In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part II

Article abstract of DOI:10.1016/j.bmcl.2010.04.023

Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D-E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC₅₀ <3 nM and inhibit the release of TNFα (IC₅₀

Full text of DOI:10.1016/j.bmcl.2010.04.023

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4719–4723
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part II
*
Laszlo Revesz , Achim Schlapbach, Reiner Aichholz, Janet Dawson, Roland Feifel, Stuart Hawtin,
Amanda Littlewood-Evans, Guido Koch, Markus Kroemer, Henrik Möbitz, Clemens Scheufler, Juraj Velcicky,
Christine Huppertz
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D–E and 16A are described as orally
Received 11 March 2010
Revised 7 April 2010
Accepted 7 April 2010
Available online 11 April 2010
active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC50 <3 nM and inhi-
bit the release of TNF
THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC50 = 0.05–0.23
potent in cells (IC50 <1.1 M), but show good oral absorption. Compound 13E (100 mg/kg po; bid)
a
(IC50<0.3
l
M) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated
lM), less
l
showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score.
Keywords:
MAPKAP-K2
MK2
Ó 2010 Elsevier Ltd. All rights reserved.
TNFa
Inhibition
Antiinflammatory
In vivo
Rheumatoid arthritis
Mitogen-activated protein kinases (MAPKs) belong to the Ser/
Thr kinase family1, control cytoskeletal architecture, cell-cycle pro-
gression and are implicated in inflammation and cancer.2 The p38/
MAPKAP kinase-2 (MAPKAP-K2; MK2) cascade plays a pivotal role
Pyrrole-tetracycles 4a (Scheme 1) were prepared via the Han-
tzsch9 reaction of bromoketone 5 and piperidinedione 6 followed
by Suzuki coupling10 with R1-substituents A–F. Furan-tetracycles
4b with a furan as c-ring (Scheme 1) were obtained in a similar
in the production of proinflammatory cytokines, such as TNF
a
, IL-6
fashion, first by reacting 5 and 6 to a 1,4-diketone intermediate
which was then cyclised to the furan-ring in the presence of H2SO4.
Desired bromoketones 5a–c (Scheme 2) were prepared in eight
steps11 from cyclopentanone, cyclohexanone and cycloheptanone.
Bromoketone 5d was gained from 2-ethoxycarbonyl cyclohexa-
none in six steps.11 Piperidinediones 6 were synthesized starting
from b-aminoesters 9a–f by their reaction with mono-chloromalo-
nate, followed by Dieckmann condensation (MeONa in refluxing
and IFNc 3
. Moreover, MK2 knock-out mice are resistant to devel-
oping disease in arthritis models.4 Thus, MK2 has emerged as a
highly desirable target in the search for efficacious and safe anti-
inflammatory drugs. MK2 inhibitors from a variety of structural
classes were published, including aminocyanopyridines, tetrahy-
dro-c-carbolines and pyrrolopyridines, pyrrolo-pyrimidinones,
benzothiophenes, 2,4-diamino-pyrimidines5 and 3-aminopyraz-
oles.6 A breakthrough with low-molecular MK2-inhibitors is still
awaited.7
N
N
Our screening efforts for MK2 inhibitors identified the pyrrol-
o[2,3-f]isoquinoline amide 1 (Fig. 1) as a modest MK2 inhibitor
O
O
R
NH2
with an IC50 value of 3.8 lM. 1 demonstrated structural similarities
N
N
NH
to the recently disclosed MK2 inhibitors 25g with a pyrrolopyridine
scaffold and submicromolar IC50. Combining the structural features
of 1 and 2 resulted in the tetracyclic MK2 inhibitor 38 with an IC50
of 10 nM. In spite of potent cellular activity, 3 was lacking oral bio-
availability. Here we report our efforts towards orally active MK2
H
H
1
3
2
(CH2)n
N
N
α
β
O
O
X
R1
N
γ
NH
NH
Y
δ
N
inhibitors by modifying the tetracyclic abcd-ring system of 4.
H
4
O
R2
O
* Corresponding author. Fax: +41 61 324 3273.
E-mail address: laszlo.revesz@pharma.novartis.com (L. Revesz).
