA
afforded 15. Further functionalization of the primary
amino group in 15 was conducted with various reagents.
Treatment of 15 with butyl formate in DMF at 80 °C
afforded formamide product 16a. Reaction of 15 with
sulfamide in dioxane at 80 °C provided 16b, and with
methanesulfonic anhydride in the presence of pyridine
afforded sulfonamide 16c.
Thiophene- and pyridine-containing analogues 17a–c
were synthesized from a-keto ester 6 and the corre-
sponding heteroarylacetamides under the conditions
described for 9a–e.
a-Keto ester 6 was also subjected to maleimide con-
densation with various commercially available arylace-
tamides 8, following the same procedure as described
above, to afford target compounds 9a–f (Scheme 2).10
The hydroxy group in 9 was further converted to the
corresponding amine. Thus, treatment of 9 with Ms2O
in pyridine/THF at 50 °C selectively produced O-sulfo-
nated product 10 with no detectable N-sulfonated iso-
mer. Substitution of the mesylate group in 10 with
excess of dimethylamine in THF afforded amine-
containing products 11a,b.
3.Enzymatic activity
Since achieving high selectivity for GSK-3b over PKC-
bII proved to be the most challenging among the
approximately 60 kinases screened with the macrocyclic
maleimide compounds,7;8 the 3-(7-azaindolyl)-4-(aryl/
heteroaryl)maleimides were tested in enzymatic assays
involving both GSK-3b and PKC-bII to determine
potency and selectivity between the two key kinases
Alkylation of 2 with Boc-protected 3-bromopropyl-
amine using Cs2CO3 as a base gave intermediate 12,
which was then condensed with 2-methoxyphenylaceta-
H
N
H
N
H
N
O
O
O
O
O
O
Ar-CH2CONH2
Ar
Ar
b
Ar
c
8
6
N
N
N
a
N
N
N
Ar = Ph, Naphthyl
11
9
HO
10
Me2N
MsO
Scheme 2. Reagents and conditions: (a) t-BuOK, THF, 0 °C, then concd HCl, 17–62%; (b) Ms2O, pyridine, THF, 50 °C; (c) Me2NH, THF, 50–65 °C,
22–31% overall yield from 9.

H.-C. Zhang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3245–3250
3247
O
H
H
N
N
OMe
O
O
O
O
O
NH2
O
MeO
OMe
OMe
13
c
a
N
N
2
N
N
N
N
b
14
15
Boc
N
H
12
Boc
O
N
H
H2N
H
N
O
O
O
S
O
O
S
O
OMe
H2N
Me
d -f
R =
H
N
N
16a
16b
16c
Reaction
conditions:
d
e
f
16
R N
H
Scheme 3. Reagents and conditions: (a) Br(CH2)3NHBoc, Cs2CO3, DMF, 68 °C, 65%; (b) t-BuOK, THF, 0 °C, then concd HCl, 43%; (c) TFA,
CH2Cl2, 84%; (d) HCO2Bu, DMF, 80 °C, 60%; (e) H2NSO2NH2, 1,4-dioxane, 80 °C, 17%; (f) Ms2O, pyridine, THF, 50 °C, 61%.
Table 1. Enzymatic activity of 3-(7-azaindolyl)-4-(aryl/heteroaryl)maleimidesa
H
N
O
O
Ar
N
N
R1
R2
Compd R1
Ar
R2
GSK-3bb
IC50 (lM)
PKC-bIIc
IC50 (lM)
PKC-ac
IC50 (lM)
PKC-cc
IC50 (lM)
7
9a
HO(CH2)3
HO(CH2)3
3-(7-Azaindolyl) N1-Et
0.065 0.010
0.031 0.001
0.010 0.001
0.014 0.003
0.004 0.001
0.006 0.002
0.045 0.004
0.14 0.003
0.015 0.003
0.007 0.001
0.037 0.004
0.008 0.001
0.020 0.002
0.014 0.001
0.031 0.006
0.48 0.13
1.07 0.18
>10
3.6
4.4
>10
ca. 10
5.5
1-Naphthyl
Ph
H
2-Cl
0.27 0.15
0.73 0.12
1.85 0.01
1.44 0.22
2.38 1.17
4.36 2.03
0.24 0.01
1.16 0.06
2.26 0.24
1.10 0.49
2.73 0.40
0.89 0.34
1.88 0.08
9b
9c
HO(CH2)3
HO(CH2)3
Ph
Ph
2-CF3
2-OMe
2-Cl–4-F
2-OH
H
ca. 10
ca. 10
4.5
ca. 10
>10
>10
>10
2.8
9d
9e
HO(CH2)3
HO(CH2)3
Ph
Ph
9f
MeO(CH2)3
Me2N(CH2)3
Me2N(CH2)3
Boc-NH(CH2)3
H2N(CH2)3
HC(O)NH(CH2)3
>10
1.4
4.0
11a
11b
14
1-Naphthyl
Ph
Ph
Ph
Ph
2-Cl
3.6
2-OMe
2-OMe
2-OMe
2-OMe
2-OMe
H
>10
ca. 10
>10
>10
4.7
>10
>10
8.7
15
16a
16b
16c
17a
17b
17c
H2NSO2NH(CH2)3 Ph
6.0
8.6
MeSO2NH(CH2)3
HO(CH2)3
HO(CH2)3
Ph
2-Thienyl
2-Pyridyl
2-Pyridyl
>10
>10
>10
>10
>10
>10
>10
H
>10
>10
HO(CH2)3
3-Cl–5-CF3 0.026 0.007
a IC50 values are expressed as mean SEM (n P 2; n ¼ 1 for values without error limits). ‘>10’ and ‘ca. 10’ mean <50% and ca. 50% inhibition at 10
lM of compound, respectively.
