Benzimidazoles as new potent and selective DP antagonists for the treatment of allergic rhinitis

Article abstract of DOI:10.1016/j.bmcl.2004.04.005

A series of 2-substituted N-benzyl benzimidazole containing molecules has been synthesized and its structure-activity relationship for the human DP receptor has been evaluated. Selective DP antagonists with nanomolar potency for the DP receptor were identified in this novel series of benzimidazoles.

Full text of DOI:10.1016/j.bmcl.2004.04.005

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3195–3199
Benzimidazoles as new potent and selective DP antagonists for the
treatment of allergic rhinitis
Christian Beaulieu,* Zhaoyin Wang, Danielle Denis, Gillian Greig, Sonia Lamontagne,
Gary O’Neill, Deborah Slipetz and Jennifer Wang
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Kirkland, QC, Canada H9R 4P8
Received 4 March 2004; revised 30 March 2004; accepted 1 April 2004
Abstract—A series of 2-substituted N-benzyl benzimidazole containing molecules has been synthesized and its structure–activity
relationship for the human DP receptor has been evaluated. Selective DP antagonists with nanomolar potency for the DP receptor
were identified in this novel series of benzimidazoles.
Ó 2004 Elsevier Ltd. All rights reserved.
The symptoms of allergic rhinitis are multifactorial and
induced by the action of a variety of lipid mediators, of
which histamine, cysteinyl leukotrienes (cys-LTs) and
prostaglandin D2 (PGD2) are considered as the most
important.1 Prostaglandin D2 is the major cyclooxy-
genase metabolite produced by the immunologic stim-
ulation of mast cells2 and is found in nasal lavage fluid
following allergen challenge of atopic individuals.3
Nasal congestion in allergic rhinitis results from tissue
edema and vasodilatation in the nasal mucosa. Com-
parative studies in humans have shown that the intra-
nasal instillation of PGD2 reproduces the airway
obstruction experienced by seasonal allergic rhinitics
with a potency 10 times greater than histamine.4 Con-
sidering its various inflammatory effects, PGD2 appears
to be an important component in the pathogenesis of
allergic diseases.3–7 PGD2 as a bioactive prostanoid
interacts preferentially with DP receptor, which is one of
eight known prostanoid receptors (DP, EP1, EP2, EP3,
EP4, FP, IP and TP).8 The role of the DP receptor in the
regulation of mucous secretion9 and the efficacy of DP
receptor blockade in allergic disease models10 supported
the idea that a selective DP antagonist might be of
therapeutic value for allergic rhinitis.
selective DP antagonists built on a 2-substituted
N-benzyl benzimidazole scaffold.
Based on radioligand competition binding assays using
recombinant human DP receptor, high throughput
screening of our sample collection revealed that N-
benzyl benzimidazole derivatives were potentially a new
series of potent DP antagonists. In the design of the
molecules to be synthesized, the selection of 4-chloro-
benzyl substitution at position-1 of benzimidazole (Fig.
1) was derived from previous studies in this program
based on a similar scaffold.11 These SAR studies showed
the superiority of 4-chlorobenzyl as substituent at
position-1. To explore the structure–activity relationship
in the series, 4-chlorobenzyl group was kept at position-
1 of the benzimidazole template and various groups and
linkers were introduced at position-2 to probe the
requirements for both potency and selectivity.
The general synthetic routes to these benzimidazole
derivatives are outlined in Schemes 1–5. The 2-benzyl-
thio benzimidazoles (Scheme 1) were prepared from the
commercially available 2-chloro benzimidazole 2.
N
2
In this communication, we describe the discovery and
detailed SAR studies of a novel series of potent and
S
N
CO2Me
1
1
Keywords: Benzimidazole; DP antagonist.
* Corresponding author. Tel.: +1-514-4283297; fax: +1-514-4284900;
e-mail: christian_beaulieu@merck.com
Cl
Figure 1.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.005

