Synthesis and biological evaluation of trisubstituted imidazole derivatives as inhibitors of p38α mitogen-activated protein kinase

Article abstract of DOI:10.1016/j.bmcl.2008.06.007

A series of trisubstituted imidazole derivatives containing a 4-fluorophenyl group, a pyrimidine ring, and a CN- or CONH₂-substituted benzyl moiety have been synthesized and evaluated for p38α MAP kinase inhibitory activity. Among them, compounds 22c, 27b, and 28b inhibited p38α MAP kinase with IC₅₀ values 27.6, 28, and 31 nM, respectively.

Full text of DOI:10.1016/j.bmcl.2008.06.007

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4006–4010
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of trisubstituted imidazole derivatives
as inhibitors of p38a mitogen-activated protein kinase
*
Dae-Kee Kim , Jin-Hwi Lim, Jung A. Lee, Purushottam M. Dewang
College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of trisubstituted imidazole derivatives containing a 4-fluorophenyl group, a pyrimidine ring, and
Received 30 March 2008
Revised 30 May 2008
Accepted 3 June 2008
Available online 6 June 2008
a CN- or CONH2-substituted benzyl moiety have been synthesized and evaluated for p38
a
MAP kinase
inhibitory activity. Among them, compounds 22c, 27b, and 28b inhibited p38
a MAP kinase with IC50 val-
ues 27.6, 28, and 31 nM, respectively.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Trisubstituted imidazole
p38a MAP kinase inhibitors
Antiinflammatory
The mitogen-activated protein kinase (MAPK) p38
threonine kinase originally identified as an enzyme that was
a
is a serine/
inhibitors (Fig. 1) such as Compound-006,14 VX-702,15 TAK-715,16
SCIO-469,17 BIRB-796,18 SB-242235,19 and 1-(2,6-dichloro-
phosphorylated and activated by lipopolysaccharide (LPS) stimu-
lation of monocytes. Subsequently, p38
shown to be involved in the biosynthesis of TNF-
the translational and transcriptional level.1–5 Activation of p38
a
MAP kinase has been
a
and IL-1b at
a
Cl
F
MAP kinase is accomplished by double phosphorylation on both
threonine-180 and tyrosine-182 by specific kinases (mainly
MKK3, MKK6) which are themselves activated by other kinases
O
N
N
NH2
F
N
N
F
(MKKK).6–8 Among the downstream substrates in the p38
a MAP
H
N
N
N
S
N
H
kinase signaling pathways, some transcription factors and MAP
kinase-activated protein kinases (MAPKAP) have been identified,
which transduce signals to specific genes as well as to other cel-
lular elements.9 The transduction cascades mediated by activated
N
O
O
N
F
H2N
O
TAK-715
VX-702
Compound-006
O
HO
p38
cytokines, mainly TNF-
roles in the pathogenesis of rheumatoid arthritis and other auto-
immune inflammatory diseases.2,3,11 TNF-
and IL-1b are pro-
duced by synovial macrophages and are present in rheumatoid
synovial fluid. Both of these cytokines have similar effects on cell
proliferation, collagenase production, adhesion molecule expres-
sion, and chemokine production.4,5,11,12
The inhibition of cytokine production through transcriptional
inhibition is an alternative strategy for therapeutic intervention.
In the expectation of providing a safer treatment for chronic
inflammation, many pharmaceutical companies are pursuing
a
MAP kinase lead to the production of proinflammatory
N
a
and IL-1b.10 TNF-
a
and IL-1b play key
N
O
O
N
O
N
O
O
a
F
N
N
N
H
N
H
N
Cl
SCIO-469
F
BIRB 796
F
H2N
N
N
O
Cl
N
N
S
Cl
N
N
p38
a
MAP kinase inhibitors to intervene in cytokine produc-
MAP kinase
tion6,11,13 As a result of these efforts, several p38
a
O
N
H
1
SB-242235
* Corresponding author. Tel.: +82 2 3277 3025; fax: +82 2 3277 2467.