Figure 1. MK2 inhibitors.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.023

4720
L. Revesz et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4719–4723
O
N
O
( )n
(CH2)n
N
N
N
N
β
β
NH
NH
R2
+
O
R1
R1
R1
O
Cl
X
Br
N
O
N
H
HN
NH
O
H
NH
6
5
a) or b)
then c)
12
2
10 (n=0)
11 (n=1)
(CH2)n
N
Scheme 4. Conformationally restricted MK2 inhibitors 10–12.
4a (X=CH or N; Y=NR)
4b (X=CH; Y=O)
n=1-3
β
α
O
X
R1
γ
δ NH
Y
Table 1
Conformationally restricted MK2 inhibitors 10–12
R2
R1:
Compd
MK2a (M)
TNFa b
(lM)
p-hsp27c
(lM)
Sol.d
(lM)
2A
3
10A
10B
11B
12A
0.560
0.010
0.037
0.040
0.180
0.230
>10
0.3
1.5
0.4
1.1
>10
8.9
1.5
2.7
1.7
4.3
10.0
337
<4
11
8
21
69
N
N
F
F
O
O
O
F
N
O
B
A
E
C
D
F
O
IC50 values are measured as described6 and are reported as a mean of P2
a
measurements with a standard deviation of less than 50%.
Scheme 1. Reagents and conditions: (a) MeOH, NH4OAc, rt, 12 h, 25–60% of 4a
b
Inhibition of LPS stimulated release of TNF
described.6
a from hPBMC is performed as
(R1 = Cl; X = CH or N); (b) (i) MeOH, NaOAc, 12 h, rt, then evaporate, (ii) H2SO4concd
,
rt, 10 min., 23–55% of 4b (R1 = Cl; X = CH); (c) R1–B(OH)2 or its pinacol ester,
Pd(PPh3)2Cl2, PPh3, 2 N Na2CO3, 1-propanol, 150 °C, 20 min., microwave, 60–80%.
c
Inhibition of anisomycin stimulated phosphorylation of hsp27 in THP-1 cells is
measured as described.6
d
Thermodynamic solubility measured at pH 6.8.
(CH2)n
N
(CH2)n
clearly superior to the non-cyclised pyrrolopyridines 2 (Table 1).
Thus, a comparison of 2A5g with 10A revealed that the former
was a weak MK2 inhibitor devoid of cellular activity in contrast
to its cyclised analogue 10A, which was 15-times more potent
a)
Br
Cl
O
O
O
5a-c (n=1-3)
7
against MK2 and inhibited LPS-induced release of TNF
hPBMCs and hsp27 phosphorylation with low micromolar IC50s.
a from
N
b)
O
Compound 10B was slightly less potent than its fully aromatic
analogue 3, but with improved solubility (8 lM vs <4 lM). Ring
expansion of 10B to 11B with a seven-membered b-ring resulted
in ꢀ3-fold lower MK2- and cellular potency. Ring contraction of
10B to a five-membered b-ring yielded 12A again with lower
Cl
N
Br
O
O
8
5d
O
O
NH2
R2
NH
R2
c)d)e)
O
MK2-affinity (IC50 = 0.23 lM) lacking cellular activity.
O
Keeping the six-membered b-ring unchanged, the influence of
three- and four-membered spirocycles attached to the lactam d-
ring was investigated (Scheme 5, Table 2). Spirocyclopropanes
13, 14 and the unsubstituted analogue 10 showed similar MK2-
and cellular inhibition profiles. IC50 for MK2 inhibition was in the
9a-f
6
Scheme 2. Reagents and conditions: (a) eight; (b) six steps as described11; (c) ethyl
malonyl chloride, NEt3, CH2Cl2, rt, 30 min, 40–60%; (d) MeONa, toluene, reflux
45 min., quant; (e) MeCN/H2O reflux, 1 h, 85%.
range of 8 nM (10C) to 0.23
TNF from hPBMCs in the range of 0.1
(14D). Intracellular p-hsp27 was inhibited at a slightly higher
range from IC50 = 0.5 M (13C) to 2.7 M (10A). Solubilities were
modest, best values reaching 10–11 M at pH 6.8 (10A and 13A).
l
M (13C), the IC50 for inhibition of
a
l
M (10D) to 1.7
lM
O
NH2
O
O
NH2
O
O
NH2
NH2
l
l
l
O
O
O
O
O
Whereas R1-substituents A–F had no major effect on kinase affinity
or cellular potency, the o-fluorophenyl substituent A had a favour-
able effect on solubility. Solubilising groups B and F failed to
enhance solubilities probably due to the rigid flat tetracyclic core
leading to a tight crystal packing.
