2-Aminoquinoline melanin-concentrating hormone (MCH)1R antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.08.006

A series of 2-aminoquinoline compounds was prepared and evaluated in MCH1R binding and functional antagonist assays. Small dialkyl, methylalkyl, methylcycloalkyl, and cyclic amines were tolerated at the quinoline 2-position. The in vivo efficacy of compound 12 was explored and compared to that of a related inactive analog to determine their effects on food intake and body weight in rodents.

Full text of DOI:10.1016/j.bmcl.2006.08.006

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5270–5274
2-Aminoquinoline melanin-concentrating hormone
(MCH)1R antagonists
Jinlong Jiang,a Myle Hoang,a Jonathan R. Young, Danny Chaung,a Ronsar Eid,a
Cherilyn Turner,a Peter Lin,a Xinchun Tong,a Junying Wang,a Carina Tan,b
Scott Feighner,b Oksana Palyha,b Donna L. Hreniuk,b Jie Pan,b Andreas W. Sailer,b,à
Douglas J. MacNeil,b Andrew Howard,b Lauren Shearman,c Sloan Stribling,c
Ramon Camacho,c Alison Strack,c Lex H. T. Van der Ploeg,b,
Mark T. Gouleta, and Robert J. DeVitaa,*
aDepartment of Medicinal Chemistry, PO Box 2000, Rahway, NJ 07065-0900, USA
bDepartment of Endocrinology and Metabolism, PO Box 2000, Rahway, NJ 07065-0900, USA
cDepartment of Pharmacology, PO Box 2000, Rahway, NJ 07065-0900, USA
Received 15 May 2006; revised 31 July 2006; accepted 1 August 2006
Available online 17 August 2006
Abstract—A series of 2-aminoquinoline compounds was prepared and evaluated in MCH1R binding and functional antagonist
assays. Small dialkyl, methylalkyl, methylcycloalkyl, and cyclic amines were tolerated at the quinoline 2-position. The in vivo effi-
cacy of compound 12 was explored and compared to that of a related inactive analog to determine their effects on food intake and
body weight in rodents.
Ó 2006 Elsevier Ltd. All rights reserved.
Melanin-concentrating hormone (MCH) is a cyclic pep-
tide present in the lateral hypothalamus that is believed
to be involved in energy homeostasis and feeding behav-
ior.1 The phenotypes of MCH KO2 and MCH1R KO3
mice along with rodent pharmacological studies in vivo
using MCH1R agonists4 and antagonists5 have
increased interest in MCH1R as an important central
nervous system G-protein coupled receptor (GPCR)
drug target. These biology and pharmacology results
generated great interest in the development of MCH1R
antagonists for the possible treatment of obesity6 and
depression or anxiety.7 Many non-peptidyl MCH1R
antagonists have appeared in the patent literature in re-
cent years8 in an effort to obtain compounds viable for
clinical validation of MCH1R antagonism as a thera-
peutic target for human health.
In the previous letter, we described our initial work in
the area of 4-aminoquinoline MCH1R antagonists.9
Significant improvements of the original lead were made
by modifications of the quinoline 2- and 6-positions to
identify MCH1R antagonists exemplified by compound
1 (Fig. 1). However, we were unable to obtain further
improvements on the series by modification of the
4-amino group. We subsequently proposed transposing
the 4-amino group to the isoelectronic 2-amino position
in the hope that modifications of the amino group at
2-position would be better tolerated for MCH1R
antagonist activity. To our delight, the 2-dimethylami-
noquinoline compound 2 was found to have equal
MCH1R binding affinity as the related 4-aminoquino-
line compound 1.
Keywords: GPCR; Antagonist; Obesity; Quinoline; Melanin-concen-
trating hormone.
*
Corresponding author. Tel.: +1 732 594 7039; fax: +1 732 594
5966; e-mail: robert_devita@merck.com
This letter will describe the structure–activity relation-
ships (SAR) of the isoelectronic 2-aminoquinoline-6-
carboxamide MCH1R antagonists and in vivo rodent
pharmacology of an optimized compound from this lead
class. After the initial publication of 4-aminoquinoline10
Present address: Merck Research Laboratories 33 Avenue Louis
Pasteur Boston, MA 02115, USA.
à
Present address: Novartis Institutes for Biomedical Research
Novartis Pharma AG WSJ-360.4.06 CH-4002 Basel, Switzerland.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.08.006

