Discovery of novel spiro-piperidine derivatives as highly potent and selective melanin-concentrating hormone 1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2009.04.016

Optimization of high-throughput screening hit 1a led to the identification of a novel spiro-piperidine class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Compound 3c was identified as a highly potent and selective MCH-1R antagonist, which has an IC₅₀ value of 0.09 nM at hMCH-1R. The synthesis and structure-activity relationships of the novel spiro-piperidine MCH-1R antagonists are described.

Full text of DOI:10.1016/j.bmcl.2009.04.016

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3072–3077
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of novel spiro-piperidine derivatives as highly potent
and selective melanin-concentrating hormone 1 receptor antagonists
a
a
a
a
Takao Suzuki a, , Minoru Moriya , Toshihiro Sakamoto , Takuya Suga , Hiroyuki Kishino ,
*
Hidekazu Takahashi a, Makoto Ishikawa a, Keita Nagai a, Yumiko Imai a, Etsuko Sekino a, Masahiko Ito b,
Hisashi Iwaasa b, Akane Ishihara c, Shigeru Tokita b, Akio Kanatani b, Nagaaki Sato a, , Takehiro Fukami
a
*
a Department of Medicinal Chemistry, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan
b Department of Metabolic Disorder, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan
c Department of Pharmacology, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Optimization of high-throughput screening hit 1a led to the identification of a novel spiro-piperidine
class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Compound 3c was identified
as a highly potent and selective MCH-1R antagonist, which has an IC50 value of 0.09 nM at hMCH-1R. The
synthesis and structure–activity relationships of the novel spiro-piperidine MCH-1R antagonists are
described.
Received 16 January 2009
Revised 1 April 2009
Accepted 3 April 2009
Available online 9 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Melanin-concentrating hormone
MCH
MCH-1R antagonists
Obesity
Melanin-concentrating hormone (MCH) is a cyclic 19-amino
acid polypeptide that is expressed predominantly in the lateral
hypothalamus (LH). The LH is a region of the brain involved in
the regulation of feeding, the neuroendocrine axis, and thermogen-
esis. Several lines of investigation suggest that MCH is an impor-
tant mediator of energy homeostasis. Mice lacking prepro-MCH
are lean, hypophagic, and have an elevated metabolic rate.1 Con-
versely, prepro-MCH overexpression in mice results in a greater
susceptibility to obesity.2 Furthermore, overexpression of MCH
mRNA has been found in obese rodents, such as ob/ob, db/db,
and Ay/a mice.3–5 Exogenous administration of MCH stimulates
food intake,3,6 and chronic ICV infusion of the MCH7,8 or a related
MCH-1R agonist9 produces obesity with hyperphagia. Even when
pair-feeding is employed to prevent hyperphagia, ICV infusion of
MCH still produces anabolic changes.10 The effects of MCH are
mediated through G protein-coupled receptors located in the
CNS, and thus far two receptor subtypes, MCH-1R and MCH-2R,
have been identified.11–14 Since rodents possess only MCH-1R, all
pharmacological effects of MCH in rodents are likely mediated
via MCH-1R.15 Recently, peptide and non-peptidic MCH-1R antag-
onists have been developed; both antagonists produced anti-obese
effects in diet-induced obese rats.9,16,17 Collectively, these data
indicate that MCH-1R is an important regulator of energy homeo-
stasis, and suggest that it may play an important role in the devel-
opment of obesity. Hence, MCH antagonists could be effective
therapeutic agents for the treatment of obesity. Screening of Merck
sample collections against human MCH-1R (hMCH-1R) resulted in
the identification of a spiro-piperidine class of lead 1a, which has
an IC50 value of 42 nM. Subsequent optimization efforts were
centered on improvement of the MCH-1R activity and reduction
of human a1A-adrenoceptor (ha1A) activity to identify the potent
and selective derivative 3c. The synthesis and structure–activity
relationships (SAR) of this novel spiro-piperidine class of MCH-1R
antagonists are described.