b Recombinant rabbit GSK-3b was used and protein phosphatase inhibitor-2 (PPI-2) as a substrate.8
c Recombinant human PKC-a; bII, and c were used and histone as a substrate.7
(Table 1). In addition, these compounds were also
screened against PKC-a and PKC-c, two isozymes
within the same PKC subfamily as PKC-bII. Bis-7-
azaindolylmaleimide 7 inhibited GSK-3b and PKC-bII
with IC50 values of 0.065 and 1.07 lM, respectively, and
was highly selective over PKC-a and PKC-c
(IC50 > 10 lM). The selectivity for GSK-3b over PKC-
bII with 7 decreased when compared to the corre-
sponding macrocyclic bis-7-azaindolylmaleimides.8
Replacement of a 7-azaindole ring in 7 with a naphthyl

3248
H.-C. Zhang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3245–3250
(9a) increased the potency for both GSK-3b and PKC-
bII (IC50 ¼ 0.031 and 0.27 lM, respectively). Substitu-
tion of the hydroxyl in 9a with dimethylamino (11a) led
to a 5-fold loss of potency for GSK-3b, while the
potency for PKC-bII was maintained. Interestingly,
replacement of the naphthyl in 9a with a 2-chlorophenyl
group (9b) further improved activity for GSK-3b
(IC50 ¼ 0.010 lM) as well as selectivity over PKC-bII
(73-fold). Modifications on the phenyl ring in 9b led to
single-digit nanomolar inhibitors of GSK-3b, 9d and 9e,
which had excellent selectivity over PKC-bII, PKC-a,
and PKC-c. For example, 9d inhibited GSK-3b with an
IC50 of 0.004 lM and exhibited P360-fold selectivity
versus PKCs bII, a, and c. Transfer of the O-methyl
group from phenol to hydroxypropyl side chain in 9d
(viz. 9f) caused an 11-fold drop in potency for GSK-3b;
however, good selectivity versus PKCs bII, a, and c was
maintained. Substitution of the hydroxyl in 9d with a
primary amine (15) decreased the potency for GSK-3b
by 9-fold. Introduction of various functionalities to the
amino group in 15, such as carbamate (14), amide (16a),
sulfamide (16b), and sulfonamide (16c), was well toler-
ated, giving potent GSK-3b inhibitors (IC50
6 0.020 lM) with various degrees of activity for PKC-
bII (IC50 ¼ 0.89–2.73 lM). The selectivity of this 7-aza-
indole maleimide series for GSK-3b over PKC-bII was
further enhanced by replacing the phenyl with a thienyl
(17a) or pyridyl group (17c), while maintaining potent
GSK-3b inhibition. In this vein, pyridine-containing
analogue 17c potently inhibited GSK-3b with an IC50 of
0.026 lM and showed excellent (>385-fold) selectivity
over PKC-bII, as well as PKC-a and PKC-c (IC50’s
>10 lM).
over the CDKs (25–62% of control). This compound
was also highly selective over the remaining kinases in
the panel, with very weak or no activity.12 To further
determine the actual degree of selectivity for 17c, we
obtained IC50 values (Table 3) for CDK1/cyclin B
(5.8 lM) and CDK2/cyclin A (2.8 lM), as representa-
tives for the CDK family, as well as MSK1 (>10 lM),
which somehow failed during single-dose screening,
reflecting GSK-3b selectivities of 220, 105, and >385-
fold relative to these kinases, respectively. We deter-
mined IC50 values for 9f and 14 against CDK1 and
CDK2, representing the CDK family, and a few other
kinases potently inhibited by 9f and 14 (Table 3). The
very potent GSK-3b inhibitor 14 (IC50 ¼ 0.007 lM) also
potently inhibited CDK1 and CDK2, with IC50 values
of 0.17 and 0.068 lM, respectively.
