Synthesis and SAR investigations of novel 2-arylbenzimidazole derivatives as melanin-concentrating hormone receptor 1 (MCH-R1) antagonists

Article abstract of DOI:10.1016/j.bmcl.2011.02.099

Compounds containing 2-arybenzimidazole ring systems linked to arylpiperidines were synthesized and evaluated as MCH-R1 antagonists. The results of structure-activity relationship studies led to the identification of compound 4c as a potent MCH-R1 antagonist (IC₅₀ = 1 nM). This compound also has good metabolic stability, and favorable pharmacokinetic and brain penetration properties. However 4c was found to be potent inhibitor of the hERG potassium channel.

Full text of DOI:10.1016/j.bmcl.2011.02.099

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2309–2312
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR investigations of novel 2-arylbenzimidazole derivatives
as melanin-concentrating hormone receptor 1 (MCH-R1) antagonists
Chae Jo Lim a, Nakjeong Kim a, Eun Kyoung Lee a,b, Byung Ho Lee a, Kwang-Seok Oh a, Sung-eun Yoo a,
Kyu Yang Yi a,b,
⇑
a Bio-organic Science Division, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-600, Republic of Korea
b Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Compounds containing 2-arybenzimidazole ring systems linked to arylpiperidines were synthesized and
evaluated as MCH-R1 antagonists. The results of structure–activity relationship studies led to the identi-
fication of compound 4c as a potent MCH-R1 antagonist (IC50 = 1 nM). This compound also has good met-
abolic stability, and favorable pharmacokinetic and brain penetration properties. However 4c was found
to be potent inhibitor of the hERG potassium channel.
Received 24 December 2010
Revised 22 February 2011
Accepted 23 February 2011
Available online 26 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Melanin-concentrating hormone (MCH)
MCH-R1 antagonists
2-Arylbenzimidazole
Obesity
The melanin-concentrating hormone (MCH) is a cyclic 19-ami-
no acid polypeptide that is expressed predominantly in the lateral
hypothalamus and zona incerta of the central nervous system.1
MCH is known to be involved in the regulation of feeding behavior
and energy homeostasis that are mediated by two types of G pro-
tein-coupled receptors, MCH receptor 1 and 2 (MCH-R1 and R2).2,3
Nearly homologous forms of MCH-R1 are present in both humans
and rodents and their pharmacological effects on MCH are not sig-
nificantly different. Owing to the observation that intracerebroven-
tricular (ICV) injection of MCH into rat stimulates food intake and
chronic administration, it can be argued that MCH is associated
with obesity and hyperphagia.4,5 Furthermore, it has been reported
that the steady-state levels of MCH mRNA are high in obese ro-
dents, such as ob/ob, db/db, Ay/a mice.6 Additionally, a transgenic
MCH-R1 knockout in mice led to reduced food intake and elevated
metabolic rates, resulting in a lean phenotype.7 In contrast, overex-
pression of MCH mRNA caused mice to have increased fat and body
weight associated with an obese phenotype.8 Indeed, numerous
MCH-R1 antagonists have shown anti-obesity efficacy in diet-in-
duced obesity (DIO) animal models.9
develop a variety of pharmacophore structures of MCH-R1 antago-
nists that might behave as anti-obesity agents. Despite good in vivo
efficacy in rodents, a number of chemical series are unable to pro-
gress to clinical development due to unsuitable PK profile and hERG
binding activity.12 To date, GW856464,13 AMG-076,14 NGD-4715,15
and ALB-127158 (structure undisclosed)16 have advanced to the
phase 1 trial stage (Fig. 1). Recently, benzimidazole based MCH-
R1 antagonists have been described by several research groups.17
In continuing efforts to uncover novel and potent MCH-R1 antago-
nists, we found that 2-aryl substituted benzimidazole derivatives,
containing the piperidinylphenyl acetamide group at the 1-posi-
tion, display highly potent binding affinities to MCH-R1.18 We de-
scribe the synthesis, biological evaluation, and structure–activity
relationships of several 2-arylbenzimidazole derivatives.
The general synthetic routes used to prepare the new 2-aryl-
benzimidazole derivatives 3–6 are outlined in Scheme 1. The aryl
substituted benzimidazoles 1, employed in these sequences are
either commercially available or readily prepared by reaction of
1,2-phenylenediamine with benzoic acid derivatives using
polyphosphoric acid (PPA). The methanesulfonate ester 9 of N-
[3-[1-(3-hydroxypropyl)-4-piperidinyl]phenyl]acetamide, used as
one coupling partner, was prepared from the known N-[3-
(4-piperidinyl)phenyl]acetamide 7.19 The route employed alkyl-
ation of 7 with 3-bromopropan-1-ol in the presence of potassium
carbonate in DMF to give N-[3-[1-(3-hydroxypropyl)-4-piperidi-
nyl]phenyl]acetamide 8. Treatment of 8 with methanesulfonyl
chloride and triethylamine in dichloromethane provided 9, which
was directly used in the next step without further purification.
Since the time that T-22629610 and SNAP-794111 were shown to
be the first small molecule MCH-R1 antagonists, a number of
pharmaceutical companies have undertaken large efforts to
⇑
Corresponding author at: Bio-organic Science Division, Korea Research Institute
of Chemical Technology, Yuseong-gu, Daejeon 305-600, Republic of Korea. Tel.: +82
42 860 7143; fax: +82 42 860 7160.
E-mail address: kyyi@krict.re.kr (K.Y. Yi).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.02.099