3196
C. Beaulieu et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3195–3199
N
b
N
a
n=0,1
NH2
H
N
R
Cl
NH2
NH2
Cl
NH
a
N
N
H
+
n=0,1
S
NH2
R
2
3
6
14
15
N
N
Cl
N
N
N
N
NH
n=0,1
R
b, c
SH
S
c
R
Cl
16
Cl
Cl
5
4
Scheme 5. Reagents and conditions: (a) 1,1-Thiocarbonyldiimidazole,
imidazole, CH3CN, reflux, 55–80%; (b) HgO, S8, EtOH, 50–55%; (c)
K2CO3, DMF, 4-Cl-PhCH2Br, 35–63%.
Scheme 1. Reagents and conditions: (a) NaH, DMF, 4-ClPhCH2Br,
80%; (b) potassium thioacetate, EtOH, reflux, 80%; (c) Cs2CO3,
CH3CN, ArCH2Br, 50–90%.
by hydrolysis catalyzed by the presence of a base in the
reaction mixture. Alkylation of 4 with various substi-
tuted benzyl bromides in the presence of cesium car-
bonate in acetonitrile gave the final 2-benzylthio
benzimidazoles 5. 2-Alkyl benzimidazoles (Scheme 2)
were prepared by a condensation reaction involving
benzene-1,2-diamine 6 and the carboxylic acid 7 using
carbonyl diimidazole as a coupling reagent and HCl as a
catalyst for cyclization. The cyclization product was
then alkylated with 4-chlorobenzyl bromide to give the
2-alkyl-1-(4-chlorobenzyl)-benzimidazoles 8. The same
starting material was used for the synthesis of 2-aryl
benzimidazole 10 (Scheme 3). The diamine 6 was con-
densed with properly substituted benzaldehydes in
nitrobenzene and the resulting benzimidazole interme-
diates were alkylated to give the product 10. The
2-phenylethenyl benzimidazoles 12 and 2-phenethyl
benzimidazoles 13 (Scheme 4) were prepared from the
2-methyl benzimidazole 11 by condensation with a
substituted benzaldehyde in the presence of acetic
anhydride. A simple hydrogenation of the double bond
of 12 afforded 13. For the synthesis of 2-alkylamino
benzimidazoles 16 (Scheme 5), we used a procedure
developed by Meissner12 which consists of acylation of
an alkylamine with thiocarbonyldiimidazole followed by
the addition of 1,2-phenylenediamine to promote the
formation of the unsymmetrical thiourea 15 which after
cyclodesulfurization provided access to the 2-alkyl-
amino benzimidazoles 16.
NH2
NH2
N
N
a, b,c
CO2H
+
R
6
7
8
R
Cl
Scheme 2. Reagents and conditions: (a) CDI, CH2Cl2; (b) HCl
(concd), MeOH, 80%; (c) K2CO3, DMF, 4-ClPhCH2Br, 86%.
CHO
NH2
NH2
N
N
R
a, b
+
R
6
9
10
Cl
Scheme 3. Reagents and conditions: (a) PhNO2, 120 °C, 50%; (b)
NaH, DMF, 4-ClPhCH2Br, 91%.
N
N
N
a, b
N
H
R
11
12
Cl
The SAR studies were first initiated with the sulfur lin-
ker series due to the simplicity of synthesis and avail-
ability of a large variety of substituted benzyl halides.
The SAR on the nature of the substitution pattern of the
benzyl moiety is summarized in Table 1 and based on
affinities measured in radioligand competition assays.13
In general, compounds were screened for affinity against
all eight human prostanoid receptors. The principal ‘off-
target’ affinity of compounds in this series was at the
thromboxane A2 receptor (TP). In addition, in order to
evaluate the effect of proteins on the affinity of com-
pounds at DP receptor, binding assays in the presence of
0.5% human serum albumin (HSA) were performed. We
were delighted to see that the first compound prepared
in this series (1, Table 1) shows a Ki of 0.073 lM on
human DP receptor and 9.1 lM on human TP receptor
N
N
c
R
13
Cl
Scheme 4. Reagents and conditions: (a) K2CO3, DMF, 4-ClPhCH2Br,
88%; (b) ArCHO, Ac2O, xylene, reflux, 35%; (c) H2, Pd/C, EtOH, 88%.
Deprotonation of 2 with NaH in DMF followed by
reaction with 4-chlorobenzyl bromide afforded the
intermediate 3. The alkylation product was then con-
verted to the 2-thio benzimidazole 4 by displacement of
the chlorine atom with potassium thioacetate followed