9b
9a
9c
NH2
O
NH2
O
N
MK2 inhibition and cellular potency of the spiroazetidines
(Scheme 6, Table 3) appeared to depend upon their position on
the d-ring.
N
N
BOC
9e
BOC
9d
9f
BOC
Scheme 3. 3-Amino propionic acid ethyl esters.
O
O
O
toluene) of the obtained amides and decarboxylation in refluxing
wet acetonitrile.11
b-Aminoesters 9a–c and 9f are commercially available, while
derivatives 9d–e are novel and were prepared as described previ-
ously11 (Scheme 3).
N
O
δ :
NH
NH
NH
R1
NH
N
δ
H
10
13
14
6
5
Regarding MK2-inhibition and cellular activity, the conforma-
tionally restricted tetracycles 10 and 11 (Scheme 4) proved to be
Scheme 5. d-Ring modifications.

L. Revesz et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4719–4723
4721
Table 2
d-Ring modifications
Compd
MK2a
(lM)
TNFab
(lM)
p-hsp27a
(lM)
Sol.d
(
lM)
10C
10D
13A
13C
13D
13E
13F
14C
14D
14E
0.008
0.080
0.140
0.230
0.175
0.050
0.100
0.100
0.130
0.027
0.5
0.1
0.9
0.8
0.2
0.3
0.2
0.9
1.7
0.7
1.3
0.7
0.7
0.5
0.7
1.1
1.4
0.9
1.2
1.4
<4
<4
10
5
<4
9
<4
<4
<4
<4
a–d
See Table 1.
O
O
O
NH
NH
NH
N
O
R1
N
N
δ :
NH
R2
N
N
δ
H
R2
6
5
15 (R2=H)
20 (R2=H)
21 (R2=Me)
22
16 (R2=Me)
17 (R2=Et)
Figure 2. Crystal structure of 16A bound to MK2.12
18 (R2=CH2CH2F)
19 (R2=Acetyl)
demonstrating the importance of a basic nitrogen at this position.
Interestingly, the o-fluorophenyl substituent A had again a pro-
nounced influence on solubility, possibly due to a slight out-of-
plane rotation (see X-ray analysis, Fig. 2). While solubilities of
Scheme 6. d-Ring modifications.
16C–E reached in the best case 47
22A and azetidine 16A with o-fluorophenyl substituents reached
solubilities of >1000 M. Compound 22A was slightly less potent
in cells (TNF IC50 = 0.2 M; p-hsp27 = 0.7 M) and against MK2
(IC50 = 4 nM).
Substituting pyridine by pyrimidine in the
cle led to the series 23–26 (Scheme 7, Table 4).
Pyrimidines 23–26 were found to be weaker than their pyridine
analogues 10 and 13-15. Spiroazetidines in this series were again
more potent than spirocyclopropanes; spiroazetidines 26A–F
lM (16E), at pH 6.8, piperidine
Table 3
d-Ring modifications
l
Compd
MK2a
(lM)
TNFab
(
lM)
p-hsp27c
(l
M)
Sol.d
(lM)
a
l
l
15A
15C
16A
16B
16C
16D
16E
16F
17A
18A
19A
20D
21D
22A
0.017
0.1
0.2
0.1
0.7
0.2
0.06
0.1
0.6
0.7
1.5
6.5
1.3
1.1
0.2
0.1
0.2
0.3
1.4
0.2
0.7
1.2
1.2
1.5
6.5
25
337
n.t.
>1000
n.t.
10
40
47
n.t.
950
n.t.
