Biaryl diamides as potent melanin concentrating hormone receptor 1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.08.043

Herein, we report the discovery of the potent and selective biaryl diamide derived MCH-R1 receptor antagonist 1, which was identified upon modification of a previously disclosed biaryl urea series. This paper describes one of the strategies incorporated t

Full text of DOI:10.1016/j.bmcl.2005.08.043

Bioorganic & Medicinal Chemistry Letters 15 (2005) 5234–5236
Biaryl diamides as potent melanin concentrating hormone
receptor 1 antagonists
Anandan Palani,* Sherry Shapiro, Mark D. McBriar, John W. Clader,
William J. Greenlee, Kim OÕNeill and Brian Hawes
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 29 July 2005; revised 16 August 2005; accepted 17 August 2005
Available online 3 October 2005
Abstract—Herein, we report the discovery of the potent and selective biaryl diamide derived MCH-R1 receptor antagonist 1, which
was identified upon modification of a previously disclosed biaryl urea series. This paper describes one of the strategies incorporated
to remove the highly mutagenic biarylaniline present in an otherwise promising biaryl urea series.
Ó 2005 Elsevier Ltd. All rights reserved.
Melanin concentrating hormone (MCH) is a 19-amino
acid cyclic peptide found in the brains of all vertebrate
species which serves as an important mediator in the
regulation of food intake and energy balance.1,2 An
icv injection of MCH in rats stimulates food intake,3
and chronic administration leads to increased body
weight.4 Mice overexpressing the MCH gene are hyper-
phagic, mildly obese, hyperglycemic, and insulin resis-
tant.5 In contrast, mice that lack the gene encoding
MCH are lean and hypophagic.6 These observations
suggest that MCH antagonists could be useful for the
treatment of obesity. Several companies have published
their efforts in identification of small molecule MCH
receptor antagonists.7–9
biarylaniline. One strategy that we followed was to re-
place the central phenyl ring of biaryl aniline with a
bicycloalkyl group. This study resulted in discovery of
the novel, orally active MCH-R1 antagonist
3
(Fig. 1).12 We report herein a different approach to mod-
ifying the biaryl aniline portion of 2, which resulted in
discovery of biaryl diamide 1, a potent and selective
MCH-R1 receptor antagonist.
The synthesis of biaryl methylene ureas is outlined in
Scheme 1. Suzuki coupling between p-bromobenzalde-
hyde and 3-cyanophenyl boronic acid followed by
reductive amination with aminoethyl pyrrolidine or
aminopropyl pyrrolidine afforded compound 4. Treat-
ment of resulting amines with aryl isocyanates afforded
the desired products 7–12.
We recently reported the MCH-R1 antagonist 2,10
which showed excellent in vitro and moderate in vivo
activity; however, further studies with this compound
were discontinued due to the presence of a highly muta-
genic, Ames positive biarylaniline subunit.11 Although 2
is non-mutagenic, and there is no evidence to suggest
that the biarylaniline is generated in vivo, the risk of
possible exposure to this highly mutagenic intermediate
at any stage in the development of the series was consid-
ered unacceptable. Therefore, we turned our attention to
identify an MCH-R1 antagonist lacking the mutagenic
The synthesis of biaryl methylene diamides and biaryl
ethylene diamides proceeded via Scheme 2. Suzuki cou-
pling between amine 5 and 3-cyanophenyl boronic acid
followed by treatment of resulting biaryl amine with a-
bromophenyl acetylamide afforded compound 6. Acyla-
tion of 6 with chloroacetyl chloride followed by nucleo-
philic substitution with various amines afforded
compounds 1, 13–18, and 23–24. The compound 6 was
then coupled with chloropropionic acid, followed by
subsequent reaction with various amines to give com-
pounds 19–22 and 25–28.
Keywords: MCH-R1 antagonists; Melanin concentrating hormone
receptor 1 antagonists.
To eliminate any possibility that 4-aminobiphenyl could
be generated in vivo, we replaced the biarylaniline with a
biarylmethylene amine. Table 1 shows the MCH-R1
*
Corresponding author. Tel.: +1 908 740 7158; fax: +1 908 740
7152; e-mail: anandan.palani@spcorp.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.043