The synthesis of compounds described herein is outlined in
Schemes 1–3. Compounds 1a–g were prepared as shown in
Scheme 1. Substituted anilines 4 were coupled with 4-meth-
ylphenylboronic acid or phenylboronic acid in the presence of cop-
per acetate (II) and triethylamine to give diaryl amines 5a–e,
which were reacted with triphosgene followed by amines 8a, 9a,
or 9b to give compounds 1a–g. Amines 8a, 9a, and 9b were derived
from N-(3-bromopropyl)-phthalimide 6 using standard procedures
as depicted in Scheme 1.18,19 Compounds 2a–g were synthesized
as outlined in Scheme 2. 3,4-Difluorobenzaldehyde (10) was con-
verted to the corresponding cyanohydrin trimethylsilyl ether 11.
The trimethylsilyloxy group of 11 was displaced by a phenyl group
followed by hydrolysis of the cyano group to give 13a. Ester 14 was
brominated to give 15. The bromo group of 15 was displaced by the
desired azoles and pyrrolidine followed by hydrolysis of the ester
* Corresponding authors. Tel.: +81 29 877 2218; fax: + 81 29 877 2029 (T.S.).
E-mail address: takao_suzuki@merck.com (T. Suzuki).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.016

T. Suzuki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3072–3077
3073
4
R1
O
R2
4
R1
4
R1
c
b
a
3
N
N
N
R3
3
3
8a, 9a, or 9b
NH2
N
H
X
5a: R1 = 4-Me, R2 = Me
4a: R1 = 4-Me
4b: R1 = 4-F
4c: R1 = 3-F
R2
5b: R1 = 4-F, R2 = Me
5c: R1 = 3-F, R2 = Me
5d: R1 = 3,4-diF, R2 = Me
5e: R1 = 3,4-diF, R2 = H
1a−g
4d: R1 = 3,4-diF
O
e
d
HN
H2N
N
HN
N
N
Br
O
X
X
X
6
7a: X = CH2
7b: X = O
8a: X = CH2
8b: X = O
9a: X = CH2
9b: X = O
Scheme 1. Preparation of urea derivatives 1a–g. Reagents and conditions: (a) Cu(OAc)2, Et3N, 4-methylphenylboronic acid or phenylboronic acid, CH2Cl2, rt, 17 h, 48–90%; (b)
triphosgene, Et3N, CHCl3, 0 °C? rt, 2–17 h, 62–99%; (c) Et3N, ClCH2CH2Cl, 60–100 °C, 2–3 h, 50–85%; (d) (i) K2CO3, KI, DMF, 80 °C, 17 h, 46–95%, (ii) H2NNH2ꢀH2O, EtOH, reflux,
3 h, 99%; (e) (i) ClCO2Et, Et3N, CHCl3, rt, 17 h, 99%, (ii) LiAlH4, 1,4-dioxane, reflux, 17 h, 98–99%.
F
F
F
F
F
F
F
F
a
c
b
CN
CN
CO2H
CHO
OTMS
10
14
11
12
13a
F
F
F
F
F
F
F
e, f, or g
d
h
CO2Me
CO2Me
CO2Me
CO2H
F
Br
R2
R2
16b: R2 = pyrazole
13b: R2 = pyrazole
15
16c: R2 = 1,2,3-triazole
16d: R2 = 1,2,4-triazole
16e: R2 = tetrazole
13c: R2 = 1,2,3-triazole
13d: R2 = 1,2,4-triazole
13e: R2 = tetrazole
16f: R2 = pyrrolidine
13f: R2 = pyrrolidine
F
F
F
F
F
F
F
F
j
k
i
CN
CO2H
CO2H
CHO
NH2
NH2
N
O
10
17
18
13g
F
F
F
F
O
N
l
CO2H
N
R2
R2
O
2a−g
13a−g
Scheme 2. Synthesis of compounds 2a–g. Reagents and conditions: (a) TMSCN, ZnCl2, CH2Cl2, rt, 4 h, 93%; (b) benzene, conc. H2SO4, 0 °C, 1.5 h, 15%; (c) conc. H2SO4, H2O,
100 °C, 17 h, 66%; (d) NBS, HBr, CCl4, reflux, 17 h, 98%; (e) pyrazole, n-BuLi, cat. 2,20-bipyridyl, THF, ꢁ30 °C? rt, 20 h, 60%; (f) 1,2,3-triazole or 1,2,4-triazole, NaH, THF, 0 °C?
