Design and synthesis of orally efficacious benzimidazoles as melanin-concentrating hormone receptor 1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.04.062

Biaryl urea lead compound 1 was discovered earlier in our MCH antagonist program. Novel benzimidazole analogues with increased chemical stability, devoid of the potential carcinogenic liability associated with a biarylamine moiety, were synthesized and evaluated to be potent MCH R1 antagonists. Two compounds in this series have demonstrated in vivo efficacy in a rodent obesity model.

Full text of DOI:10.1016/j.bmcl.2006.04.062

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3674–3678
Design and synthesis of orally efficacious benzimidazoles
as melanin-concentrating hormone receptor 1 antagonists
Wen-Lian Wu,* Duane A. Burnett, Mary Ann Caplen, Martin S. Domalski,
Chad Bennett, William J. Greenlee, Brian E. Hawes, Kim O’Neill, Blair Weig,
Daniel Weston, Brian Spar and Timothy Kowalski
Schering Plough Research Institute, 2015 Galloping Hill Road, MS 2800, Kenilworth, NJ 07033-0539, USA
Received 9 March 2006; revised 21 April 2006; accepted 21 April 2006
Available online 11 May 2006
Abstract—Biaryl urea lead compound 1 was discovered earlier in our MCH antagonist program. Novel benzimidazole analogues
with increased chemical stability, devoid of the potential carcinogenic liability associated with a biarylamine moiety, were synthe-
sized and evaluated to be potent MCH R1 antagonists. Two compounds in this series have demonstrated in vivo efficacy in a rodent
obesity model.
Ó 2006 Elsevier Ltd. All rights reserved.
CN
Melanin-concentrating hormone (MCH),
a
cyclic
X
19-amino-acid peptide, was first identified in teleost fish
where it appears to regulate color change.1 The MCH
R1 receptor was discovered in 1999.2 More recently,
the MCH R1 receptor has been investigated thoroughly
for its possible role in regulating eating behavior in
mammals. MCH-deficient mice have reduced body
weight and are lean due to hypophagia;3a MCH mRNA
levels are increased in ob/ob mice and in fasted mice;3b
transgenic mice overexpressing the MCH gene are
susceptible to insulin resistance and obesity;3c and dis-
ruption of MCH receptor 1 expression resulted in resis-
tance to diet-induced obesity despite hyperphagia.3d All
these findings suggest that MCH receptor antagonists
could be useful for the treatment of obesity. A variety
of small molecule MCH R1 antagonists have appeared
in the literature.4,5 Herein, we would like to report the
design and synthesis of a series of novel orally effica-
cious MCH R1 antagonists.
Cl
Ar
N
O
N
H
N
N
N
Cl
H
N
R
1
Ki = 2.5 nM
Kb = 3.1 nM
Figure 1. Lead compound and the design of benzimidazole analogues.
strategy is to modify the biaryl part.4c We reasoned that
the biarylaniline N atom is sp2-like and might be
replaced with a vinyl carbon atom. Furthermore, the
phenylamide moiety would be substituted with an
isosteric benzimidazole skeleton based on our earlier
findings.8 Thus, our design involves two distinctly new
elements and is depicted in Figure 1.
The urea lead 1 was identified earlier in our MCH antag-
onist program;6 however, it contains a biarylaniline moi-
ety which was found to be highly mutagenic in the Ames
test.7 In order to circumvent this potential liability, one
The first-generation synthetic route started with substi-
tuted phenylenediamines (Scheme 1). The SEM-protect-
ed benzimidazole 2, obtained in two steps from
commercially available diamines, was coupled with the
known ketone 39 to give the tertiary alcohol 4. Chlorina-
tion of 4 followed by elimination with pyridine afforded
the desired tetrasubstituted alkene 5 as the major prod-
uct and some endo-alkene isomer, which can be partially
Keywords: Melanin-concentrating hormone receptor; Antagonist;
Obesity.
