The development of potent and selective bisarylmaleimide GSK3 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2004.12.063

Many 3-aryl-4-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl) maleimides exhibit potent GSK3 inhibitory activity (<100 nM IC₅₀), although few show significant selectivity (>100 ×) versus CDK2, CDK4, or PKCβII. However, combining 3-(imidazo[1,2-a]pyridin-3-yl), 3-(pyrazolo[1,5-a]pyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4- tetrahydro[1,4]diazepino[6,7,1-hi]indol -7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (≤5 nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).

Full text of DOI:10.1016/j.bmcl.2004.12.063

Bioorganic & Medicinal Chemistry Letters 15 (2005) 899–903
The development of potent and selective bisarylmaleimide
GSK3 inhibitors
*
Thomas A. Engler, Sushant Malhotra, Timothy P. Burkholder, James R. Henry,
David Mendel, Warren J. Porter, Kelly Furness, Clive Diefenbacher, Angela Marquart,
Jon K. Reel, Yihong Li, Joshua Clayton, Brian Cunningham, Johnathan McLean,
John C. OꢀToole, Joseph Brozinick, Eric Hawkins, Elizabeth Misener, Daniel Briere,
Richard A. Brier, Jill R. Wagner, Robert M. Campbell, Bryan D. Anderson,
Renee Vaughn, Donald B. Bennett, Timothy I. Meier and James A. Cook
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 1 November 2004; revised 18 December 2004; accepted 21 December 2004
Available online 19 January 2005
Abstract—Many 3-aryl-4-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)maleimides exhibit potent GSK3 inhibitory activity
(
<100 nM IC50), although few show significant selectivity (>100 ·) versus CDK2, CDK4, or PKCbII. However, combining 3-(imid-
azo[1,2-a]pyridin-3-yl), 3-(pyrazolo[1,5-a]pyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]in-
dol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (65 nM) with >160 to >10,000-fold selectivity
versus CDK2/4 and PKCbII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma
glucose in a rat model of type 2 diabetes (ZDF rat).
ꢀ
2005 Elsevier Ltd. All rights reserved.
Glycogen synthase kinase 3 (GSK3) is an integral com-
ponent of the insulin signaling pathway as a modulator
of glycogen synthase (GS), the enzyme that catalyzes the
H
N
H
N
H
N
O
O
O
O
O
O
Cl
X
1
last, and rate-limiting, step in glycogen biosynthesis.
GSK3 is a constituently active negative regulator of
GS; that is, phosphorylation of GS by GSK3 turns off
Y
Z
N
R
X
N
N
N
X
N
H
2
HN
GS. Thus, inhibitors of GSK3 are expected to leave
GS in an active state stimulating the conversion of glu-
cose to glycogen (mimicking the effect of insulin), and
X
Y
Z
R
O
O
1
2
Cl CH CH CH3
CF3 N (CH2)3OH
3, X = CH
4, X = N
5
O
N
3
have potential utility for treatment of type 2 diabetes.
A variety of bis-aryl maleimides (BAMs) have been re-
ported as potent GSK3 inhibitors. Early studies affor-
Figure 1. Selected maleimide kinase inhibitors.
4
,7
3d,e
ded BAMs that also inhibited PKCs and CDKs,
a property common to many other structurally distinct
5
,7
6 5b
GSK3 inhibitors; for example, 1, 3 (Fig. 1). Further
SAR has produced potent inhibitors of GSK3 that dem-
and selective inhibitors of PKCb and are currently under
clinical evaluation for the treatment of diabetic compli-
cations and cancer, respectively. Efforts toward the
design of cyclin-dependant kinase inhibitors have not
only afforded a rich SAR on the maleimido-indolo-
3
8
5b
onstrate increased selectivity; for example, 2 and 4.
Lilly has a history of maleimide kinase inhibitors. Rub-
9
a,b
9c–e
oxistaurin mesylate
and enzastaurin
are potent
10a
10b–e
carbazoles 5
evaluate the inhibition of other kinases.
but also a large array of BAMs
to
Keywords: GSK3 Inhibitors; Bisarylmaleimides.
*
Corresponding author. Tel.: +1 317 433 2885; fax: +1 317 276
177; e-mail: engler_thomas@lilly.com
Since cross-reactivity with PKCs and CDKs is a feature
common to many GSK3 inhibitors, we postulated that
1
0
960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.12.063

900
T. A. Engler et al. / Bioorg. Med. Chem. Lett. 15(200 5) 899–903
O
O
from the corresponding arylbromides via Li–halogen ex-
change followed by reaction with dimethyl oxalate. Re-
moval of the tert-butyl carbamate protecting group in 10
under acidic conditions and acylation of the resulting
secondary nitrogen under standard conditions gave 12.