rt, 17 h, 34–46%; (g) tetrazole or pyrrolidine, K2CO3, DMF–THF, rt, 3 h, 40–78%; (h) 4 N NaOH aq, MeOH, rt? 50 °C, 2–17 h, 60–97%; (i) NH3 aq, MeOH, 0 °C, 3 h, and then
TMSCN, rt, 17 h, 94% over two steps; (j) 40% H2SO4 aq, 90 °C, 17 h, 99%; (k) (i) 4-chlorobutanoyl chloride, Et3N, 1,4-dioxane-H2O, 0 °C, 30 min, 60%, (ii) tert-BuOK, THF, 0 °C, 2 h,
85%; (l) amine 9b, EDCIꢀHCl, HOBtꢀH2O, NaHCO3, DMF, rt, 17 h, 17–98%.

3074
T. Suzuki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3072–3077
a or b
H2N
OH
OH
OH
BocN
R3
OH
20a: R3 = Me
19
21
20b: R3 = Et
c
BocN
H
BocN
R3
20c: R3 = CH2CH2F
OH
e
d
N
BocN
BocN
R3
N
F
R3
N
HN
F
O
20a: R3 = Me
20b: R3 = Et
20c: R3 = CH2CH2F
22a: R3 = Me
22b: R3 = Et
22c: R3 = CH2CH2F
O
23
F
O
f
N
3a−c
F
N
R3
N
F
N
N
O
24a: R3 = Me
24b: R3 = Et
24c: R3 = CH2CH2F
Scheme 3. Preparation of spiro-fluorofuropyridine derivatives 3a–c. Reagents and conditions: (a) (i) HCO2Et, THF, rt, 17 h, (ii) LiAlH4, 0 ? 60 °C, 3 h, (iii) Boc2O, 1 N NaOH aq,
THF, rt, 2 h, 67% over three steps; (b) (i) Ac2O, THF, rt, 17 h, (ii) LiAlH4, 0?70 °C, 2 h, (iii) Boc2O, 1 N NaOH aq, THF, rt, 2 h, 85% over three steps; (c) (i) TBDMSCl, imidazole,
DMF, rt, 2.5 h, 99%, (ii) 2-fluoroethyltosylate, NaH, DMF, rt, 60 h, 67%, (iii) TBAF, THF, 0 °C?rt, 1 h, 92%; (d) (i) MsCl, N,N-diisopropylethylamine, EtOAc, 0 °C, 30 min, 99%, (ii)
23, K2CO3, KI, DMF, 80 °C, 17 h, 43–81%; (e) (i) 4 N HCl–EtOAc, 0 °C, 30 min, 99%, (ii) 13b, EDCIꢀHCl, HOBtꢀH2O, NaHCO3, DMF, rt, 17 h, 28–76%; (f) chiral resolution by HPLC
(CHIRALCEL OD, hexanes/EtOH = 8/2).