E-mail address: dkkim@ewha.ac.kr (D.-K. Kim).
Figure 1. Structures of p38a MAP kinase inhibitors under development.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.06.007

D.-K. Kim et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4006–4010
4007
phenyl)-1-(4-(4-fluorophenyl)thiazol-2-yl)urea (1) 20 have entered
into clinical trials or are under preclinical development.
enhancement of the methyl protons at d 1.85. Oxidation21 of the
methyl sulfides 8 and 10 with OxoneÒ in H2O/MeOH gave the
sulfones 12 and 18 in 94% and 95% yields, respectively. Nucleo-
philic aromatic substitution21 of 12 with 4-methoxybenzylamine,
The design of target compounds was based on the known inhib-
itor SB-24223519 and our potent inhibitors of transforming growth
factor-b type1 receptor kinase (ALK5) (Fig. 2). It was previously
demonstrated that incorporation of a methoxypyrimidine or an
aminopyrimidine moiety in place of an unsubstituted 4-pyridine
moiety improved selectivity profile and decreased p450
inhibition19,21 During the development of ALK5 inhibitors in our
laboratory, we realized that a cyano- or carboxamide-substituted
phenyl substitution on a central five-membered heterocyclic ring
leads to dramatic increase in activity and selectivity22–28 The use
of this strategy for ALK5 inhibitors has resulted in the discovery
of highly potent and selective preclinical candidates IN-1166
(IC50 = 11.7 nM)24 and IN-1130 (IC50 = 36 nM)23,25,26 The selectivity
profiles of IN-1166 and IN-1130 on a panel of tyrosine and serine/
threonine kinases showed that the most sensitive kinase except
(S)-(À)-a-methylbenzylamine, cyclopropylamine, and NaOMe
yielded 14a and 14c–e in 89%, 90%, 51%, and 94% yields, respec-
tively. Removal of 4-methoxybenzyl group of 14a was affected
in 3 M HCl to give 14b in 59% yield. Conversion of the nitrile
functionality of 14b–e to carboxamide was accomplished by
treatment of 28% H2O2 and 1 N NaOH in 95% EtOH to give 16a–
d in 43%, 57%, 68%, and 39% yields, respectively. The target com-
pounds 20a–e and 22a–d, the positional isomers of 14a–e
and 16a–d, were prepared by the same procedures for 14a–e
and 16a–d. To compare the inhibitory activity of m-cyano- or
m-carboxamide-substituted derivatives with p-cyano- or
p-carboxamide-substituted ones, the trisubstituted imidazole
analogs, 15a, 15b, 17a, 17b, 21a, 21b, 23a, and 23b, were pre-
ALK5 was p38
a
MAP kinase (IN-1166; IC50 = 1.03
lM, IN-1130;
pared by alkylating 5 with a-bromo-p-tolunitrile (7) and follow-
IC50 = 4.3 M). This is not surprising that the kinase domain of
l
ing similar sequence as for the counterpart m-cyano and m-
carboxamide derivatives, 14c, 14e, 16b, 16d, 20c, 20e, 22b, and
22d. Also, the related series, in which imidazole carries substitu-
tion at 2-position, was prepared as outlined in Scheme 2. Synthe-
sis of the (imidazol-2-yl)methylbenzonitriles 27a–e and
(imidazol-2-yl)methylbenzamides 28a–c was initiated using dike-
tone 4. Cyclization of 4 with 3-cyanophenylacetaldehyde (24) in
t-BuOMe/MeOH in the presence of NH4OAc at 0 °C produced 3-
((4-(4-fluorophenyl)-5-(2-(methylthio)-pyrimidin-4-yl)-1H-imi-
dazol-2-yl)methyl)benzonitrile (25) in 13% yield. Oxidation of
the methylsulfide 25 and followed by nucleophilic aromatic sub-
stitutions as described for Scheme 1 yielded 27a and 27c–e in
98%, 96%, 69%, and 99% yields, respectively. Amino derivative
27b was obtained from 27a in 76% yield by acidic cleavage of
4-methoxybenzyl group. The nitrile functionality of 27c–e was
converted as mentioned for Scheme 1 to carboxamide analogs
28a–c in 60%, 64%, and 52% yields, respectively. Compound 1 spe-
cifically claimed in a patent filed by Vertex Pharmaceuticals was
synthesized according to a published procedure for comparison of
biological activity.20
ALK5 is known to be the most homologous to that of p38a MAP ki-
nase29 Therefore, we envisioned that incorporation of a 4-fluoro-
phenyl group and a pyrimidine ring moiety of SB-242235 into
our imidazole ALK5 scaffold may result in highly potent and selec-
tive inhibitors of p38a MAP kinase. To our delight this approach
was successful to provide several potent inhibitors that possess
activity in micromolar or submicromolar range against p38
MAP kinase.
