Synthesis and structure-activity relationships of piperidine-based melanin-concentrating hormone receptor 1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.04.061

Isosteric replacement of the urea group of lead compound 1 led to novel substituted piperidine phenylamide analogues. SAR on the electron-induced effects of various linkers as well as substituents on the phenyl rings and the piperidine nitrogen has been investigated. Many single-digit nanomolar MCH R1 antagonists have been identified from this series.

Full text of DOI:10.1016/j.bmcl.2006.04.061

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3668–3673
Synthesis and structure–activity relationships of piperidine-based
melanin-concentrating hormone receptor 1 antagonists
Wen-Lian Wu,* Duane A. Burnett, Richard Spring, Li Qiang,
Thavalakulamgara K. Sasikumar, Martin S. Domalski, William J. Greenlee,
Kim O’Neill and Brian E. Hawes
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—Isosteric replacement of the urea group of lead compound 1 led to novel substituted piperidine phenylamide analogues.
SAR on the electron-induced effects of various linkers as well as substituents on the phenyl rings and the piperidine nitrogen has
been investigated. Many single-digit nanomolar MCH R1 antagonists have been identified from this series.
Ó 2006 Elsevier Ltd. All rights reserved.
Melanin-concentrating hormone (MCH),
a
cyclic
substituted an amide group for the urea moiety
(L = CH2). Moreover, for convenience of synthesis,
heteroatom linkers (L = N or O) were also inserted into
the chain as shown in Figure 1.
19-amino-acid neuropeptide, is expressed exclusively
within the lateral hypothalamus and has been regarded
as an appetite-stimulating agent in the past decade.1
The recent discovery of the G-protein-coupled MCH
receptor 1 (MCH R1) has prompted much interest in
developing MCH receptor antagonists for the treatment
of obesity.2,3 Several lines of pharmacologic evidence
indicated the important role of MCH on food intake
and body weight: injection of MCH into the lateral ven-
tricles of rats resulted in increased food consumption;4a
disruption of melanin-concentrating hormone receptor 1
expression leads to hyperphagia and resistance to diet-
induced obesity;4b transgenic mice overexpressing the
MCH gene are susceptible to insulin resistance and
obesity;4c and mice lacking MCH hormone are hyper-
phagic and lean.4d A variety of small molecule MCH
R1 antagonists have been disclosed in the literature.5,6
Herein we would like to report the synthesis and SAR
development of a series of piperidine-based phenylamide
MCH R1 antagonists.
The syntheses of the phenylamide analogues are depict-
ed in Scheme 1. Compound 2 was converted to the ester
3 by the following steps: (i) reductive alkylation; (ii)
reduction of the nitrile to an aldehyde; and (iii) Horn-
er–Emmons elongation to give the a,b-unsaturated ester
3. Hydrogenation of the olefin followed by bromination
of the phenyl ring gave compound 4. After installation
of the 3-cyanophenyl moiety by Suzuki reaction, treat-
CN
Cl
O
1
N
N
H
Cl
Ki = 2.5 nM
Kb = 3.1 nM
H
N
Urea compound 1 emerged as a lead compound for our
MCH R1 antagonist program.5d In order to explore
potential novel linkers and structural requirements, we
Y
O
X
L
N
H
L = CH2, NH, O
Keywords: Structure–activity relationship; Melanin-concentrating
hormone receptor 1; Antagonist.