group to afford carboxylic acids 13b–f. Treatment of aldehyde 10
with aqueous ammonia followed by trimethylsilanecarbonitrile
furnished 17, which was subjected to acidic conditions for hydro-
lysis of the nitrile group to give carboxylic acid 18. The amino
group of 18 was coupled with 4-chlorobutanoyl chloride followed
by treatment with potassium tert-butoxide to effect intramolecular
pounds 24a–c were obtained by deprotection of the Boc group of
22a–c followed by coupling of the resulting amino group with
the carboxylic acid 13b. The racemates 24a, 24b, and 24c were re-
solved by HPLC to give the corresponding active enantiomers 3a,
3b, and 3c, respectively.22
High-throughput screening of Merck sample collections against
hMCH-1R led to the identification of 1a, which has an IC50 value of
42 nM. Compound 1a was found to have moderate activity for
cyclization to afford 13g. The
a-substituted phenyl acetic acids
13a–g were coupled with amine 9b to give the target compounds
2a–g. The preparation of compounds 3a–c is outlined in Scheme 3.
The 3-alkylaminopropanols 20a–c protected by a tert-butoxylcar-
bonyl (Boc) group were prepared by standard procedures as shown
in Scheme 3.20 The hydroxyl group of 20a–c were mesylated and
displaced by the piperidine analogue 2321 to give 22a–c. Com-
ha1A (IC50 = 540 nM) (Fig. 1). Modification of 1a was initiated to
increase MCH-1R activity and reduce h 1A activity (Table 1). The
a
4- and 3-fluorophenyl derivatives 1b and 1c were equipotent to
1a. The 3,4-difluorophenyl derivative 1d was found to be more po-
tent than 1a. The potency was further improved by N-methylation
as in 1e (IC50 = 2.1 nM), a 20-fold improvement over 1a. The intro-
duction of an oxygen atom to the spiro-indane portion, as in 1f, re-
O
sulted in reduced ha1A activity while retaining MCH-1R activity.
Removal of a 4-methyl group on the distal N-phenyl group (1g)
was found to be detrimental for MCH-1R activity (IC50 = 19 nM).
Conversion of the urea linkage of 1g to the amide led to the iden-
tification of the potent amide derivative 2a, which shows an IC50
value of 1.0 nM at hMCH-1R (Table 2). The R2 substituent of 2a
was further explored. The pyrazole and triazole derivatives 2bꢁd
N
N
N
H
1a
displayed good activities for hMCH-1R and decreased ha1A activ-
ities. The tetrazole derivative 2e exhibited decreased activity. The
pyrrolidine derivative 2f showed a significant loss of potency;
however, the corresponding oxo-derivative 2g was surprisingly po-
tent, with an IC50 value of 2.7 nM at hMCH-1R. Permeability-glyco-
hMCH-1R binding IC50 : 42 nM
1A binding IC50 : 540 nM
h
α
Figure 1. Structure of the lead compound 1a.

T. Suzuki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3072–3077
3075
Table 1
Human MCH-1R and a1A binding activity of urea derivatives 1a–ga
4
R1
O
3
N
N
N
R3
X
R2
Compound
R1
R2
R3
X
hMCH-1Rb (IC50, nM)
h
a
1Ac (IC50, nM)
1a
1b
1c
1d
1e
1f
4-Methyl
4-Fluoro
3-Fluoro
3,4-Difluoro
3,4-Difluoro
3,4-Difluoro
3,4-Difluoro
Me
Me
Me
Me
Me
Me
H
H
H
H
H
Me
Me
Me
CH2
CH2
CH2
CH2
CH2
O
42
54
42
9.6
2.1
2.1
19
540
340
490
350
230
470
920
1g
O
a
The values are the means of two experiments.
Inhibition of [125I]MCH binding to hMCH-1R in CHO cells.
b
c
Inhibition of [3H]prazosin binding to human 1A-adrenoceptor in LMtkꢁ cells.
a
Table 2
Human MCH-1R and a1A binding activity and P-gp susceptibility of compounds 2a–ga
F
O
F
N
N
R2
O
P-gp Susceptibilitye,f transcellular transport ratio (B-to-A)/(A-to-B)
Compound
R2
hMCH-1Rb,c (IC50, nM)
ha
1Ab,d (IC50, nM)
MDR1
mdr1a
2a
2b
2c
2d
2e
2f
1.0
1.7
1.9
2.9
9.9
125
2.7
600
1.4
3.7
N
N
3600
1920
1910
1910
1160
1000
1.8
4.1
9.2
NT
4.9
4.9
3.4
NT
N
N
N
N
N
N
N
N
N
N
N
NT
NT
N
2g
24.8
32.9
O
a
Compounds 2a–g were tested as racemates.
b
c
d
e
f
The values are the means of two experiments.