5.Cellular activity
Selected compounds 9f, 14, and 17c were tested for their
ability to increase glycogen synthase (GS) activity in
HEK293 cells, a direct functional assay to measure the
cellular activity of GSK-3b inhibitors. The results in
Table 4 indicate effective blockade of GSK-3b and
increased GS activity within cells by these compounds,
with EC50 values of 0.04–0.62 lM. LiCl, a known
inhibitor of GSK-3b,13 was basically inactive in this cell-
based assay, while another GSK-3b inhibitor reference
compound, SB-216763,5k had an EC50 of 0.20 lM.
4.Kinase selectivity
6.Molecular docking
With potent inhibition of GSK-3b and excellent selec-
tivity over PKC-bII achieved, we selected representative
compounds for further screening against a broad panel
of 70 protein kinases (Upstate Biotech Inc.) to assess
kinase selectivity. Compound 9d, one of the most potent
GSK-3 inhibitors, showed potent inhibition (<10% of
control at 10 lM of compound in the presence of 10 lM
of ATP) against PKC-bII, CDK1-6, and RSK3. In
addition, some activity (<50% of control) was observed
with 9d against other kinases, including AMPK, BLK,
CAMK, CHK1, CK1, JNK3, LYN, MSK1, PDK1,
PKC-a, PKC-e, PKC-h, PRK2, RSK1, and RSK2 (data
not shown). Similarly, 15 and 16b showed poor selec-
tivity and inhibited most of the kinases listed above
(data not shown). Improvement of selectivity was ob-
served with 9f and 14, where the number of kinases
inhibited was greatly reduced (Table 2). It appears to be
a generalized effect with this acyclic 7-azaindole-based
maleimide series that the CDK family is potently
inhibited in addition to GSK-3b and PKC-bII.11 With
the macrocyclic bis-7-azaindolylmaleimides8 or bis-
indolylmaleimides,7 the GSK-3b selectivity relative to
the CDKs was more easily achieved. Pyridyl compound
17c exhibited a significant improvement of selectivity
Given the X-ray structure of GSK-3b (pdb code:
1q3d),14 a molecular docking study can be performed to
probe the possible binding mode of a GSK-3b inhibitor.
Figure 1 illustrates 17c docked into the ATP binding site
of GSK-3b.15 The key interactions for this complex in-
clude two hydrogen bonds between the maleimide por-
tion of 17c to Asp-133 and Val-135 backbone carbonyl
and amide hydrogen, respectively. The R1 hydroxyl
group forms another hydrogen bond with Gln-185. The
ꢀ
azaindole nitrogen is only about 3.6 A from the carboxyl
group of Asp-200 and may form an additional hydrogen
bond depending on the protonation state of Asp-200.
This binding mode is very similar to those revealed by
recent X-ray structures of PDK1/bisindolylmaleimide
complexes.16 Thr-138 and Arg-141 are about 5 A from
ꢀ
pyridyl group, and the electrostatic interaction between
pyridyl and the positively charged guanidine is ener-
getically favorable. In contrast, the two corresponding
residues on these positions in PKC-bII are Asp-97 and
Tyr-100. The electrostatic interaction between the
negatively charged side chains and the pyridyl group is
not energetically propitious. This difference may con-
tribute to the excellent GSK-3b over PKC-bII selectivity
for 17c.