J. Jiang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5270–5274
5271
Me
Me
F3C
F3C
N
H
N
H
N
H
N
4
2
Me
O
O
N
Me
N
Me
compound 1
MCH-1R Binding IC50 = 12nM
compound 2
MCH-1R Binding IC50 = 13nM
Figure 1. 4-Aminoquinoline (compound 1) and 2-aminoquinoline (compound 2) MCH1R antagonists.
and 2-aminoquinoline11 MCH antagonist patent appli-
cations from these laboratories, related aminoquinoline
MCH1R antagonists have been reported by other
laboratories.12
less active than the mono- and dimethyl amine analogs;
results which are in contrast to those of the 4-amino-
quinoline designs, where the more active analogs con-
tained the primary amino group. This result allowed
for further elaboration of the structure–activity relation-
ships of the 2-aminoquinoline series. A series of dialkyl
amine analogs showed that smaller dialkyl groups were
preferred, for example, dimethylamino compound (en-
try 3) had superior binding affinity as compared to the
diethyl and di-n-propyl analogs (entries 6 and 7). How-
ever, the unsymmetrical combination of a larger alkyl
group with a methyl group on the amine afforded com-
pounds with excellent binding affinity and functional
antagonist activity. N-Propyl-N-methylamino (entry 4),
N-i-propyl-N-methylamino (entry 5) groups were partic-
ularly active analogs. Cycloalkyl groups were also toler-
ated such as N-methylcyclopentyl amine and N-methyl-
cyclohexyl amine, while the N-methyl-N-phenyl amino
compound (entry 10) had significantly reduced MCH1R
binding affinity. A series of cyclic amines were evaluated
to complete the simple amino group SAR. Analogs con-
taining small cyclic amines such as azetidine, pyrrolidine
and piperidine rings (entries 11–13) were superior to the
analog possessing the larger azepine ring (entry 14). In
addition, the bridged bicyclic amino analog (entry 15)
had comparable MCH1R binding affinity and function-
al activity as compared to the small ring analogs. These
results allowed for the exploration of substituents on the
cyclic amine analogs in order to find functional groups
that might modulate the physical–chemical properties
of the 2-aminoquinoline series of MCH1R antagonists.
The synthesis of 2-aminoquinoline-6-carboxamide
derivatives11 is outlined in Scheme 1. Dihydroquinoli-
none 3 was converted according to literature procedures
to the 6-nitro compound 4 under standard conditions
followed by treatment with POCl3 to provide 2-chloro-
6-nitroquinoline 5.13 A variety of amines 6 could be added
to the 2-position of the quinoline by refluxing with an
excess of the amine in ethanol. The resulting 2-amino
derivatives 7 were subsequently converted to 6-amino
derivatives 8 by reduction of the 6-nitro group using
FeCl3–NH2NH2 system.14 Simple carboxamide forma-
tion using acid chlorides 9 or carboxylic acids 10 provided
the desired 2-aminoquinoline-6-carboxamide derivatives
11.
Compounds were evaluated for their binding affinity to
cloned human MCH1R in a competition binding assay
with [125I]-[Phe13,Tyr19]-hMCH as the radioligand
(Binding in Tables).15 Functional activation of rat
MCH1R was also assessed by stimulation of IP3-cou-
pled mobilization of intracellular calcium in human
HEK-293 cells expressing rat MCH1R (rAeq in Ta-
bles).15 Compounds from the 2-aminoquinoline class
were also screened on MCH2R and found to exhibit less
than 50% inhibition at a screening dose of 4 lM, show-
ing good selectivity for MCH1R over MCH2R.16
The MCH1R binding affinities and functional activities
for analogs with a variety of amine substituents are
shown in Table 1. The primary amine (entry 1) is much
The pyrrolidine ring was chosen for further functionali-
zation with the subset of analogs prepared shown in Ta-
ble 2. Simple methyl substitution of the pyrrolidine 2- or
aq. HNO3
O2N
DDQ,
POCl3
N
O
aq. H2SO4
N
H
O
H
benzene
4
3
R1
R2
O2N
O2N
N
FeCl3-C
H
R2
6
N
Cl
N
N
R1
NH2NH2
MeOH
EtOH, reflux
5
7
R3COCl (9),
HOAc
H
N
H2N
R3
or
R2
O
R2
N
N
R1
N
N
R1
R3CO2H (10),
EDC, DMAP
8
11
Scheme 1. Standard synthesis of 2-aminoquinoline-6-carboxamide MCH1R antagonist analogs. For full experimental details, see Ref. 11.