N
R
*
Corresponding author. Tel.: +1 908 704 6525; fax: +1 908 740
7164; e-mail: wen-lian.wu@spcorp.com
Figure 1. Lead compound and isosteric analogues.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.04.061

W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3668–3673
3669
CN
COOMe
CN
Br
a, b, c
Br
d, e
OH
OH
N
N
b
OH
a
H
2
3
N
N
Boc
H
N
Boc
13
CN
12
CN
Br
O
X
CO2Me
O
N
H
X
f, g
O
c, d
e, f
N
N
H
N
N
14
Boc
4
5
CN
Scheme 1. Reagents and conditions: (a) cyclopentanone, NaB-
H(OAc)3, DCM; (b) DIBAL, DCM, À78 °C to room temperature;
(c) (MeO)2P(O)CH2CO2Me, NaH, 50% in 3 steps; (d) Pd(OH)2/C,
HCO2NH4, MeOH, 96%; (e) 3,5-dibromohydantoin, MeSO3H, DCM,
80%; (f) 3-cyanophenylboronic acid, Pd(PPh3)4, 2 N Na2CO3, toluene–
MeOH (1:1), reflux, 91%; (g) anilines, 2 equiv n-BuLi, THF, 40–70%.
O
X
O
N
H
N
R
15
Scheme 3. Reagents and conditions: (a) (Boc)2O, MeOH, 100%; (b)
3-cyanophenylboronic acid, Pd(PPh3)4, 2 N Na2CO3, toluene–MeOH
(1:1), reflux, 56%; (c) KH, BrCH2COOH, 92%; (d) anilines, DCC,
DMAP, THF, 50–80%; (e) TFA–DCM (1:1), 53–85%; (f) aldehydes or
ketones, NaBH(OAc)3, DCM.
ment of the ester with various anilines in the presence of
base gave the final analogues 5.7
The corresponding N-linked amide analogues 10 and 11
were prepared according to Scheme 2. The piperidine
alcohol 7, derived from readily available 6, was convert-
ed to the primary amine 8 in two steps.8 The bromo sub-
stituent was exchanged to a 3-cyanophenyl group
through Suzuki coupling; the amine 9 was then alkyl-
ated with a variety of 2-bromoacetamides, which are
easily prepared by treatment of 2-bromoacetyl bromide
with various anilines.9 Finally, the N-Me-linked ana-
logues 11 were obtained by reductive alkylation of 10
with formaldehyde.
Scheme 3 shows the synthesis of the O-linked analogues
15. Commercially available 4-(4-bromophenyl)-4-pipe-
ridinol was converted to 13 by treatment with Boc2O
and subsequent Suzuki coupling with 3-cyanophenylbo-
ronic acid. Treatment of 13 with potassium hydride
followed by 2-bromoacetic acid gave an acid intermedi-
ate,10 which in turn was coupled with various anilines in
the presence of DCC to afford the O-linked amides 14.
Deprotection of N-Boc followed by conventional
derivatization of the piperidine NH gave final
targets 15.
Br
Br
Br
OH
OH
NH2
a
b,c
In conjunction with the SAR of the right side amides, a
series of biaryls of the left side was explored by parallel
synthesis utilizing intermediate 8 (Scheme 4).
d
N
H
N
N
Finally, by altering the sequence of reactions used previ-
ously, we could explore the SAR of the piperidine
N-substituent as shown in 21 (Scheme 5).
6
7
8
CN
CN
Y
O
X
NH2
L
Br
F
N
e
O
H
H
N
NH2
N
Cl
N
N
a, b
10 L = NH
H
f
N
N
9
11 L = NMe
Scheme 2. Reagents and conditions: (a) cyclopentanone, NaB-
H(OAc)3, DCM, room temperature, 82%; (b) concd H2SO4, MeCN,
60%; (c) 2 N HCl, reflux, 98%; (d) 3-cyanophenylboronic acid,
Pd(PPh3)4, 2 N Na2CO3, toluene–MeOH (1:1), reflux, 85%; (e) 2-
bromoacetamides, K2CO3, MeCN, 60 °C, 30–50%; (f) 37% aqueous
HCHO, NaBH(OAc)3, DCM.
8
16
Scheme 4. Reagents and conditions: (a) 3-chloro-4-fluorophenyl
2-bromoacetamide, K2CO3, 31%; (b) appropriate boronic acids,
Pd(PPh3)4, 2 N Na2CO3, toluene–MeOH (1:1), reflux.