a
N-Substituted imidazole derivatives 14–17 and 20–23 were
prepared as shown in Scheme 1. The commercially available 2-
mercapto-4-methylpyrimidine hydrochloride (2) was reacted
with NaOH and MeI in EtOH to give 4-methyl-2-thiomethylpyr-
imidine30 in 94% yield. Coupling of this thiomethyl compound
with methyl 4-fluorobenzoate in anhydrous THF using NaHMDS
as a base gave the monoketone 330 in 94% yield. Oxidation of 3
with HBr (48 wt.% in water) in DMSO gave the diketone 430 in
62% yield, which was subsequently cyclized with HCHO/NH4OAc
in AcOH to afford the imidazole 5 in 91% yield. Alkylation of 5
with
a-bromo-m-tolunitrile (6) using Cs2CO3 in anhydrous DMF
produced the trisubstituted imidazoles 8 and 10 in 54% and 22%
yields, respectively. These two positional isomers were separated
by MPLC, and each isomer was identified through the NOE study.
Irradiation of the methylene group for compound 10 at d 5.62
gave an enhancement of the methyl protons at d 2.49, while irra-
diation of the methylene group for compound 8 at d 5.02 gave no
To investigate whether these compounds could inhibit p38a
MAP kinase, IC50 values of these were measured. As shown in Ta-
ble 1, compounds having a CN- or CONH2-substituted benzyl
group at the nitrogen adjacent to the 4-fluorophenyl ring in the
central imidazole ring did not show potent p38
a MAP kinase
inhibition (IC50 > 1.0 M). However, all the compounds having
l
that group at the nitrogen which is next to the pyrimidine ring
or at 2-position on the central imidazole ring showed significant
p38a MAP kinase inhibition. Among the m-CN-substituted benzyl
derivatives (20a–e) that possess substitution at the nitrogen
which is next to the pyrimidine moiety on the central imidazole
ring, amine derivatives (20a–d) are more inhibitory than OMe
derivative (20e). Introduction of larger functionalities such as
CN
O
N
N
N
N
NH2
HN
N
N
N
H
N
H
(S)-(À)-a-methylbenzyl (20c) and 4-methoxybenzyl (20a) on pri-
N
N
N
mary amine of compound 20b did not lead to the improvement of
activity. However, a smaller cyclopropyl group seemed to be
accommodated favorably leading to increase in activity, and the
resulted cyclopropylamino compound (20d) is the most potent
with an IC50 value of 27.6 nM among the amine derivatives
(20a–d). The m-CN-substituted derivatives 20c and 20e were
compared with the corresponding p-CN-substituted ones 21a
IN-1130
IN-1166
F
F
R2
1
N
N
N
2
N
3
N
N
N
and 21b. In the case of compounds that contain (S)-(À)-
a-meth-
R1
H
*
N
H
O
ylbenzylamino group, m-CN derivative 20c was slightly less po-
tent than the corresponding p-CN derivative 21a. But methoxy
derivatives (20e and 21b) showed significant variation in inhibi-
tory activity. The m-CN derivative 20e was 3.3-fold more inhibi-
tory than the p-CN analog 21b. The SAR of m-CN (20b–e) and
m-CONH2 (22a–d) derivatives reveals the contribution of CN
s
R1 NHCH -Ph-p-OMe;
=
NH C Ph;
NH2; NH-c-Pr or OMe
2
SB-242235
Me
R2 = CN or CONH2
_
_
14 17, 20 23, 27, 28
Figure 2. Rationale behind the design of target compounds.