5272
J. Jiang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5270–5274
Table 1. In vitro biological activity of 2-amino substituents of
2-aminoquinoline-6-carboxamide MCH1R antagonistsa
Table 2. In vitro biological activity of pyrrolidine substitutents of
2-pyrrolidine quinoline-6-carboxamide MCH1R antagonistsa
F3C
F3C
H
H
N
N
O
O
N
R
N
R
Entry
1
R
hBinding IC50
rAeq. EC50
320
Entry
1
R
hBinding IC50
rAeq. EC50
720
H
N
N
H
3
5
240
20
13
10
2
Me
Me
N
H
2
3
270
400
580
1770
200
44
2
3
330
110
140
140
830
nd
N
N
Me
N
Me
2
Me
CO2Me
Me
N
Me
4
800
25
12
5
4
N
N
Me
5
5
Ph
N
Me
Me
Et
N
N
N
Et
6
6
88
490
2
NH2
O
Pr
N
Pr
7
7
N
H
Me
Ph
O
N
N
8
10
1
110
90
8
350
1200
nd
N
Me
N
H
O
Me
Me
9
9
18
3700
4
N
H
N
Me
O
10
11
12
13
14
15
N
N
Me
6
30
10
11
12
13b
14
15
N
H
N
H
N
Me
H
N
N
N
3
50
56
N SO2Me
1
150
70
3
320
110
1800
190
N
N
N
13
210
0.5
12
36
3
O
N
490
140
N
H
N
N
NH
a In vitro data in nM are the average of at least two experiments.
a In vitro data in nM are the average of at least two experiments.
b Cinnamide analog.
affinity, while addition of the phenyl group to the 3-po-
sition was also deleterious to MCH1R antagonist activ-
ity. The addition of a 3-amino group (entry 6) was well
tolerated and allowed for the further elaboration of the
amino group into other functionalized analogs. For
example, N-acetyl, N-benzoyl, and N-isobutyryl carbox-
3-positions (entries 2 and 3) had minimal effect on
MCH1R binding affinity and functional activity as com-
pared to the unsubstituted pyrrolidine. The prolinate
analog (entry 4), with a methyl carboxylate group at
the 2-position, showed a significant decrease in binding