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W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3668–3673
Table 1. SAR of substituents on the amide phenyl ringa,b
CN
Br
CO2Me
CO2Me
CN
a, b
c, d
N
H
N
N
O
Bn
Bn
17
X
L
18
19
N
H
Br
F
F
N
O
g, h, i
e, f
N
H
N
20
Boc
Compound
L
X
MCH Ki (nM)
CN
5a
5b
CH2
CH2
CH2
CH2
CH2
NH
NH
NH
NH
NH
NMe
NMe
NMe
NMe
NMe
O
3,5-Cl2
42
128
30
40
13
3
3-CF3-4-Cl
3-Cl-4-F
3-5-F2
F
F
O
5c
5d
N
H
5e
3,4-F2
3,5-Cl2
10a
10b
10c
10e
10f
11a
11b
11c
11d
11e
15a
15b
N
R
3-CF3-4-Cl
3-CF3-4-F
3-Cl-4-F
3-5-F2
23
16
3
21
Scheme 5. Reagents and conditions: (a) DIBAL, DCM, 0 °C to room
temperature, 48%; (b) (MeO)2P(O)CH2CO2Me, NaH, THF, 85%; (c)
Pd(OH)2/C, HCO2NH4, MeOH, 60 °C, 97%; (d) 3,5-dibromohydan-
toin, MeSO3H, DCM, 54%; (e) (Boc)2O, MeOH, 70%; (f) anilines,
2 equiv n-BuLi, THF; (g) 3-cyanophenylboronic acid, Pd(PPh3)4, 2 N
Na2CO3, toluene–MeOH (1:1), reflux, 60%; (h) TFA–DCM (1:1); (i)
reductive alkylation or other derivatization.
3
3,5-Cl2
9
3-CF3-4-Cl
3-CF3-4-F
3-Cl-4-F
3-5-F2
16
18
4
6
3,5-Cl2
3-CF3-4-Cl
2
49
O
a Inhibition of MCH-mediated Ca2+ influx into cells expressing
hMCH-R1 via FLIPR assay. Affinity at h-MCH-R2 > 3 lM for all
compounds.
The compounds described above were evaluated in a
radioligand binding assay.11 As revealed in Table 1,
within each series of same linker (L), electron-withdraw-
ing groups (either 3,4- or 3,5-disubstituents) on the
amide phenyl ring showed more or less similar potency.
In terms of the effect of various linkers, the order is as
follows: O > NH = NMe > CH2 (based on our full data
set), reflecting their decreased electronegativity and
therefore lower acidity of the attached amide N–H moi-
ety. These results indicated that the amide N–H moiety
serves as a hydrogen-bond donor when binding to the
MCH R1 receptor.12
b Mean values (n = 3). h-MCH-R1.
Table 2. SAR of substituents on the biaryl phenyl ringa
X
F
O
H
N
N
Cl
H
N
In terms of the SAR of the biaryl part, more than 50
compounds were prepared, and selected data are
reported in Table 2. It is clear that analogues with 3-sub-
stituents are more active than those bearing 2- or 4-sub-
stituents. Within the 3-substituted series, the 3-cyano
group remained the best, consistent with earlier findings
for the related urea series as for compound 5c
(Ki = 30 nM).5d
Compound
X
MCH Ki (nM)
16a
16b
16c
16d
16e
16f
16g
16h
16i
H
241
523
3247
1428
180
281
63
4-CN
4-CF3
4-Cl
4-F
3-CF3
3-Cl
The piperidine N-substituent effects can be seen in
Table 3, exemplified by the C-linked amide analogues.
Small alkyl groups are well tolerated, although cyclo-
propylmethyl is the best (21c). Interestingly, some ana-
logues bearing a nonbasic piperidine moiety are also
quite potent (21f and 21i).