4008
D.-K. Kim et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4006–4010
Scheme 1. Reagents and conditions: (a) NaOH, MeI, EtOH, rt, 16 h; (b) NaHMDS, anhydrous THF, rt, 0.5 h then methyl 4-fluorobenzoate, rt, 3 h; (c) 48% HBr, DMSO, 55 °C, 1 h;
(d) HCHO, NH4OAc, AcOH, reflux, 2 h; (e) Cs2CO3, anhydrous DMF, rt, 1 h; (f) OxoneÒ, H2O/MeOH, rt, 1 h (for 12, 13 and 19) or 40 °C, 1.5 h (for 18); (g) RNH2, 140 °C, 2 h (for
14a, 14c, 15a, 20a, 20c, and 21a), cyclopropylamine, anhydrous DMF, 100 °C, 3 h (for 14d and 20d), or NaOMe, MeOH, rt, 1 h (for 14e, 15b, 20e, and 21b); (h) 3 M HCl, reflux,
30 h; (i) 28% H2O2, 1 N NaOH, EtOH, 60 °C (40–50 °C for 16c and 22c), 1 h.
and CONH2 group to the inhibitory activity. The m-CN derivative
20b was 3.4-fold more inhibitory than the m-CONH2 derivative
22a. However, in other cases, the m-CONH2 derivatives 22b and
22c were 2.5- and 2.3-fold more potent inhibitors of p38 MAP
a

D.-K. Kim et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4006–4010
4009
Scheme 2. Reagents and conditions: (a) NH4OAc, t-BuOMe, MeOH, 0 °C, 1 h; (b) OxoneÒ, H2O/MeOH, 40 °C, 1.5 h; (c) 4-methoxybenzylamine, 140 °C, 1 h (for 27a), (S)-(À)-
a-
methylbenzylamine, 140 °C, 1 h (for 27c), cyclopropylamine, DMF, 100 °C, 1 h (for 27d), or NaOMe, MeOH, rt, 1 h (for 27e); (d) 3 M HCl, 110 °C, 1 h; (e) 28% H2O2, 1 N NaOH,
EtOH, 40–50 °C, 1 h.
Table 1 (continued)
Table 1
R1
R2
IC50
p38aa
(l
M)
ALK5b
Inhibitory activity of trisubstituted imidazoles, 14–17, 20–23, 27, and 28, on p38
MAP kinase
a
Compound
27d
27e
28a
28b
28c
1
NH-c-Pr
OMe
m-CN
m-CN
m-CONH2
m-CONH2
m-CONH2
0.0544
0.0628
0.0780
0.0310
0.0485
0.822
>1.0
>1.0
>1.0
>1.0
>1.0
F
F
F
(S)-(À)-
NH-c-Pr
OMe
a
-methylbenzylamino
R2
N
N
N
N
N
R2
R2
N
H
N
N
N
N
N
N
a
p38
a MAP kinase was expressed as untagged human recombinant protein in
R1
R1
R1
_
_
Escherichia coli. The enzyme was purified by Ni-NTH-agarose (Qiagen). A Proprie-
tary radioisotopic protein kinase assay (33PanQinaseÒ Activity Assay) was per-
formed at ProQinase GmbH (Freiburg, Germany) using ATF2 as a substrate.