H2N
OCH3
+
O
O
H
N
N
O
O
Ar
Ar
N
N
BOC
6
7
8
a
Ar
b
As summarized in Table 1, maleimides with a diverse
array of Ar substituents were examined. Of these, the
O
N
H3CO
O
ꢁ
31 exhibited the best GSK3 inhibition (IC 1–
ortho-oxo fusedꢀ aromatics 13, 16, 18, 26–28, and 30–
N
NH2
+
R
50
N
15
1
1
0, R = BOC
1, R = H
13 nM). They also potently inhibited PKCbII and
CDK2/4. With highly potent inhibitors in hand, our
attention focused on selectivity, which emerged as a
more significant challenge for SAR. Notably, some of
the N-acylated derivatives, for example, 27–28 and 30–
c
12, R = acyl
BOC
9
(see Tables 1-3)
Scheme 1. Reagents and conditions: (a) KO-t-Bu, DMF, 73%; (b) 4 N
HCl/EtSH/dioxane, 86%; (c) N,N-dimethylcarbamoyl chloride, TEA,
MeOH, 80%. Yields shown are for 31 as a representative compound.
3
1, showed somewhat improved selectivity against
PKCbII, CDK2, and CDK4.
As an approach to improved selectivity, we explored
isosteric replacement of CH@ to N@ in the benzofuran
series with encouraging results (Table 2). Compound
32a was synthesized starting from 7-bromo-5H-
spanning the 1,7-indole positions of a 3-aryl-4-(3-indol-
yl)maleimide with a ring system, as in 5, could be used to
design novel, potent and selective inhibitors. Initially,
we focused attention on the 3-aryl-4-[1,7-aza-annu-
lated-indol-3-yl]maleimides 11/12 (Scheme 1); preference
was given to bicyclic heteroaromatic Ar groups.
1
3
furo[3,2-c]pyridin-4-one, which was converted to the
4
1
2-(furo[3,2-c]pyridin-7-yl)acetamide.
The resulting
acetamide was condensed with glyoxylate 6 and depro-
tected using 4 N HCl/dioxane/EtSH. The 3-furo-
[3,2-c]pyridin-7-yl series 32 consistently gave excellent
GSK3 activity and the N-acyl derivatives 32b–f demon-
strated on average somewhat improved selectivity
against CDK4 and PKCbII (Table 2; for example, 26
versus 32b, 30 versus 32d).
Maleimides 12 were prepared as shown in Scheme 1.
1
1
Condensation of indole 3-glyoxylate 6 or 3-acetamide
with the corresponding aryl acetamide 8 or aryl gly-
7
oxylate 9 gave maleimides 10. The 1,7-aza-annulated
indole–gyloxylate 6 and –acetamide 7 were prepared
1
0
by routes reported by Al-awar and co-workers. Aceta-
mides 8 were synthesized by hydrolysis of the corre-
The promising activity of the 3-furo[3,2-c]pyridin-7-yl
series suggested a search for other aza-heterocycles
1
2
sponding nitriles. The glyoxylates 9 were prepared
Table 1. Kinase inhibition of 3-aryl-4-[1,7-aza-annulatedindol-3-yl]maleimides 12
X
O
12, Ar =
X
X
O
NR
O
O
h, R=CH3
O
O
a
b
c
d
e
f
g
i, R=(CH2)3OH
Compound
R
Ar
GSK3 IC50 (nM)
Ratio of IC50s
CDK2
GSK3
CDK4
GSK3
PKCbII
GSK3
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
H
H
H
H
H
H
H
H
H
H
H
H
H
a, X = O
b, X = O
3.4
41
3
5
5
1
183
39
c
d, X = CH
64
––
10
––
7
––
7
37
53
2
3.3
130
13
e
d, X = O
––
2
35
103
15
a, X = S
b, X = S
45
34
2
1
––
42
––
––
11
11
7
––
18
––
––
1
24
f
27
83
202
47
g
a, X = NH
150
33
15
28
h
i
a, X = O
27
1
9
80
COMe
COMe
COMe
COMe
CONMe
CONMe
1.5
1.1
2.5
19
25
77
50
7
d, X = CH
d, X = O
a, X = S
a, X = O
d, X = O
2
16
24
4
133
240
7
2
2
2.7
3.2
25
139
35
89
89
190

T. A. Engler et al. / Bioorg. Med. Chem. Lett. 15(200 5) 899–903
901
Table 2. Kinase inhibition of 3-furo[3,2-c]pyridin-7-yl-maleimides 32
lysis of ethyl (E)-4,4-dimethoxy-but-2-enoate. The
resulting ethyl esters were converted to acetamides 57,
O
O
O
O
R =
12, Ar =
H
R
N
N
H
N
a
b, R=Me
c, R=Et
d
e, X=O
X
N
O
O
f, X=CH
2
CN
N
Compound
R
GSK3 IC50 (nM)
Ratio of IC50
s
a, b
c,d
34, 39,
4
7, 53
CDK2
GSK3
CDK4
GSK3
PKCbII
GSK3
N
N
N
N
3
3
3
3
3
3
2a
a
b
c
d
e
f
3.2
0.9
1.0
1.2
0.8
2.1
2
9
6
60
54
422
375
––
5
4
N
55
a
2b
BOC
a
a
2c
13
13
49
17
98
H
N
H2N
2d
112
158
92
O
O
N
a
2e
O
––
a
2f
108
e, f
g, h
N
N
N/C
N/C
N/C
a
HCl salt.