J. Jiang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5270–5274
5273
amides (entries 7–9) possessed excellent binding affinities
and functional MCH1R antagonist activity of near or
below 100 nM. Other small functionalized amino groups
such as the N-methyl urea (entry 10) and methanesulf-
onamide (entry 11) also showed low nanomolar
MCH1R binding affinity and excellent functional antag-
onist activity. A series of bicyclic amine analogs (entries
11–15) was similarly active in the binding assay and
demonstrated the variety of functionalized pyrrolidines
that were useful in defining the SAR of the 2-amino-
quinoline lead series.
cokinetics, with similar half-lives and clearances, such
that continuous iv infusion was determined as the
optimal method of compound delivery.
Male Sprague–Dawley rats were used to assess acute
effects of an MCH1R antagonist on energy homeosta-
sis. In order to obtain constant circulating levels of
compound, lean male Sprague–Dawley rats were
implanted with indwelling infusion pumps (Kent Sci-
entific, Torrington, CT) and given an iv bolus of
either compound,5 followed by a continuous com-
pound infusion (iv bolus 1.6 mg/kg followed by ip
infusion of 1.33 mg/kg/h in 30% HPCD) for 18 h
(overnight with lights out) with access to a palatable
moderate high-fat diet (32% kcal fat). Compound 12
decreased overnight food intake by 26% (p = 0.049
vs. vehicle) with a non-significant reduction in body
weight gain (p = 0.065) as compared to vehicle-treated
controls. In a separate study, the related inactive ana-
log, compound 13, administered at a molar equivalent
(iv bolus 5.8 mg/kg followed by ip infusion of 1.2 mg/
kg/h in 30% HPCD) had no significant effects on food
intake or body weight gain during the overnight
study. These results indicate that the 2-aminoquinoline
MCH1R antagonists, exemplified by compound 12, re-
duce food intake in rodents. These feeding effects are
most likely mechanism-based by antagonism of
MCH1R and not due to structure-based toxicity, since
the closely related inactive analog compound 13 had
no effect on food intake in the parallel study.
The 2-aminoquinoline series had been sufficiently
developed to provide many compounds with low
nanomolar binding affinities and functional antagonist
activity useful for proof-of-concept studies in vivo.
The usefulness of peptidyl MCH antagonists for the
reduction of food intake and body weight had been
previously demonstrated5 but the need to establish
similar in vivo effects with the 2-aminoquinoline
MCH antagonist series remained. Table 3 shows the
profiles of two compounds chosen for intravenous
infusion studies for the reduction of food intake and
modulation of body weight in rats. Compound 12,
the 2-azabicyclo[2.2.2]quinoline MCH1R antagonist
analog possessing the (2-trifluoromethylpyridin-5-
yl)propionamide, was paired in a study with less active
analog compound 13 containing a shortened (2-triflu-
oromethylpyridin-5-yl)carboxamide at the quinoline
6-position. Inclusion of the pyridyl group improved
vehicle solubility for iv dosing as compared to the
phenyl series of analogs.
We have described the structure–activity relationships
of the 2-aminoquinoline series of MCH1R antago-
nists. A variety of 2-amino groups were explored with
small dialkyl, methylalkyl, and methyl-cycloalkylam-
ines providing MCH1R antagonists with high binding
affinity. In addition, small cyclic, bridged, and spirocy-
clic amines were well tolerated at the quinoline 2-posi-
tion. It was also found that aminoquinolines with
2-position pyrrolidines functionalized at the C-3 with
amino, urea, carboxamide, and sulfonamide groups
afforded compounds with exceptional binding and
functional antagonist activity. In vivo efficacy studies
showed that compound 12 from this class of MCH1R
antagonists is useful for the inhibition of food intake
but not body weight gain after iv bolus followed by
continuous iv infusion. These effects were most likely
mechanism-based since the control experiment with a
closely related analog failed to have any effects on
food in take and body weight thereby diminishing
the possibility that non-mechanism-based toxicity or
off-target activities accounted for these biological ef-
fects. These results indicate the potential of the 2-ami-
noquinoline class for the reduction of food intake in
mammals and contribute to the ongoing validation
of MCH1R as a potential target for obesity.
Compound 12 possesses low nanomolar binding affin-
ity on the human and rat MCH1R, and an EC50 of
25 nM in the rat functional assay. The related com-
pound 13 has very poor binding affinity and function-
al activity making it a useful tool to determine if any
impact on feeding is mechanism-based and not due to
inherent toxicity of the structure class. The com-
pounds were also matched with respect to rat pharma-
Table 3. Biological profile of 2-azabicyclo[2.2.2]-quinoline-6-carbox-
amide MCH1R antagonist compounds 12 and 13a
F3C
n
H
N
N
O
N
N
Compound
12 (n = 12)
13 (n = 0)
MCH1R binding
Human
Rat
IC50
5 nM
13 nM
IC50
30%I at 5 lM
20%I at 5 lM
MCH1R function
Rat
EC50
25 nM
EC50
>10 lM
Rat Pharmacokinetics
Clp (mL/min/kg)
Vdss (L/kg)
Acknowledgments
36
57
1.0
0.6
3.92
1.1
The authors thank Dr. A. Kanatani and Dr. M. Ito
(MRL Tsukuba) for screening compounds on
MCH2R.
t1/2 (h)
a In vitro data in nM are the average of at least two experiments.

5274
J. Jiang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5270–5274
11. (a) DeVita, R. J.; Chang, L.; Hoang, M.; Jiang,
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