H.-C. Zhang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3245–3250
Table 2. Activities at protein kinases assaysa
3249
Protein kinase
Activity (% of control)
14 17c
Protein kinase
Activity (% of control)
9f
9f
86
14
17c
GSK3b (h)
Abl (m)
AMPK (r)
1
0
3
93
74
67
76
82
34
25
30
62
25
59
59
73
92
66
56
74
81
64
89
78
76
83
95
80
93
76
82
85
66
91
93
85
74
MKK4 (m)
MKK6 (h)
MKK7b (h)
MSK1 (h)
p70S6K (h)
PAK2 (h)
PDGFRa (h)
PDGFRb (h)
PDK1 (h)
PKA (b)
101
95
87
86
68
Failb
88
78
86
77
79
86
87
64
69
70
70
72
67
66
59
71
74
90
97
66
77
60
81
94
86
86
87
93
76
93
91
86
68
75
63
82
9
91
64
63
60
91
3
83
71
57
87
94
99
96
78
99
92
93
82
46
32
59
49
46
82
76
74
100
94
48
54
33
84
102
120
97
98
99
86
89
100
101
61
Blk (m)
CAMKII (r)
CAMKIV (h)
CDK1/cyclinB (h)
CDK2/cyclinA (h)
CDK2/cyclinE (h)
CDK3/cyclinE (h)
CDK5/p35 (h)
CDK6/cyclinD3 (h)
CDK7/cyclinH (h)
CHK1 (h)
82
93
108
93
9
2
11
26
9
3
20
3
112
95
2
PKA (h)
50
47
78
75
58
93
89
79
79
94
80
83
81
88
75
63
52
84
81
78
92
100
97
94
24
60
95
49
85
103
95
87
83
63
86
89
91
94
81
84
68
67
20
81
92
89
85
100
PKBa (h)
PKBb (h)
PKCa (h)
PKCbII (h)
PKCc (h)
PKCe (h)
PKCh (h)
PRAK (h)
PRK2 (h)
c-RAF (h)
ROCK-II (h)
ROCK-II (r)
Rsk1 (r)
103
99
38
15
CHK2 (h)
CK1 (y)
76
54
CK2 (h)
CSK (h)
71
57
Fes (h)
FGFR3 (h)
Fyn (h)
68
92
IGF-1R (h)
IKKa (h)
IKKb (h)
IR (h)
78
91
38
31
Rsk2 (h)
Rsk3 (h)
JNK1a1 (h)
JNK2a2 (h)
JNK3 (r)
24
SAPK2a (h)
SAPK2b (h)
SAPK3 (h)
SAPK4 (h)
SGK (h)
109
106
122
100
105
74
Lck (h)
Lyn (m)
MAPK1 (h)
MAPK2 (h)
MAPK2 (m)
MAPKAP-K2 (h)
MEK1 (h)
cSRC (h)
Syk (h)
88
42
Yes (h)
ZAP-70 (h)
112
a Performed at Upstate Biotech Inc.
b Compound 17c was retested against MSK1 and an IC50 value of >10 lM was determined.
Table 3. IC50 values for selected kinasesa
Table 4. Glycogen synthase activity in HEK293 cellsa
Compd
Kinase
IC50 (lM)
Compd
EC50 (lM)
9f
CDK1/cyclinB (h)
CDK2/cyclinA (h)
Rsk3 (h)
0.70
0.43
2.0
9f
14
0.39
0.04
17c
LiCl
SB-216763b
0.62
>3000
0.20
14
CDK1/cyclinB (h)
CDK2/cyclinA (h)
Lyn (h)
0.17
0.068
1.8
a Values are an average of triplicate determinations. HEK293 cells were
treated with compounds and GS activity was determined in cell
extracts by measuring 14C-UDP glucose incorporation into glycogen.
b GSK-3 inhibitor reference compound.5k
PDK1 (h)
Rsk3 (h)
0.57
0.64
5.8
17c
CDK1/cyclinB (h)
CDK2/cyclinA (h)
MSK1 (h)
2.8
>10
bisindolylmaleimides,7 or bis-7-aza-indolylmaleimides.8
Screening against a panel of 70 kinases revealed that this
acyclic series potently inhibits the CDK family and has
some activity against a number of other kinases. Intro-
duction of a substituted pyridyl group led to potent
GSK-3b inhibitor 17c, with a significant improvement in
selectivity over the CDKs and excellent selectivity over
the remaining kinases in the panel. Representative
compounds, including 17c, were effective intracellularly,
increasing glycogen synthase activity via the blockade of
GSK-3b.
a Values are an average of duplicate determinations. Assays were
performed at Upstate Biotech Inc.
7.Conclusion
We identified a novel series of 3-(7-aza-indolyl)-4-(aryl/
heteroaryl)maleimides as potent GSK-3b inhibitors with
excellent selectivity (>300-fold) over PKC-bII, the most
difficult kinase among a broad panel to achieve high
selectivity over with the previously reported macrocyclic

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H.-C. Zhang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3245–3250
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Acknowledgements
We thank Earl Danser, and Dr. Indrasena Reddy for
excellent technical assistance; and Upstate Biotech Inc.
for kinase screening data.
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