Inhibition of [125I]MCH binding to hMCH-1R in CHO cells.
Inhibition of [3H]prazosin binding to human 1A-adrenoceptor in LMtkꢁ cells.
a
Transcellular transport ratio ((B-to-A)/(A-to-B)) in human MDR1- and mouse mdr1a-transfected LLC-PK1 cell line.
NT, not tested.

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T. Suzuki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3072–3077
Table 3
Human MCH-1R and a1A binding activity and P-gp susceptibility of compounds 24a and 3a–c
F
O
N
F
N
N
F
N
R3
N
O
Compound
R3
hMCH-1Ra,b (IC50, nM)
ha
1Aa,c (IC50, nM)
P-gp Susceptibilityd transcellular transport ratio (B-to-A)/(A-to-B)
MDR1
mdr1a
24a (racemate)
1.3
>10,000
>10,000
>10,000
>10,000
3.3
5.5
2.2
2.7
6.8
3a (active isomer of 24a)e
3b (active isomer of 24b)e
0.46
0.15
0.09
16.9
1.5
3c (active isomer of 24c)e
3.7
F
a
The values are the means of two experiments.
Inhibition of [125I]MCH binding to hMCH-1R in CHO.
b
c
Inhibition of [3H]prazosin binding to human 1A-adrenoceptor in LMtk– cells.
a
d
e
Transcellular transport ratio ((B-to-A)/(A-to-B)) in human MDR1- and mouse mdr1a-transfected LLC-PK1 cell line.
Single isomer. The absolute configuration was not determined.
protein (P-gp) susceptibility of potent derivatives was evaluated
by transcellular transport ratios obtained from human MDR1-
and mouse mdr1a-transfected porcine renal epithelial (LLC-PK1)
cell monolayers.23 P-gp is expressed in the blood-brain barrier
and excludes its substrates from the brain. In this P-gp transport
assay, a compound with a B-to-A/A-to-B ratio above 3 is consid-
ered to be a P-gp substrate. All test compounds were human
and mouse P-gp substrates except for 2a and 2b in human P-
gp; compounds 2a and 2b were found not to be a human P-gp
substrate (Table 2). In addition, 2b showed the best selectivity
References and notes
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isobenzofurane structure of 2b with the spiro-fluorofuropyridine
structure as in 24a is very effective to reduce the ha1A activity
(Table 3) while retaining MCH-1R activity. The racemate 24a
was resolved, and the active isomer 3a24 was found to have a
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tency enhancement was achieved by modification of the N-alkyl
group (R3). The ethyl derivative 3b (active isomer)24 displayed
an IC50 value of 0.15 nM. Compound 3b was further substituted
with fluorine as in 3c,24,25 which has an IC50 value of 0.09 nM
at the MCH-1R. This highly potent compound 3c showed good
selectivity over MCH-2R (IC50 > 1
lM) and a panel of 171 diverse
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l
M for all the binding sites
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tested) and not a human P-gp substrate.
In summary, the highly potent and selective MCH-1R antagonist
3c was identified by structural optimization of high-throughput
screening hit 1a. Evaluation of 3c to assess its potential for clinical
development is ongoing. Compound 3c is also an attractive com-
pound as a PET tracer due to its excellent potency, hydrophilicity
(log D7.4 = 2.3), and possible labeling with 18F.
Acknowledgments
We would like to thank Dr. Norihiro Takenaga for performing
the P-gp assays and Atsushi Hirano for measuring the log D values.