3-OCF3
3-OMe
3-F
76
77
16j
99
21
16k
16l
3-CHO
2-Cl
2-F
690
178
2162
786
141
52
16m
16n
16o
16p
16q
16r
3,4-Cl2
3,5-Cl2
3-5-F2
2,5-Cl2
2,6-Cl2
In order to further improve the potency, a homologated
series was prepared (Scheme 6). Condensation of 4-
bromophenylacetonitrile with 4-piperidinone gave com-
pound 22. Sequential reduction of the olefin and then
the nitrile group using DIBAL afforded an aldehyde
1667
a See Table 1 notes.

W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3668–3673
Table 3. SAR of substituents on the piperidine nitrogena Table 4. SAR of homologous amide analoguesa
CN
CN
3671
F
F
F
F
O
O
N
N
H
H
N
R
N
R
Compound
R
MCH Ki (nM)
Compound
R
MCH Ki (nM)
21a
21b
21c
21d
21e
21f
21g
21h
21i
Boc
H
51
25
26a
26b
26c
Bn
H
MeSO2
1
1.2
Cyclopropylmethyl
Cyclobutyl
Cyclopentyl
MeCO
8
19
26
13
61
a See Table 1 notes.
MeSO2
EtOCO
190
249
45
As shown in Table 4, the homologated compounds are
more potent than the 4,4-disubstituted analogues.
Et2NCO
Et2NSO2
21j
193
a See Table 1 notes.
Imidazole and benzimidazole have been used as isosteric
replacements for an amide moiety to circumvent the po-
tential instability of amide bond.14 Thus, several benz-
imidazole analogues were prepared (Scheme 7). The
ester intermediate 25 was reduced to an aldehyde inter-
mediate, which was treated with diamines to form benz-
imidazole compounds 27.15 Suzuki coupling gave
compounds 28a–28d.
Br
Br
CN
CN
O
Br
+
CN
N
N
N
Bn
Bn
22
Bn
The NH-linked benzimidazole analogues 33a–d were
synthesized according to Scheme 8. The known ketone
2916 was first converted to the amine 30 by reductive
amination. After Suzuki reaction, the resulting amine
was treated with the benzimidazole compound 3217 to
give compound 33a. Deprotection revealed the NH moi-
ety, and further reductive alkylation gave compounds
33c and 33d.
23
Br
Br
CO2Me
CO2Me
f, g
e
c, d
N
N
Bn
Bn
25
24
CN
As can be seen from Tables 5 and 6, the benzimidazole
analogues showed quite good potency, although not as
F
O
26a R = Bn
26b R = H
h
N
F
X
Br
Br
a, b
H
N
i
CO2Me
26c R = MeSO2
c
N
N
R
H
N
N
Scheme 6. Reagents and conditions: (a) EtONa, EtOH, reflux, 56%;
(b) 1.2 equiv DIBAL, DCM, À78 °C, 65%; (c) 1.5 equiv DIBAL,
DCM, À50 °C to room temperature, 85%; (d) (MeO)2P(O)CH2-
CO2Me, NaH, THF, 50%; (e) H2, Rh/Al2O3, room temperature,
95%; (f) Pd(PPh3)4, 3-cyanophenylboronic acid, 2 N Na2CO3, toluene–
MeOH (1:1), reflux, 65%; (g) 3,4-difluorophenylaniline, Me3Al, tolu-
ene, reflux, 55%; (h) 1—ClCO2C(Cl)HMe, DCE, reflux; 2—MeOH,
reflux; (i) MeSO2Cl, TEA, DCM.
Bn
Bn
25
27
CN
X
28a X = 3-Cl, 4-F
28b X = 4,6-Cl,Cl
28c X = 3,5-Cl,Cl
28d X = 4-F, 5-CF3
N
N
H
intermediate.13 Horner–Emmons elongation followed
by selective hydrogenation provided the ester intermedi-
ate 25, which was coupled with 3-cyanophenyl boronic
acid under Suzuki conditions to give compound 26a.
Deprotection revealed the piperidine NH, and sulfony-
lation gave compound 26c.