N
H2N
N
N
56
57
N
BOC
i
incorporating a nitrogen in a similar orientation as in
1
5
3
2. We focused on imidazo[1,2-a]pyridine 48, aza-ana-
33, 35-38, 40-46, 48-52
logs 49–52, and pyrazolo[1,5-a]pyridine 53 (Table 3).
Maleimides 12z (Table 3) were prepared as shown in
Scheme 2. Pyrazolo[1,5-a]pyridin-3-yl-acetonitrile 54
was hydrolyzed to the acetamide, condensed with 6 to
give 55, deprotected, and acylated. To prepare male-
imides 12u–y, the appropriate 2-amino pyridines 56
Scheme 2. Yields shown for 39 are representative: Reagents and
conditions: (a) KOH, t-BuOH, reflux, 30 min, 82%; (b) 6, KO-t-Bu,
DMF, 64%; (c) 4 N HCl/dioxane, EtSH, rt, 92%; (d) morpholine–4-
carbonyl chloride, TEA, MeOH, 68%. Yields shown for 33 are
1
6
representative: (e) ethyl (E)-4,4-dimethoxy-but-2-enoate, CH
3
CN,
H
2
O, TsOH, reflux; (f) NH
3
, MeOH, 100 ꢁC, ꢀ20–30% for two steps;
(
enoate, generated in situ via an acid catalyzed hydro-
Scheme 2) were condensed with ethyl (E)-4-oxo-but-2-
1
(g) 6, KO-t-Bu, DMF, 60%; (h) 4 N HCl/dioxane, EtSH, rt, quant.; (i)
N,N-dimethylcarbamoyl chloride, TEA, MeOH, 78%.
7
Table 3. In vitro and in vivo activities of imidazo[1,2-a]pyridinyl, and pyrazolo[1,5-a]pyridinyl maleimides
N
1
2, R= (a) C(O)NMe2
(e) C(O)i-Pr
Ar =
N
N
N
N
N
N
a
(
(
(
b) C(O)-N-morpholine (f) C(O)-4-THP
N
N
z
c) C(O)-N-piperidine
d) C(O)Me
(g) H
N
N
N
N
N
N
N
u
v
w
x
y
b
pTau IC50 (nM) In vivo glucose lowering (ZDF rat, 10 mpk)
c
Compound
R
Ar GSK3 IC50 (nM)
Ratio of IC50
s
CDK2
GSK
CDK4
GSK
PKCb
GSK
1
5
5
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
a
a
b
b
b
b
b
c
u
z
1.6
4.7
1.3
1284
469
907
370
635
235
893
12
38
104
69
1
u
w
x
y
z
2491
1308
>282
4551
2.6
119
d
71
>282
>6300
>11,800
2332
>282
>6300
––
11
––
f
f
3.2
1.7
1.3
2.0
0.7
2.1
1.9
1.9
1.8
0.8
3.5
À2
8575 >11,800
297
––
À43
1900
2420
1327
8916
576
281
66
124
137
64
15
u
v
2680
620
1.6
0.3
8.7
c
1305
>9500
>1507
457
c
x
y
u
u
u
z
>9500
f
c
>10,500 10,022
53
À61
d
e
331
1977
6880
466
63
483
2024
2653
309
13
111
5
––
109
––
10
––
––
––
––
––
––
522
f
1745
160
7.7
e
13
––
––
––
––
––
––
e
e
g
g
g
g
g
g
u
v
12
4.8
330
28
133
14
23
15
14
w
x
y
z
3
e
e
e
60
120
30
93
73
19
20
>334
112
18
25
10
a
THP = tetrahydropyranyl.
b
c
d
e
f
Inhibition of tau phosphorylation.
