4-Aminoquinoline melanin-concentrating hormone 1-receptor (MCH1R) antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.08.008

Structure-activity relationships of a 4-aminoquinoline MCH1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4-, and 6-positions of the original HTS hit. Improvements to the original screening lead included lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl, and hydrocinnamyl carboxamides at the 6-position. Modifications of the 4-amino group were not well tolerated.

Full text of DOI:10.1016/j.bmcl.2006.08.008

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5275–5279
4
-Aminoquinoline melanin-concentrating hormone
1
-receptor (MCH1R) antagonists
a
a
a
a
b
Jinlong Jiang, Peter Lin, Myle Hoang, Lehua Chang, Carina Tan,
Scott Feighner, Oksana C. Palyha, Donna L. Hreniuk, Jie Pan,
b
b
b
b
b,
b
b
Andreas W. Sailer, Nancy R. Morin, Douglas J. MacNeil,
b
b,à
Andrew D. Howard, Lex H. T. Van der Ploeg,
a,à
a,
*
Mark T. Goulet and Robert J. DeVita
a
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
b
Received 12 May 2006; revised 31 July 2006; accepted 1 August 2006
Available online 17 August 2006
Abstract—Structure–activity relationships of a 4-aminoquinoline MCH1R antagonist lead series were explored by synthesis of
analogs with modifications at the 2-, 4-, and 6-positions of the original HTS hit. Improvements to the original screening lead
included lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl, and hydrocinnamyl carboxamides at the 6-position.
Modifications of the 4-amino group were not well tolerated.
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, feeding behavior
as viable therapeutic agents for the treatment of human
disease remain elusive.
1
as well as other potential functions. Pre-prohormone
MCH KO mice were shown to have reduced food in-
In this letter, we describe our initial work in the area of
9
,10a
aminoquinoline MCH 1R antagonists.
This letter
2
take. In addition, MCH has been shown to stimulate
3
will focus on our early high-throughput screening hit
from the 4-aminoquinoline MCH antagonist class, while
feeding in rodents, while MCH1R KO mice are hyper-
4
10b
phagic and lean. Development of MCH1R antagonists
has been of interest for the possible treatment of obesi-
the subsequent letter will describe the isoelectronic 2-
aminoquinoline
aminoquinoline
series.
Related
5
6
ty and depression or anxiety. To that end, peptidyl
MCH1R antagonists have been identified by modifica-
MCH1R antagonists have been reported by other labo-
ratories after the initial publication of patent applica-
11
tions from these laboratories.
7
a
tion of MCH and chronic infusion of peptidyl agonists
or antagonists altered appetite, body weight, and adi-
7
b
posity in rats. Many non-peptidyl MCH1R antago-
8
Our initial high-throughput screening hit was a 4-ami-
noquinoline derived from an earlier medicinal chemistry
nists have appeared in the literature in recent years
but human clinical data to validate MCH1R antagonists
1
2
program (see entry 1, Table 1). Early analog synthesis
to optimize the 2-substituent, as well as to prepare
2
-propyl substituted intermediates for optimization of
Keywords: MCH; Melanin-concentrating hormone; Antagonist;
Obesity; Depression; Anxiety; Quinoline.
the 6-amino substituent closely followed the literature
synthesis. Treatment of 4-acetylaminoaniline (1) with
the appropriately substituted ketonylacetates 2 in the
presence of catalytic acid provided the vinylogous ure-
thane intermediates 3. Alternatively, alkyl substituted
acetylene carboxylates 4 were also used to prepare the
vinylogous urethane quinoline precursors 3 from aniline
*
Corresponding author. Tel.: +1 732 594 7039; fax: +1 732 594
966; e-mail: robert_devita@merck.com
5
Present address: Novartis Institute for Biomedical Research,
Novartis Pharma AG, WSJ-360.4.06, CH-4002 Basel, Switzerland.
Present address: Merck Research Laboratories, 33 Avenue Louis
Pasteur, Boston, MA 02115, USA.
à
0
960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.08.008