24
<0.003
<0.003
<0.003
<0.003
<0.003
<0.003
<0.003
<0.003
0.230
0.12
0.012
0.045
0.004
a
-ring of the tetracy-
inhibited MK2 with potencies ranging from IC50 <0.003
lM (26D
and 26F) to IC50 = 0.034 M (26A). Unfortunately, the cellular effi-
l
cacies did not reach the level of the pyridine analogues; the most
potent compound in terms of p-hsp27 inhibition was spiroazeti-
3.1
17.0
0.7
32
<4
>1000
dine 26E (IC50 = 1.8
lM).
Further, we also explored the
c
-ring of the tetracyclic core by
a–d
See Table 1. n.t.: not tested.
replacement of the pyrrole in 15C and 16C by furan leading to
derivatives 27 and 28 (Scheme 8, Table 5). Compound 27 showed
weak MK2-affinity (IC50 = 0.2 lM) and proved to be 10–100-fold
Spiroazetidines at the 5-position (15–17) were highly potent,
weaker in cells compared to its pyrrole-NH analogue 15C. Corre-
sponding N-methyl azetidine 28 was even weaker (1000-fold)
against MK2 than its pyrrole-NH analogue 16C. To investigate the
importance of the pyrrole-NH for the MK2-binding, pyrrole-NMe
derivatives 29 and 30 were prepared and tested. Interestingly, a
less dramatic drop in activity was observed in comparison to the
furan analogues: 29 and 30 still showed some cellular efficacies.
while their analogues at the 6-position (20 and 21) were consider-
ably weaker, especially after azetidine N-methylation, exemplified
by 21D with a dramatic loss of cellular activity in the p-hsp27 as-
say (IC50 = 17 lM). The inhibition of TNFa by 21D (IC50 = 1.1 lM)
may result from an off-target effect. Azetidines 16A–F and 17A
with their N-methyl and N-ethyl groups pointing into the sugar
pocket belong to the most potent MK2-inhibitors presented here,
all with IC50 = <0.003 l
M, independent of R1. An explanation for
their high affinity is offered by the crystal structure of 16A, which
reveals a water mediated interaction between the basic azetidine
nitrogen of this ligand and the carboxylic residue Glu-145 of
MK2 (Fig. 2).
O
O
O
O
N
α
N
O
NH
NH
NH
NH
δ:
R1
NH
N
δ
These derivatives exhibit also a potent inhibition of TNF
hPBMCs ranging from IC50 = 0.06 M (16D) to 0.7 M (17A and
16B), inhibition of p-hsp27 was in the range of IC50 = 0.2
(16C) to 1.5 M (17A). N-Fluoroethyl (18A) and N-acetyl (19A)
showed a dramatic decrease in MK2- and cellular activity, thus
a in
N
H
l
l
24
25
23
26
lM
l
Scheme 7. Pyrimidines.

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L. Revesz et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4719–4723
Table 4
Pyrimidines
shows lower exposure levels than the less soluble 13D and 13E.
This is no contradiction, since the thermodynamic solubilities mea-
sured at pH 6.8 do not predict oral exposures which depend upon
further additional parameters.
d
Compd
MK2a
(
lM)
TNFab
(
l
M)
p-hsp27c
(
l
M)
Sol.
(lM)
23D
24A
24D
24E
24F
25D
26A
26B
26C
26D
26E
26F
0.270
0.860
0.900
0.120
0.180
0.150
0.034
0.006
0.006
0.9
2.3
nt
4.3
15.3
2.5
12.0
3.2
5.6
5.6
6.7
4.5
<5
8
<4
<4
<4
<4
373
n.t.
n.t.
43
173
n.t.
Good pharmacokinetic properties of compound 13E in rats
(1 mg/kg po; F: 24%; Cmax: 105 nM; clearance: 12 mL minÀ1 kgÀ1
;
Vss: 1.9 L kgÀ1; AUC: 2000 nmol h LÀ1; t1/2: 1.3 h) permitted this
compound to be tested in chronic models of rheumatoid arthritis
in mice and rats. In the collagen-induced arthritis in DBA/1 mice14
(100 mg/kg po bid) 13E significantly reduced swelling and histo-
logical scores (Fig. 3) (joint damage and erosions, proteoglycan loss
and inflammatory cell infiltrates).