C. Beaulieu et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3195–3199
Table 1. Dissociation equilibrium constant determination of selected Table 1 (continued)
analogs for the SAR on the aryl ring of the benzylic group
3197
Compds
R
DPa Ki (lM)
TPa Ki (lM)
N
S
N
31
0.31
>74
R
O
N
N
N
Cl
Compds
R
DPa Ki (lM)
TPa Ki (lM)
32
33
0.096
0.33
>74
1.5
N
O
1
0.073
9.1
CO2Me
CO2Me
17
18
3.5
1.1
4.7
9.3
a Radioligand competition binding assays using recombinant human
prostaglandin D2 (DP) and recombinant human thromboxane
receptor (TP).
CO2H
CO2Me
CO2Et
in the radioligand competition assays. The selectivity of
compound 1 on DP over TP is 125-fold based on Ki
values. The hydrolysis of the methyl ester 1 to the cor-
responding carboxylic acid 17 resulted in the loss of
potency by approximately 50-fold. Based on this
observation we concentrated our efforts on non-acid
groups at this position. The substitution at the para
position of the phenyl ring appeared to be critical for the
affinity on DP receptor. Thus the ester 18 and the diester
19 substituted in meta position are much less active than
the corresponding para substituted compound and that
was also true with the unsubstituted analog 20. Once the
para substitution on the phenyl ring was defined as
optimal, we focused on finding groups that provide
better potency than the methyl ester. Introduction of
nonpolar electron-withdrawing groups such as CF3 (21)
and fluorine atom (22) significantly reduced the potency.
Introduction of groups such as methylthioether (23),
methylsulfone (24), sulfonamide (25), dimethyl carbox-
amide (26) and nitrile (27) resulted in compounds less
active than 1. The presence of methyl ketone (28), sec-
ondary alcohol (29) and tertiary alcohol (30) also
diminished the activity to some extent. However, the
potency of these analogs is approaching that of 1. Of
particular interest is the tertiary alcohol 30 with a Ki of
0.14 lM at DP. In addition, the affinity at DP receptor is
minimally shifted (3.5-fold) in the presence of 0.5%
HSA. The methyl ester group in 1 is metabolically labile,
therefore it would be desirable to replace it with ester
mimetics such as methyl oxadiazole ring. Among the
two isomeric oxadiazole analogs prepared, 31 is less
potent than 1, whereas the other isomer 32 retains the
potency of 1 and its potency is shifted only by 2-fold in
the presence of 0.5% HSA with a Ki of 0.195 lM com-
pared to a Ki of 0.297 lM for 1 in the same assay. We
also observed loss of activity with 33 in which a methyl
phenyl acetate group replaces the methyl benzoate
group from 1.
19
>43
>71
CO2Et
20
21
6.7
2.6
4.2
>73
CF3
22
23
24
25
26
>42
0.55
1.1
6.1
>73
2.0
F
SMe
SO2Me
1.2
>70
2.0
SO2NH2
CONMe2
0.8
27
28
29
4.2
0.3
0.95
3.8
CN
COMe
0.27
1.5
OH
OH
In summary, the SAR studies done on the phenyl ring of
the benzyl group at position-2 on the benzimidazole core
did not provide any improvement of potency compared
30
0.14
11.9

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C. Beaulieu et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3195–3199
to that of 1. It appeared that methyl ester group and
methyl oxadiazole were the best substituents and we
decided to investigate the impact of the spacer separat-
ing the benzimidazole ring and the para substituted
phenyl ring on the activity and the results are summa-
rized in Table 2.
nitrogen atom and the phenyl group of 37 did not
improve dramatically the activity as observed for 38.
However the 2-phenylethenyl benzimidazole 39 and the
2-phenethyl benzimidazole 40 showed improved activity
over 1. These new spacers improved the activity on DP
by 2- and 3-fold, respectively (39: DP Ki ¼ 0.038 lM, 40:
DP Ki ¼ 0.024 lM). The potency of 40 in the presence of
0.5% HSA is shifted to the same extent than 1, and the
potency of 39 is 2-fold less shifted than 1. However, 39
and 40 are 4- and 2-fold more active than 1, respectively,
in the presence of 0.5% HSA, which is a significant
improvement over 1. The selectivity of 40 over the TP
receptor is similar to 1, however 39 is more selective than
1 and 40 by ꢀ15-fold.
The first modification to the spacer between the benz-
imidazole ring and the phenyl ring was the oxidation of
the sulfide group from 1 to the sulfoxide 34 and that
resulted in a 8-fold loss of activity. The need of a spacer
is demonstrated by the low activity obtained with the 2-
aryl benzimidazole 35. Slightly better potency was
observed for the 2-benzyl benzimidazole analog 36 that
has a methylene group as the spacer. The replacement of
the methylene group of 36 by a nitrogen atom in 37
increased the activity but was still 20-fold less than that
for 1. The addition of a methylene group between the
In conclusion, the SAR around the spacer between the
benzimidazole ring and the phenyl group allowed design
of compounds with improved activity and less protein
Table 2. Dissociation equilibrium constant determination for selected analogs with different spacers separating the benzimidazole ring and the phenyl
ring
N
R
N
Cl
Compds
R
DP Ki (lM)
DP + 0.5% HSA Ki (lM)
TP Ki (lM)
S
1
0.073
0.297
9.1
CO2Me
CO2Me
S
O
34
0.55
1.5
3.1
35
36
8.0
6.2
0.8
7.0
4.0
CO2Me
>12
CO2Me
H
N
37
1.5
5.4
0.9
CO2Me
N
H
38
39
1.1
n.d.
6.0
CO2Me
0.038
0.067
>75
CO2Me
CO2Me
40
0.024
0.137
2.2

C. Beaulieu et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3195–3199
3199
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next step in evaluating the potential of these compounds.
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