%
of insulin (10 units) response.
Not tested.
HCl Salt.
Glucose levels higher than vehicle control.

902
T. A. Engler et al. / Bioorg. Med. Chem. Lett. 15(200 5) 899–903
condensed with glyoxylate 6, and acylated. Although
some of the parent NH compounds 48–53 were potent
GSK3 inhibitors, most showed only modest potency
and selectivity. However, the acylated derivatives 33–
P.; Andjelkovich, M.; Hemmings, B. A. Nature 1995, 378,
85; (c) Eldar-Finkelman, H.; Ilouz, R. Expert Opin.
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. Cohen, P. In The Enzymes; Academic: New York, 1986;
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. (a) Cohen, P.; Frame, S. Nat. Rev. Mol. Cell. Biol. 2001, 2,
7
2
3
3
5 and 37–47 proved significant breakthroughs. These
compounds not only demonstrated very good GSK3
inhibition but also dramatically improved selectivity
versus PKCbII, CDK2, and CDK4.
7
2
69; (b) Cohen, P.; Goedert, M. Nat. Rev. Drug. Disc.
004, 3, 479; (c) Nikoulina, S. E.; Ciaraldi, T. P.;
Mudaliar, S.; Mohideen, P.; Cartet, L.; Henry, R. R.
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H.-Q. J. Med. Chem. 2004, 47, 4716, and references cited
in the above.
Having identified numerous single digit nM inhibitors,
we suspected that this was the lower limit of the assay.
1
5
This was shown to be the case using 33. Kinetic ana-
lysis revealed a K considerably lower than the bio-
i
chemical IC . The K was determined either though
0
5
i
traditional kinetics (K = 0.38 nM) or using Biacore
i
technology (K = 0.23 nM). In addition, the IC50 varied
i
with GSK3 enzyme concentration consistent with tight
binding inhibition. Thus, we suspect that inhibitors
with IC s < 3–5 nM likely have K ꢀs in the pM range
5
0
i
and greater selectivity than the biochemical IC s
imply.
4. (a) Hers, I.; Tavare, J. M.; Denton, R. M. FEBS Lett.
1999, 460, 433; (b) Davis, P. D.; Hill, C. H.; Lawton, G.;
Nixon, J. S.; Wilkinson, S. E.; Hurst, S. A.; Keech, E.;
Turner, S. E. J. Med. Chem. 1992, 35, 177.
5
0
To differentiate the selective inhibitors, we relied on a
cell-based assay measuring inhibition of Ser396 phos-
phorylation of tau, a natural substrate of GSK3 in
5
. (a) See Ref. 3 above and; (b) Kuo, G.-H.; Prouty, C.;
DeAngelis, A.; Shen, L.; OꢀNeill, D. J.; Shah, C.;
Connolly, P. J.; Murray, W. V.; Conway, B. R.; Cheung,
P.; Westover, L.; Xu, J. Z.; Look, R. A.; Demarest, K. T.;
Emanuel, S.; Middleton, S. A.; Jolliffe, L.; Beavers, M. P.;
Chen, X. J. Med. Chem. 2003, 46, 4021.
1
8
SY5Y cells. This assay was quite effective in differenti-
ating compounds (Table 3).
Finally, the selective inhibitors were examined in an ani-
1
6. Coghlan, M. P.; Culbert, A. A.; Cross, D. A. E.;
Corcoran, S. L.; Yates, J. W.; Pearce, N. J.; Rausch, O.
L.; Murphy, G. J.; Carter, P. S.; Cox, L. R.; Mills, D.;
Brown, M. J.; Haigh, D.; Ward, R. W.; Smith, D. G.;
Murray, K. J.; Reith, A. D.; Holder, J. C. Chem. Biol.
5
mal model of type 2 diabetes. Zucker diabetic fatty
1
9
(
ZDF) rats were dosed via oral gavage with 10 mg/
kg of inhibitor and 4 h post-dose plasma glucose levels
were compared to vehicle and insulin (10 units) treated
controls, with results expressed as a percentage of the
positive control insulin response. Taken with the PKC/
CDK selectivity data, the in vivo data (Table 3) clearly
established a superior profile for the imidazopyridine
series u and v (e.g., 33, 35, 40–41, and 45) relative to
the other aza-imidazopyridines w–y and the pyrazolo-
pyridine series z.
2
000, 7, 793.