2310
C. J. Lim et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2309–2312
F
F
O
N
N
H
O
O
O
O
O
N
N
H
N
H
N
F
N
H
O
N
T-226296
SNAP-7941
F3C
O
O
O
N
O
N
H
O
N
N
N
S
N
O
CO2H
Cl
N
H
Br
H
PhSO3H
GW856464 (GSK)
AMG076 (Amgen)
NGD-4715 (Neurogen)
Figure 1. Representative structures of MCH-R1 antagonists.
R1
R1
NH2
NH2
O
N
a
b
N
H
HO
R1
1
N
N
O
c
n N
NH
R1
N
N
d
3-6 (n=2-5)
n
Cl
2
HN
HN
HN
O
O
O
f
e
N
HN
N
MsO
HO
7
8
9
Scheme 1. Reagents and conditions: (a) PPA, reflux, 3 h; (b) 9, K2CO3, DMF, 80 °C, 5 h; (c) 1-chloro-n-iodoalkane, K2CO3, DMF, rt, 10 h; (d) 7, K2CO3, KI, DMF, 100 °C, 5 h; (e) 1-
bromopropanol, K2CO3, DMF, 60 °C, 5 h; (f) MsCl, Et3N, CH2Cl2, 0 °C to rt, 3 h.
The target compounds 4 (n = 3) were obtained by reaction of benz-
imidazoles 1 with 9 in the presence of potassium carbonate in DMF.
Alternatively, compounds 3–6 can be generated from 1 by alkyl-
ation with the appropriate 1-chloro-n-iodoalkanes followed by
reaction with 7.
with acetamide 4. Hydrolysis of 4 by treatment with 5 N HCl in
methanol afforded the free amine 10, which was then reacted with
an appropriate acid chloride in the presence of triethylamine in
dichloromethane to afford the corresponding amides 11.
The 2-arylbenzimidazole derivatives were evaluated for their
binding affinities to the membranes of CHO cells expressing human
As shown in Scheme 2, the routes for preparation of anilide
derivatives 11 utilized simple synthetic manipulations starting
MCH-R1. These measurements were performed by using
a
R1
R1
N
N
N
R1
N
N
b
N
a
N
H
N
N
N
R2
H
N
NH2
O
11
O
10
4
Scheme 2. Reagents and conditions: (a) 5 N HCl, MeOH, 50 °C, 3 h; (b) R2COCl, Et3N, CH2Cl2, 0 °C to rt, 1 h.