*
Corresponding author. Tel.: +1 908 704 6525; fax: +1 908 740
7164; e-mail: wen-lian.wu@spcorp.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.04.062

W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3674–3678
3675
X
Br
Br
NH2
NH2
N
Br
a,b
c
N
X
X
OH
Br
CN
CHO
N
b
a
N
H
SEM
CN
2
X = 4, 5-Cl, Cl
X = 4, 5-F, F
+
O
N
N
4
N
Boc
Boc
Boc
7
d
8
NBoc
CN
Br
CN
3
X
X
Br
X
X
N
Br
N
N
N
c
N
N
H
d,e
f,g
h
H
N
N
H
H
N
N
Boc
9
10
Boc
N
N
R
5
6
Boc
Scheme 1. Reagents and conditions: (a) HCO2H, HCl, reflux, 97%
(X = 4,5-Cl,Cl); (b) NaH, Me3SiCH2CH2OCH2Cl, DMF, rt, 62%; (c)
n-BuLi, THF, ketone, 93%; (d) SOCl2, pyridine, 94%; (e) pyridine,
150 °C, 43%; (f) TFA–DCM (1:1), rt, 100%; (g) 3-cyanophenylboronic
acid, Pd(PPh3)4, 2N Na2CO3, toluene–MeOH (1:1), 58%; (h) aldehyde
or ketone, NaBH(OAc)3, DCM or Ac2O–TEA.
e, f
e, f
X
X
Br
Ar
N
N
d
N
N
H
H
or g, h
N
11
12
N
converted to 5 under basic conditions.10 Suzuki coupling
installed the required 3-cyanophenyl moiety. Deprotec-
tion of the N-Boc group and subsequent derivatization
of the revealed NH by conventional methods provided
the N-substituted piperidine analogues 6a–c.
R
Scheme 2. Reagents and conditions: (a) 1-Boc-4-piperidinone, EtONa,
EtOH, reflux, 87%; (b) DIBAL, DCM, À78 °C, 38%; (c) substituted
1,2-diphenylamines, 40% NaHSO3, EtOH, 27–40%; (d) 3-cya-
nophenylboronic acid, Pd(PPh3)4, 2N Na2CO3, toluene–MeOH (1:1),
reflux, 90%; (e) TFA–DCM (1:1), 100%; (f) aldehyde or ketone,
NaBH(OAc)3, DCM or Ac2O–TEA; (g) bispinacolatodiboron, KOAc,
PdCl2(dppf)2, DMSO, 100 °C, 47%; (h) ArBr, Pd(PPh3)4, 2N Na2CO3,
toluene–MeOH (1:1), 120 °C, 10 min (microwave).
A more efficient synthesis is depicted in Scheme 2. Con-
densation of 4-bromobenzonitrile with 1-Boc-4-piperi-
done gave compound 7. Selective reduction with
DIBAL afforded aldehyde 8,11 which was treated with
diamines in the presence of sodium bisulfite to give benz-
imidazole 9.12 From this advanced intermediate, a reac-
tion sequence (d-e-f), namely: (i) Suzuki coupling, (ii)
deprotection of the N-Boc, and (iii) N-substitution via
parallel synthesis (reductive amination or acylation),
provided the final targets 12. Alternatively, removal of
the N-Boc group first, followed by reductive alkylation,
gave the bromo-compound 11, which set the stage for
another parallel synthesis to explore the SAR of the bia-
ryl moiety (e-f-d). Suzuki coupling of 11 with various
phenylboronic acids furnished the targets 12. In cases
where the boronic acids were not easily available, com-
pound 11 was converted to its pinacolboronic ester13
and then coupled with appropriate aryl bromides to give
the final analogues (12d, 12e). Through these flexible
reaction sequences, we developed SAR in both direc-
tions handily.
Table 1. SAR of substituents at the benzimidazole phenyl ringa
CN
X
N
N
H
N
Compound
X
MCH Ki (nM)
6a
6b
5,6-Cl2
5,6-F2
15
52
6c
4,6-Cl2
5-CN
5-F, 6-CF3
87
133
3.5
12b
12c
The analogues mentioned above were evaluated in a
radioligand binding assay as described in the preceding
article8 and the results are shown in Table 1.
a Mean values (n = 3). h-MCH R1.