0.7
0.3
0.4
1.6
1.5
0.5
0.1
0.7
0.1
<0.003
0.007
<0.003
3.0
1.8
2.8
Similarly, 13E (100 mg/kg po bid) reduced swelling in the rat
antigen-induced arthritis15 (rAIA) model (Fig. 4). In addition, 13E
was well tolerated; no body weight reduction compared to vehicle
treatment was observed. Blood samples taken 2, 6 and 16 h after
the last dosing revealed good exposure of 13E in both models:
a–d
See Table 1. n.t.: not tested.
N
F
N
16, 2.4 and 0 lM (in mCIA) and 11.7, 9.8 and 0.5 lM (in rAIA).
O
O
F
Due to the high plasma concentrations it can not be ruled out, that
the effects seen in chronic models may not be the result of MK2-
inhibition alone, but may also be attributed to the inhibition of
other kinases.16
γ
γ
NH
NH
O
N
R1
N
N
R2
R2
27 (R2=H)
29 (R1=Me; R2=H)
N
O
NH
28 (R2=Me)
30 (R1=Me; R2=Me)
N
N
Scheme 8.
c-Ring modifications.
F
H
13E
Table 5
c
-Ring modifications
Compd
MK2a
(
l
M)
TNFab
(
l
M)
p-hsp27c
(
l
M)
Sol.d
(lM)
In summary, our SAR studies have led to the discovery of two
orally active MK2 inhibitor series: the spirocyclopropanes 13C–E
and the spiroazetidine 16A. The spiroazetidines belong to the most
potent MK2 inhibitors known to date with IC5 <3 nM and show
27
28
29
30
0.200
3.300
0.020
0.013
2.5
n.t.
1.8
1.1
17
51
n.t.
54
41
n.t.
1.3
1.7
high cellular potencies (IC50 <0.3 lM) in inhibiting TNFa release
a–d
See Table 1. n.t.: not tested.
from LPS challenged hPBMCs as well as in inhibiting hsp27 phos-
phorylation in THP-1 cells, while they generally suffer from low
oral absorption and high clearance. Spirocyclopropanes on the
Selected compounds were tested in the LPS-induced TNF
a re-
other hand are less potent against MK2 (IC50 = 0.05–0.23
lM) and
lease model in mice13 at 100 mg/kg po (Table 6). Unfortunately,
none of the in vitro highly potent azetidine-NH analogues 15
showed any oral efficacy (not shown in Table 6). Among the N-
methyl azetidine analogues only 16A showed good oral activity,
while none of the other R1-substituents C–E was able to confer oral
efficacy within the 16-scaffold. The spirocyclopropanes 13 and
14—indistinguishable in vitro—demonstrated big differences in
vivo, where only the series 13 yielded good oral efficacies. Com-
in cells (IC50 <1.1 M), but they display better absorption and mod-
l
erate clearance in vivo. Selected compound 13E showed oral activ-
ity in rAIA and mCIA at 100 mg/kg po bid, by significantly reducing
swelling and histological scores.
25
20
Collagen - induced arthritis (CIA) in DBA/1 mice
Paw swelling
pounds 13D and 13E inhibited 81% and 96% of TNF
mice at 25 M and 30 M plasma concentrations. Their isomers
14D and 14E inhibited only 16% and 30% of TNF at 0.6 M and
1.9 M plasma exposures. Interestingly, the highly soluble 16A
a release in
l
l
HPMC 603/Tween80
13E
10 ml/kg p.o. b.i.d., n=8
100 mg/kg p.o. b.i.d., n=8
0.3 mg/kg p.o. q.d., n=5
a
l
Dexamethasone
l
15
Table 6
TNF inhibition in LPS-treated mice
scoring of
a
paws
10
Compd
%TNFa
inhibitiona
Plasma exposure (lM)
(0-24)
13C
13D
13E
14D
14E
16A
16C
16D
16E
55
81
96
16
30
90
0
15
25
30
0.6
1.9
6
1
0.1
0.6
*
**
**
**
**
5
Immunization
**
**
**
**
0
Booster (collagen type II)
0
5
10
15
20
25
30
35
40
45
50
0
26
days after immunization
a
MK2-inhibitors were administered at a dose of 100 mg/kg po.13
Figure 3. Inhibition of mCIA by 13E.14

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4723
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Wishart, N.; Wu, X.; Zhang, X.; Zmetra, T. R.; Talanian, R. V. Bioorg. Med. Chem.