A. Palani et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5234–5236
5235
CF3
Cl
F
F
CF3
HN
Cl
O
NH
O
NH
O
N
N
N
N
N
N
N
O
OH
OH
NC
CN
CN
1
2
3
MCH-R1 Ki = 3.7 nM
MCH-R1 Ki = 8.9 nM
MCH-R1 Ki = 2.7 nM
Figure 1. MCH-R1 antagonists.
CHO
N
N
n
a,b
N
n
c
N
H
O
NH
Ar
Br
4
n = 1, 2
CN
CN
7-12
Scheme 1. Reagents: (a) 3-cyanophenyl boronic acid, Na2CO3, Pd(PPh3)4, toluene:EtOH:H2O or PdCl2(PPh3)2, K3PO4, DME:H2O, 50–80%;
(b) 1-aminoethyl pyrrolidine or 1-aminopropyl pyrrolidine, NaCNBH3, HCl, MeOH 60–90%; (c) ArNCO, Et3N, CH2Cl2, 75–100%.
H
O
N
N
Ar
X
H
O
O
N
NH2
Ar
X
R
X
a,b
N
H
CN
1, 13-18, 23-24
H
N
O
Br
Ar
6
CN
5
X
N
X = CH2, CH2CH2, CH(Me)
R= Amines
O
R
19-22, 25-28
CN
Scheme 2. Reagents: (a) 3-cyanophenyl boronic acid, Na2CO3, Pd(PPh3)4, toluene:EtOH:H2O or PdCl2(PPh3)2, K3PO4, DME:H2O, 50–80%; (b)
ArNHCOCH2Br, CH2Cl2, 90%; (c) chloroacetyl chloride CH2Cl2, 70%; (d) amine, K2CO3, NaI, CH3CN, 75–100%; (e) chloropropionic acid, EDCl,
CH2Cl2, 80%.
Table 1. MCH receptor binding for biaryl methylene ureas
activities of several representative biaryl methylene
ureas containing modifications at the urea phenyl. The
propyl linker was preferred over the ethyl linker. The
3,5-dichloro and 3-chloro-4-fluorophenyl substitutions
(10 and 11) were the best among the several disubstitut-
ed ureas prepared and tested. Note that the 4-fluoro-3-
trifluoromethyl substitutions which was one of the best
in the biaryl aniline series, showed 50-fold less MCH-
R1 affinity in the biarylmethylene series. We speculated
that this considerable loss of activity with biarylmethyl-
ene series could be due to changes in the orientation of
the biaryl as well as the hydrogen bonding interaction
provided by urea N–H with the receptor.
N
n
N
O
NH
R
CN
Compound
n
R
h-MCH-R1a Ki (nM)
7
8
1
1
1
2
2
2
3,5-diCl
151 29
3-Cl, 4-F
4-F, 3-CF3
3,5-diCl
287
159 40
4
9
10
11
12
48
48
70
3
2
1
3-Cl, 4-F
4-F, 3-CF3
After the limited success with biarylmethylene com-
pounds, we next explored alterations to the urea function-
ality by introducing diamides instead of changing the
a Mean values (n = 3) SEM. h-MCH-R1 denotes human MCH-R1.
Affinity at h-MCH-R2 > 3 lM for all compounds.

5236
Table 2. MCH receptor binding for biarylmethylene diamides
Cl Cl
A. Palani et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5234–5236
To further improve the MCH-R1 affinity, we studied the
replacement of the biarylmethylene with a biarylethylene
linker. Table 3 shows MCH-R1 binding of selected biaryl-
ethylene amides. The unsubstituted pyrrolidine 23 gave
slightly better activity for MCH-R1 than the correspond-
ing biarylmethyelene amide 13. Again, similar to biarylm-
ethylene diamide series, the (S)-OH pyrrolidines 1 and 28
showed better MCH-R1 affinity than (R)-OH isomer and
unsubstituted compounds 23 or 26. Compound 1 was
identified as a potent and selective MCH-R1 antagonist,
which was selected for followup studies.
O
Y
NH
X
N
O
N
n
R1
CN
X,Y
Compound
n
R1
h-MCH-R1a Ki (nM)
In summary, a systematic SAR modification strategy of
compound 2 resulted in the identification of several
structurally novel, non-biarylaniline containing MCH-
R1 antagonists. Compound 1 showed excellent in vitro
activity; further in vivo studies with this compound will
be reported in due course.
13
14
15
16
17
18
19
20
21
22
H, H
H, H
H, H
1
1
1
1
1
1
2
2
2
3
H
35
61
27
2
8
4
(R)-OH
(S)-OH
(S)-OH
(S)-OH
H
Me, H
H, Me
Me, Me
H,H
31 0.5
16
131
21
1
2
5
H
Me, H
H, Me
Me, H
(S)-OH
(S)-OH
(S)-OH
23 0.5
18
76
1
5
Acknowledgments
a Mean values (n = 3) SEM. h-MCH-R1 denotes human MCH-R1.
Affinity at h-MCH-R2 > 3 lM for all compounds.
We thank Dr. Michael Graziano, Dr. John Piwinski,
and Dr. Catherine Strader for helpful discussions, sup-
port, and encouragement.
Table 3. MCH receptor binding for biarylethylene diamides
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Cl
Cl
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