As shown in Table 1, compound 12c displayed single-
digit nanomolar affinity to the MCH R1 receptor. These
initial results prompted us to focus on the 5-F–6-CF3
substituents on the benzimidazole and explore the
SAR of the biaryl part. As revealed in Table 2, 3-cyan-
ophenyl remained optimal for MCH R1 binding, consis-
tent with our earlier findings.8 Small changes such as
those in compounds 12d and 12e were also tolerated.
Other substituted analogues were less potent.
The SAR of the piperidine N-substituent is summarized
in Table 3. The N–H analogue 12a was equally potent as

3676
W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3674–3678
Table 3. SAR of substituents at the piperidine nitrogena
CN
Table 2. SAR of modification of biarylsa
F
Ar
F
N
CF3
N
N
H
CF3
N
H
N
N
R
Compound
Ar
CN
MCH Ki (nM)
Compound
R
H
MCH Ki (nM)
12a
12c
12m
12n
3.6
3.5
12c
3.5
Cyclopropylmethyl
HOCH2CH2
NH2COCH2
7.2
15.5
CN
N
12o
12p
12q
12r
45
31
21
20
12d
12e
12f
3.9
10.3
26
S
MeCO
F
CN
O
N
S
N
O
O
CN
12s
10.1
12t
Me2NCO
Et2NCO
MeSO2
37
22
12u
12v
12w
12x
N
OH
71.4
129
64
12g
99
i-PrSO2
Me2NSO2
NC
HO
a Mean values (n = 3). h-MCH R1.
N
12h
12i
174
95
the presence of base to give compound 13 in excellent
yield.15 Following similar reaction steps as per Scheme
2 led to compounds 15a–i.
N
N
CONH2
SO2Me
As shown in Table 4, the cyclopropyl benzimidazole
analogues (racemic) were very potent MCH R1 ligands,
and followed a similar SAR trend as corresponding
alkene-linked countparts, confirming the isosteric equiv-
alence of cyclopropyl and ethylene groups in this series.
12j
12k
12l
77
132
464
Several potent compounds were selected for pharmacoki-
netic investigation in rats16 and a mouse ex vivo binding
assay.17,18 The profiles are reported in Table 5. The alkene
analogues (6a, 12c, 12d, 12p, and 12t) exhibited very good
exposure in rats, indicating the tetra-substituted olefin
bonds are metabolically quite stable. The lower AUC of
cyclopropyl analogue 15b compared to compound 6a
was a surprise and may be a result of poorer absorption
relative to the olefinic analogue. All the compounds
showed good to excellent ex vivo binding in mice.
CN
a Mean values (n = 3). h-MCH R1.
the cyclopropylmethyl analogue 12c. Polar substituents
as in 12e and 12f were also tolerated, although slightly
less potent. It is noteworthy that some non-basic piper-
idine analogues such as amides, ureas, and sulfonamides
retained quite good activity (12p–x).
Compounds 6a and 12c have been demonstrated to be
full MCH R1 antagonists in a functional assay (with
Kb values of 70 and 25 nM, respectively).19 More impor-
tantly, compounds 6a and 12c were chosen for further
in vivo study and, as seen in Table 6 both compounds
produced a robust reduction of food intake after oral
Considering the potential metabolic instability of the
alkene moiety, we replaced it with a cyclopropane isoste-
re to generate cyclopropyl benzimidazole analogues as
depicted in Scheme 3.14 To this end, the a,b-unsaturated
nitrile 7 was treated with trimethylsulfoxonium iodide in
dosing at 30 mg/kg in a fasted DIO mouse model20,21
.