14 17
20 23
27, 28
Compound
R1
R2
IC50 (lM)
b
ALK5 was expressed in Sf9 insect cells as human recombinant GST-fusion
p38aa
ALK5b
protein by means of the vaculovirus expression system. A Proprietary radioisotopic
protein kinase assay (33PanQinaseÒ Activity Assay) was performed at ProQinase
GmbH (Freiburg, Germany) using casein as a substrate.
14a
14b
14c
14d
14e
15a
15b
16a
16b
16c
16d
17a
17b
20a
20b
20c
20d
20e
21a
21b
22a
22b
22c
22d
23a
23b
27a
27b
27c
NHCH2-Ph-p-OMe
NH2
m-CN
m-CN
m-CN
m-CN
m-CN
p-CN
p-CN
m-CONH2
m-CONH2
m-CONH2
m-CONH2
p-CONH2
p-CONH2
m-CN
m-CN
m-CN
m-CN
m-CN
p-CN
p-CN
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
0.191
0.101
0.140
0.0626
0.260
0.0871
0.859
0.344
0.0551
0.0276
0.225
0.0556
0.916
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
(S)-(À)-
a
-methylbenzylamino
-methylbenzylamino
-methylbenzylamino
-methylbenzylamino
NH-c-Pr
OMe
(S)-(À)-
a
kinase than the corresponding m-CN derivatives 20c and 20d,
respectively. The inhibitory activity of m-CONH2-substituted
derivatives 22b and 22d were compared with that of the corre-
sponding p-CONH2-substituted ones 23a and 23b. Although com-
pounds 22b and 23a showed the similar level of inhibitory
activity, m-CONH2 derivative 22d was 4.1-fold more inhibitory
than p-CONH2 derivative 23b. The derivatives (27a–e) that pos-
sess a m-CN-substituted benzyl group at 2-position of imidazole
ring were found to be 1.3-, 3.6-, 1.5-, 1.2-, and 4.1-fold more po-
tent than the corresponding derivatives (20a–e) that possess the
same substitution at nitrogen which is next to the pyrimidine
ring. Among the 2-substituted imidazole compounds, m-CONH2
analogs (28a–c) were 1.2-, 1.8-, and 1.3-fold more inhibitory than
the respective m-CN derivatives (27c–e). As expected, all the tri-
substituted imidazole derivatives we prepared were devoid of
ALK5 inhibitory activity up to the maximum concentration of
OMe
NH2
(S)-(À)-
a
NH-c-Pr
OMe
(S)-(À)-
a
OMe
NHCH2-Ph-p-OMe
NH2
(S)-(À)-
a
-methylbenzylamino
-methylbenzylamino
-methylbenzylamino
-methylbenzylamino
NH-c-Pr
OMe
(S)-(À)-
a
OMe
NH2
m-CONH2
m-CONH2
m-CONH2
m-CONH2
p-CONH2
p-CONH2
m-CN
(S)-(À)-
a
NH-c-Pr
OMe
(S)-(À)-
a
OMe
1 lM tested. Among all the compounds, 22c (IC50 = 27.6 nM),
27b (IC50 = 28 nM), and 28b (IC50 = 31 nM) are the most active
compounds, and these compounds are approximately 27- to 30-
NHCH2-Ph-p-OMe
NH2
0.148
0.0280
0.0954
m-CN
m-CN
(S)-(À)-
a
-methylbenzylamino

4010
D.-K. Kim et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4006–4010
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(IC50 = 822 nM) of Vertex Pharmaceuticals.
In this report, a series of trisubstituted imidazole derivatives
containing a 4-fluorophenyl group, a pyrimidine ring, and a CN-
or CONH2-substituted benzyl moiety have been synthesized and
evaluated for p38
ture–activity relationships in this series of compounds have
been established and discussed. Compounds 22c, 27b, and 28b
showed the most significant p38a MAP kinase inhibitory activity
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a MAP kinase inhibitors to obtain the selectivity over
ALK5. Moreover, our strategy that was successfully used in the
development of ALK5 inhibitors22–28 has been found to be appli-
cable to the design of p38
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a
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activity.
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