C. J. Lim et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2309–2312
2311
Table 1
Table 2
Effects of chain length on MCH-R1 binding affinity
Effects of substituents on the 2-aryl group of benzimidazole derivatives
R1
N
N
N
N
O
n
N
NH
N
H
N
a,b
Compound
n
MCH-R1 IC50 (nM)
O
3
4
5
6
2
3
4
5
10,000
2
a,b
Compound
R1
H
2-CI
3-CI
MCH-R1 IC50 (nM)
29
74
4
2
10
5
4a
4b
4c
4d
4e
4f
4g
4h
4i
a
Binding affinities of compounds for MCH-R1 were determined by using com-
petitive binding with Eu-MCH and a TRF assay.
4-CI
1
b
Values are means of at least two measurements.
2-CF3
3-CF3
4-CF3
2-OMe
3-OMe
4-OMe
4-F
4-Br
4-Et
4-i-Pr
4-Ph
4-OPh
4-CN
50
30
3
747
7
competition binding assay with Eu-labeled MCH and a time-re-
solved fluorometric (TRF) assay (Table 1).20 The initial SAR study
was aimed at determining the distance between the benzimidazole
and arylpiperidine moieties that leads to optimal binding to MCH-
R1. Among those tested (3–6), compound 4 containing a three-car-
bon linker showed the most potent MCH-R1 binding activity.
When the length of the linker is increased from C-3 (4) to C-4 (5)
and C-5 (6), a large decrease in MCH-R1 binding affinity was ob-
served. Interestingly, the C2-linked compound 3 does not bind to
MCH-R1. These results indicate that the length of the linker be-
tween the benzimidazole and arylpiperidine groups plays a signif-
icant role in binding to MCH-R1.
9
56
5
32
60
8
42
16
3
4j
4k
41
4m
4n
4o
4p
4q
4r
4s
4t
2,4-di-CI
3,4-di-CI
2-F-4-CI
3,4-di-F
2-CI-4-F
24
1
4
4u
4
a
Binding affinities of compounds for MCH-R1 were determined by using com-
With the optimal linker length determined (n = 3), the effects of
various substituents on the aryl group at the 2-position of the
benzimidazole moiety were investigated. As the results displayed
in Table 2 show, introduction of a chlorine group at the para-aryl
position (4c) gives an improved affinity for MCH-R1 (IC50 = 1 nM)
as compared to 4. However the ortho- and meta-analogs 4a and
4b, have 10- and 5-fold reduced binding affinities, respectively.
Independent of their different electronic properties, the trifluoro-
methyl (4d–4f) and methoxy (4g–4i) derivatives display similar
structure–activity relationships.
petitive binding with Eu-MCH and a TRF assay.
b
Values are means of at least two measurements.
Table 3
Effects of the anilide group on the arylpiperidine moiety on MCH-R1 binding affinity.
N
Cl
N
A further exploration of the effects of substituents at the para
position of aryl group demonstrated that the bromo and phenyl
substituted substances, 4k and 4n, have high MCH-R1 binding
affinities. In contrast, other para-substituents such as fluoro 4j,
ethyl 4l, i-propyl 4m, phenoxy 4o, and nitrile 4p have detrimental
effects on binding. The effects of disubstitution on the aryl group
were investigated next. Incorporation of 2-F and 4-Cl groups (4s)
resulted in a potency that is comparable to both the unsubstituted
compound 4 and the 4-chloro derivative 4c. Except for 3,4-di-Cl 4r,
disubstituted substrates such as 2,4-di-Cl 4q, 3,4-di-F 4t, and 2-Cl-
4-F 4u had low IC50 values in the range of 1–4 nM.
Having discovered that p-chloro is the optimal substituent on
the 2-aryl ring of benzimidazoles, our attention next turned to
the anilide moiety in the arylpiperidine part of these compounds.
As the data in Table 3 indicate, while placement of an acetanilide
group at the meta-position (4c) leads to excellent MCH-R1 binding
affinity, introduction of this group at the ortho (11a) and para (11b)
positions resulted in a loss of binding. In addition, introduction of a
i-propyl-anilide moiety at the meta-position (11c) in place of acet-
anilide led to a slight reduction in activity. However, the presence
of benzoyl anilides such as phenyl (11d), tolyl (11e), and m-chloro-
phenyl (11f) were detrimental to MCH-R1 binding. Additionally,
replacement of the anilide group by small substituents such as
N
O
R2
N
H
a,b
Compound
Position
R2
MCH-R1 IC50 (nM)
4c
3-
2-
4-
3-
3-
3-
3-
Me
Me
Me
i-Pr
Ph
4-Me-Ph
3-CI-Ph
1
11a
11b
11c
11d
11e
11f
>6000
5380
5
19
300
213
a
Binding affinities of compounds for MCH-R1 were determined by using com-
petitive binding with Eu-MCH and a TRF assay.
b
Values are means of at least two measurements.
fluorine, methoxy, and methyl resulted in a drop in binding affinity
(data not shown). These findings indicate that the position and size
of the anilide group, which serves as both a H-bonding donor and
acceptor, might be critical for binding to MCH-R1.
The metabolic stability of 4c, which was shown to have the
highest MCH-R1 binding affinity, was evaluated. This substance

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Oral AUC (mg h/mL)
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Vdss (L/kg)
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Acknowledgments
This research was supported by grants from the Center for Bio-
logical Modulators of the 21st Century Frontier R&D Program, the
Ministry of Science and Technology, Korea.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.02.099.
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