W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3674–3678
3677
F
Br
Br
Br
N
CF3
CN
CN
a
N
b, c
H
N
N
N
Boc
Boc
Boc
7
13
14
CN
F
R = Boc
R = H
N
CF3
e
f
d
N
H
R = Bn, etc
15
N
R
Scheme 3. Reagents and conditions: (a) Me3S(O)+IÀ, t-BuOK, DMSO, 97%; (b) DIBAL, DCM, À78 °C, 27%; (c) 1,2-diamino-4-fluoro-5-
trifluoromethylbenzene, 40% NaHSO3, EtOH, 94%; (d) Pd(PPh3)4, 2N Na2CO3, 3-cyanophenylboronic acid, toluene–MeOH (1:1), 110 °C
(microwave, 18 min), 73%; (e) HCl in ether, 87%; (f) aldehyde or ketone, NaBH(OAc)3, DCM or Ac2O–TEA.
Table 4. SAR of cyclopropane-linked benzimidazole analoguesa
Table 6. In vivo efficacy in DIO micea
Compound
% Inhibition at indicated time
CN
2 h
6 h
24 h
F
6a
12c
37.4 6.5
31.0 5.6
41.8 5.6
32.6 5.4
26.8 7.2
18.6 5.5
N
CF3
N
H
a All values are significantly different (p < 0.05) from vehicle control
animals and represent the % inhibition of cumulative food intake at
the indicated times in fasted DIO mice. There are 15 mice per
group.
N
R
Compound
R
MCH Ki (nM)
15a
15b
15c
15d
15e
15f
15g
H
1.7
4.8
In summary, we have designed and synthesized potent
novel benzimidazole MCH R1 antagonists. Among
them, compounds 6a and 12c demonstrated good phar-
macokinetics in rats and oral efficacy in a DIO mouse
model for weight loss.
Cyclopropylmethyl
Bn
10.3
15
Et2NCH2CH2
HOOCCH2
Me2NCO
Et2NCO
41
32
221
N
O
Acknowledgments
15h
44
67
The authors thank Dr. Michael P. Graziano, Dr. Mar-
garet Van Heek, and Dr. John W. Clader for their sup-
port and helpful discussions. We thank Dr. Briendra
Pramanik’s group and Dr. Tse-Ming Chan’s group for
analytical support.
15i
i-PrSO2
a Mean values (n = 3). h-MCH R1.
Table 5. Rat Pharmacokinetics and mouse MCH receptor ex vivo
binding of selected compoundsa,b
Ex vivo bindingb
a
AUC0–6 h (ng/mL h)
Compound
References and notes
6 h
24 h
6a
6637
2882
3001
5252
1292
1032
68 16
96 23
92 22
48 11
50 12
74 18
54 13
84 20
80 18
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and frozen. Brain sections from the caudate were placed
on slides and allowed to bind to radiolabeled MCH-ADO
([125I]-S36057, NEN)18 for 30 min. The sections were then
rinsed with binding buffer and dried. The amount of
radiolabeled MCH-ADO that remained bound to the
brain section following washing was specific to MCH
binding sites. Addition of nonlabeled MCH to the binding
reaction completely abolished radiolabeled MCH-ADO
binding to the brain section. Radioactivity bound to the
section was quantified using a Storm 860 phosphorimager.
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19. Inhibition of MCH-mediated Ca2+ influx into cells
expressing hMCH-R1 via FLIPR assay. Affinity at h-
MCH-R2 > 3 lM for all compounds.
20. In vivo efficacy was determined by incorporation of a
fasted, diet-induced obese (DIO) mouse model. Mice were
fasted for 24 h and dosed orally 1 h prior to dark onset.
Food was returned at dark onset and intake was measured
at 2, 6, and 24 h after food presentation.
21. Data from our ex vivo binding studies were used to
prioritize compounds for in vivo evaluation. Receptor
occupancies ꢀ P 60% were predictive of activity in the
DIO mouse model. Furthermore, receptor occupancy at
24 h suggested a significant potential for duration of
action. Further correlation of receptor occupancy and
in vivo efficacy was not rigorously established.
8. See the preceding paper. Wu, W.-L. et al., Bioorg. Med.
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