T. Suzuki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3072–3077
3077
16. Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marzabadi, M. R.; DeLeon, J.; Lagu,
B.; Heurich, R.; Lichtblau, H.; Shaposhnik, Z.; Daniewska, I.; Blackburn, T. P.;
Branchek, T. A.; Gerald, C.; Vaysse, P. J.; Forray, C. Nat. Med. 2002, 8, 825.
17. Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marzabadi, M. R.; DeLeon, J.;
Heurich, R.; Lichtblau, H.; Shaposhnik, Z.; Daniewska, I.; Blackburn, T. P.;
Branchek, T. A.; Gerald, C.; Vaysse, P. J.; Forray, C. Nat. Med. 2002, 9, 1039.
18. For the preparation of compound 6, see: Cesari, N.; Biancalani, C.; Vergelli, C.;
Piaz, D. V.; Graziano, A.; Biagini, P.; Ghelardini, C.; Galeotti, N.; Giovannoni, P.
M. J. Med. Chem. 2006, 49, 7826.
19. For the preparation of compound 7a, see: (a) Chambers, M. S.; Baker, R.;
Billington, D. C.; Knight, A. K.; Middlemiss, D. N.; Wong, E. H. F. J. Med. Chem.
1992, 35, 2033; For the preparation of compound 7b, see: (b) Marxer, A.;
Rodriguez, H. R.; McKenna, J. M.; Tsai, H. M. J. Org. Chem. 1975, 40, 1427.
20. Yokoyama, H.; Ejiri, H.; Miyazawa, M.; Yamaguchi, S.; Hirai, Y. Tetrahedron:
Asymmetry 2007, 18, 852.
22. Compounds 24a–c were resolved by CHIRALCEL OD, eluting with hexanes/
EtOH = 8/2. Compound 3a was obtained as the second-eluted enantiomer by
the HPLC resolution of 24a. Compounds 3b and 3c were obtained as the first-
eluted enantiomers by the HPLC resolution of 24b and 24c, respectively.
23. (a) Yamazaki, M.; Neway, W. E.; Ohe, T.; Chen, I.-W.; Rowe, J. F.; Hochman, J. H.;
Chiba, M.; Lin, J. H. J. Pharmacol. Exp. Ther. 2001, 296, 723; (b) Ohe, T.; Sato, M.;
Tanaka, S.; Fujino, N.; Hata, M.; Shibata, Y.; Kanatani, A.; Fukami, T.; Yamazaki,
M.; Chiba, M.; Ishii, Y. Drug Metab. Dispos. 2003, 31, 1251.
24. The IC50 values for the corresponding enantiomers of 3a, 3b and 3c are 9.1, 1.1,
and 22 nM, respectively.
25. Data of 3c: 1H NMR (400 MHz, CDCl3) d 1.65–2.12 (m, 6H), 2.34–2.52 (m, 4H),
2.72–2.97 (m, 2H), 3.32–3.42 (m, 1H), 3.45–3.67 (m, 2H), 3.70–3.93 (m, 1H),
4.46–4.78 (m, 2H), 5.04 (s, 2H), 6.30 (t, 3/4H, J = 2.0 Hz), 6.32 (t, 1/4H,
J = 2.0 Hz), 6.56 (s, 1/4H), 6.77 (s, 1H), 6.90 (s, 3/4H), 7.02–7.12 (m, 1H), 7.13–
7.24 (m, 2H), 7.45 (d, 3/4H, J = 2.4 Hz), 7.50 (d, 1/4H, J = 2.4 Hz), 7.54 (d, 3/4H,
J = 2.0 Hz), 7.56 (d, 1/4H, J = 2.0 Hz), 7.96 (s, 1/4H), 7.98 (s, 3/4H); MS (ESI) m/z
532.3 [M+H]+; HPLC purity (99.6%).
21. Moriya, M.; Sakamoto, T.; Ishikawa, M.; Kanatani, A.; Fukami, T. WO 069798,
2004.