7
. Zhang, H.-C.; White, K. B.; Ye, H.; McComsey, D. F.;
Derian, C. K.; Addao, M. F.; Andrade-Gordon, P.;
Eckardt, A. J.; Conway, B. R.; Westover, L.; Xu, J. Z.;
Look, R.; Demarest, K. T.; Emanuel, S.; Maryanoff, B. E.
Bioorg. Med. Chem. Lett. 2003, 13, 3049.
8. Zhang, H.-C.; Ye, H.; Conway, B. R.; Derian, C. K.;
Addo, M. F.; Kuo, G.-H.; Hecker, L. R.; Croll, D. R.; Li,
J.; Westover, L.; Xu, J. Z.; Look, R.; Demarest, K. T.;
Andrade-Gordon, P.; Damiano, B. P.; Maryanoff, B. E.
Bioorg. Med. Chem. Lett. 2004, 14, 3245.
In conclusion, the development of a series of very potent
and highly selective GSK3 inhibitors is reported. These
compounds inhibit tau phosphorylation in a neuronal
cell line, lower plasma glucose in the ZDF rat model
of type 2 diabetes, and hold considerable promise as po-
tential therapeutic agents for diabetes and Alzheimerꢀs
disease.
9
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Acknowledgements
We thank Steven Queener, Thomas E. Eessalu,
Rebecca A. Owens, and Kathleen Valasek for develop-
ing and validating the GSK and pTau assays used for
this work and Eugene Kogut for scaling up some
intermediates.
1
857.
1
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O
Br
X
Y
H2N
O
2
O
a
O
c
O
f
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Engler, T. A.; Al-awar, R. S.; Brooks, H. B.; Watkins, S.
A.; Spencer, C. D.; Schultz, R. M.; Dempsey, J. A.;
Considine, E. L.; Patel, B. R.; Ogg, C. A.; Vasudevan, V.;
Lytle, M. L. Bioorg. Med. Chem. Lett. 2004, 14, 3057; (e)
Faul, M. M.; Engler, T. A.; Sullivan, K. A.; Grutsch, J. L.;
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Kolis, S. P.; Furness, K.; Malhotra, S.; Al-awar, R. S.;
Ray, J. E. J. Org. Chem. 2004, 69, 2967, and references
cited therein.
NH
N
N
N
O
X=Br
Y=CN
b
d
X=H
Y=CH OH
2
e
Y=CH2CN
(
7
1
a) (i) NBS, 75%; (ii) POBr
3
, 50%; (b) Pd(PPh
5%; (c) CuCN, CuI, DMF, 94%; (d) (i) NH
00%; (ii) BH ÆTHF, 73%; (e) (i) HCl, Et O; (ii) SOCl ; (iii)
3
)
4
, NaO
2
CH,
4
OH, 150 ꢁC,
3
2
2
NaCN, EtOH, H O, 67%; (f) KOH, t-BuOH, 85%.
2
1
5. Engler, T. A.; Henry, J. R.; Malhotra, S.; Cunningham,
B.; Furness, K. W.; Brozinick, J.; Burkholder, T. P.; Clay,
M. P.; Clayton, J.; Diefenbacher, C. G.; Hawkins, E.;
Iversen, P. W.; Li, Y.; Lindstrom, T. D.; Marquart, A. L.;
McLean, J.; Mendel, D.; Misener, E.; Briere, D.; OꢀToole,
J. C.; Porter, W. J.; Queener, S.; Reel, J. K.; Owens, R.;
Brier, R. A.; Eessalu, T. E.; Wagner, J. R.; Campbell, R.
M.; Vaughn, R. J. Med. Chem. 2004, 47, 3934.
1
1. (a) Faul, M. M.; Winneroski, L. L.; Krumrich, C. A.
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6
3, 6053.
1
2. (a) Engler, T. A.; Furness, K.; Malhotra, S.; Diefenbacher,
C.; Clayton, J. R. Tetrahedron Lett. 2003, 44, 2903; (b)
The arylacetonitriles were prepared from the correspond-
ing arylbromides 12c via arylaldehydes, synthesized
either through Li–halogen exchange or generation of
the Grignard reagent and reaction with DMF, followed
by homologation to the acetonitrile; (c) Briner, K.;
Burkhart, J. P.; Burkholder, T. P.; Fisher, M. J.; Gritton,
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1
1
1
1
6. Miki, Y.; Yagi, S.; Hachiken, H.; Ikeda, M. Heterocycles
1
994, 38, 1881.
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9. Glucose lowering in ZDF rats has been reported for
structurally distinct series of GSK3-b inhibitors. Ring, D.
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2
000044737.
3. Shiotani, S.; Morita, H. J. Heterocycl. Chem. 1982, 19,
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1
1