N
Bn
Scheme 7. Reagents and conditions: (a) DIBAL, DCM, À78 °C, 95%;
(b) substituted 1,2-phenyldiamines, Na2S2O5, DMA, 100 °C, 33%; (c)
Pd(PPh3)4, 2 N Na2CO3, 3-cyanophenylboronic acid, toluene–MeOH
(1:1), reflux, 61%.

3672
W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3668–3673
CN
potent as their corresponding amide analogues. These
results are very encouraging and will be exploited in fu-
ture designs.18
Br
Br
O
NH2
NH2
In summary, we have successfully replaced the urea moi-
ety of our lead structure, 1, with isosteric amide and
benzimidazole groups to generate novel MCH antago-
nists. Extensive SAR exploration with various linkers
as well as the substituent effects led to the discovery of
many potent and selective MCH-R1 antagonists, such
as compounds 10a–f, 11a–e, and 26a–b.
b
a
N
N
N
Boc
29
Boc
Boc
31
30
CN
F
F
Cl
N
N
Cl
N
H
H
Acknowledgments
Cl
32
N
N
H
c
We thank Dr. Michael P. Graziano, Dr. Margaret Van
Heek, and Dr. John W. Clader for their support and
helpful discussions. We thank Dr. Briendra Pramanik’s
group and Dr. Tse-Ming Chan’s group for analytical
support.
33a R = Boc
33b R = H
33c-d
d
N
R
e
Scheme 8. Reagents and condition: (a) NH4OAc, NaCNBH3, MeOH,
room temperature, 90%; (b) 3-cyanophenylboronic acid, Pd(PPh3)4,
2 N Na2CO3, toluene–MeOH (1:1), reflux, 57%; (c) K2CO3, MeCN,
room temperature, 60%; (d) TFA–DCM (1:1), 100%; (e) cyclopropyl-
carboxyaldehyde or cyclopentanone, NaBH(OAc)3, DCM.
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X
N
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H
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Bn
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MCH Ki (nM)
28a
28b
28c
28d
3-Cl, 4-F
4,6-Cl,Cl
3,5-Cl,Cl
4-F,5-CF3
46
53
26
92
a See Table 1 notes.
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33b
33c
33d
Boc
H
48
20
39
14
Cyclopentyl
Cyclopropylmethyl
a See Table 1 notes.

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H. WO 2002/051809.
17. Burnett, D. A.; Wu, W.-L.; Sasikumar, T. K.; Domalski,
M. S. WO 2004/002987.
10. Hayashita, T.; Goo, M. J.; Lee, J. C.; Kim, J. S.;
Krzykawski, J.; Bartsch, R. A. Anal. Chem. 1990, 62,
2283.
11. Membranes from CHO cells expressing MCH-
R1(0.1 mg/mL) were incubated with SPA beads (1 mg/
mL) in a binding buffer (25 mM HEPES, 10 mM MgCl2,
5 mM MnCl2, and 0.1% BSA, pH 7.4) for 5 min on ice
forming a bead/membrane mixture. The bead/membrane
mixture was centrifuged (4 min at 300g) and resuspend-
ed in the binding buffer. The bead/ membrane mixture
was then pelleted again (4 min at 300g), resuspended in
the binding buffer, and set aside. Binding buffer (50 lL/
well) containing vehicle alone (2% DMSO), various
compound concentrations, or 4 lM MCH (for nonspe-
cific binding) was added to a 96-well plate. Subsequent-
ly, 50 lL of binding buffer containing 0.5 nM [125I]MCH
was added to each well of the 96-well plate. Finally,
100 lL of the bead/membrane mixture was added to
each well of the 96-well plate. The binding reactions
were incubated for 2–4 h at room temperature. Binding
of
detected using a TOPCOUNT (Packard). Ki values were
[
125I]MCH to the bead/membrane mixture was
18. See the following paper. Wu, W.-L.; et al. Bioorg. Med.
Chem. Lett. 2006.
19. Sasikumar, T. K.; Burnett, D. A. US 7,030,113.
determined using nonlinear regression analysis and