Lett. 2010, 20, 334.
Control (Vehicle) 5ml/kg p.o.
Dexamethasone 0.3mg/kg p.o.
13E 2x100mg/kg p.o.
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1.0
0
1
2
3
4
5
6
7
Time (days)
Start of compound dosing
Figure 4. Inhibition of rAIA by 13E.15
6. Velcicky, J.; Feifel, R.; Hawtin, S.; Heng, R.; Huppertz, C.; Koch, G.; Kroemer, M.;
Moebitz, H.; Revesz, L.; Scheufler, C.; Schlapbach, A. Bioorg. Med. Chem. Lett.
2010, 20, 1293.
7. Schlapbach, A.; Huppertz, C. Future Med. Chem. 2009, 1, 1243–1257.
8. Revesz, L.; Schlapbach, A.; Waelchli, R. WO 2008025512; Chem. Abstr. 2008,
148, 331658.
Acknowledgements
9. Elderfield, R.; Dodd, T. N. Heterocycl. Compd. 1950, 1, 132.
10. Suzuki, A. Pure Appl. Chem. 1991, 63, 419.
11. Schlapbach, A.; Revesz, L.; Koch, G. WO 2009010488; Chem. Abstr. 2009, 150,
168327.
12. The X-ray coordinates are deposited with RCSB Protein Data Bank, deposition
code is 3M2W. The protein used in this study is a segment of MK2 containing
residues 47–364d(216–237)G.
13. MK2-inhibitors (100 mg/kg p.o.) were administered to OFI mice (female,
8 weeks old), followed by LPS injection (20 mg/kg) 1 h later. One hour post LPS
injection the experiment was terminated and blood withdrawn. Compound
The kilolab is gratefully acknowledged for preparing ample
quantities of 4-aza-spiro-[2.5]octane-5,7-dione, 7,9-dioxo-2,6-dia-
za-spiro-[3.5]nonane-2-carboxylic acid tert-butyl ester and
3-chloro-7,8-dihydro-6H-isoquinolin-5-one. We thank Dr. Karl
Welzenbach for technical assistance in measuring phosphorylation
of hsp27 using flow cytometry.
blood levels were determined by LC–MS/MS and plasma levels of mouse TNF
determined by ELISA.
a
References and notes
14. Mouse CIA: Male DBA/1 mice (Janvier 10–12 weeks of age, were immunized
with bovine collagen type II in CFA intradermally at the base of the tail. A
second injection of bovime collagen type II in PBS was given ip on day 21. Upon
initiation of swelling, mice were randomized into groups of 8 (test substance
and vehicle) or 5 (steroid positive control) and treated with 13E, vehicle or
dexamethasone from day 28 to day 41.
15. Rat AIA: Arthritis was induced in the right knee of rats by intra-articular
injection of methylated bovine serum albumin (mBSA), in animals previously
sensitised to the same antigen. Treatment was started orally on day 0, the day
of arthritis induction, and continued for 7 days. Knee swelling was measured
using digital calipers and expressed as a ratio of right (arthritic) vs left (control)
knee swelling. The area under the curves (AUCs) of the treatment groups were
then calculated as percentage inhibitions of the control vehicle treated
animals.
1. Chen, Z.; Gibson, T. B.; Robinson, F.; Silvestro, L.; Pearson, G.; Xu, B.; Wright, A.;
Vanderbilt, C.; Cobb, M. H. Chem. Rev. 2001, 101, 2449.
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5. (a) Schlapbach, A.; Feifel, R.; Hawtin, S.; Heng, R.; Koch, G.; Moebitz, H.; Revesz,
L.; Scheufler, C.; Velcicky, J.; Waelchli, R.; Huppertz, C. Bioorg. Med. Chem. Lett.
2008, 18, 6142; (b) Anderson, D. R.; Hegde, S.; Reinhard, E.; Gomez, L.; Vernier,
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16. Compound 13E was tested against a panel of 262 kinases at 1
14 human kinases with P95%: CaMKIIb, ,d; CK1 2,3; DAPK1,2; Met; Mnk2;
PDGFR (D842V); Pim-1; PRAK; ULK2; ZIPK.
lM and inhibited
v
v
a