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J. Jiang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5275–5279
Table 1. In vitro biological activity of substituted cinnamyl carbox-
a
amides
OEt
O
O2N
cat. acid
ROH
2
O N
O
OR
Me
+
NH2
O
Me
reflux
N
NH2
H
H
N
8
X
9
10
OH
N
Cl
O
N
CH3
2
O N
POCl3
O2N
3 4
NHR R
Ph-O-Ph
heat
o
80 C
Me ROH
heat
Me
N
Entry
X
Binding IC50
Aeq. EC50
1
1
12
1
2
3
4
5
6
7
8
9
2-Ci
H
120
1000
1100
6
500
nd
R3
R4
R3
R4
O
N
N
N
H
FeCl3-C
2R
Cl
or
O
2R
N
O2N
3-Ci
4-Ci
4-F
4-Br
4-I
nd
96
NH2NH2
Me MeOH
O
N
Me
130
4
200
93
1
3
2R
14
OH
2.3
9
280
71
Scheme 2. Standard synthesis of 2-propyl-4-substituted aminoquino-
line MCH1R antagonist analogs. For full experimental details, see
Ref. 9.
4-Me
4-CF
4-Et
3
1.3
1.4
4
61
10
11
12
13
14
15
16
17
18
19
20
21
22
160
3600
740
520
910
71
4-n-Pr
4-n-Bu
4-i-Pr
45
2.9
22
A more versatile intermediate, from which selective reac-
tions at the 4- and 6-positions could be achieved, was
prepared as outlined in Scheme 2. Condensation of
4-t-Bu
4-SMe
4-Ph
9
1.1
6.6
60
118
904
990
310
nd
4
-nitroaniline (8) with ethyl 3-oxohexanoate (9) provid-
2,4-DiCi
3,4-DiCi
ed the intermediate vinylogous urethanes 10, which
upon heating in diphenyl ether gave 2-propyl-4-
hydroxy-6-nitroquinoline (11). Treatment with POCl3
at 80 °C provided 4-chloroquinoline intermediate 12,
suitable for selective amination of the 4-position. Treat-
ment with a variety of amines provided analogs to
explore the 4-position structure–activity relationships
for MCH1R binding affinity. Later, clean reduction of
4-NO
4-NH
2
20
2
790
95
4-OAc
4-OH
630
nd
1100
nd, not determined.
a
In vitro data in nM are the average of at least two experiments.
1
3
the 6-nitro group with FeCl -hydrazine system, fol-
3
lowed by derivatization of the intermediate 6-amino
group, afforded the 6-acylamino quinoline analogs 14
with alkyl substituents on the 4-amino group.
1
in good yields. Heating the intermediates 3 at high
temperature in diphenyl ether resulted in the smooth
cyclization to 2-alkyl-4-hydroxy-6-acetamido quinoline
intermediates 5. Subsequent alkylation with dimethyl
sulfate provided ether intermediates 6. Heating with
ammonium acetate at 150 °C followed by hydrolysis of
the acetamide provided the 4,6-diaminoquinolines.
Selective derivatization at the more reactive 6-position
using standard reaction protocols to execute, for exam-
ple, amide bond formation, provided the 2-alkyl-4-ami-
noquinoline-6-aminocarboxamide analogs 7 Scheme 1.
Compounds were evaluated for their binding affinity to
cloned human MCH1R in a competition binding assay
with [ I]-[Phe13,Tyr19]-hMCH as the radioligand
1
25
7
a
(
binding in Tables). Functional activation of MCH1R
was also assessed by stimulation of IP3-coupled mobili-
zation of intracellular calcium in human HEK-293 cells
7
a
expressing MCH1R (Aeq. In Tables). This series of
compounds had good selectivity over MCH2R; most
compounds had less than 50% inhibition at a screening
dose of 2 lM.
AcHN
OR
O
OR
cat. acid
ROH
O
The HTS hit, from a C5a-receptor antagonist program,
the 2-chlorocinnamide shown in Table 1, entry 1, had
MCH1R binding affinity of 120 nM. We initially ex-
plored the structure–activity relationships of the cinna-
mide group and rapidly found that substitution at the
4-position was preferred. No 4-substituent, entry 2 or
3-Cl substituted analog, entry 3, provided compounds
with 10-fold decreased binding affinity, while the 4-Cl
analog, entry 4, showed 19-fold improved binding affin-
ity and functional activity of 96 nM as compared to the
2-Cl HTS hit. We rapidly expanded the SAR and found
that a wide variety of lipophilic 4-substituents including
bromide, iodide, alkyl, trifluoroalkyl, and phenyl groups
provided compounds with binding affinities less than
10 nM with good functional antagonist activity. 4-Fluo-
ro substituent, disubstituted phenyl, and more polar
NH2
O
+
or
1
O
R1
4
R1
reflux
2
AcHN
OH
N
OR Ph-O-Ph
R1
Me2SO4
AcHN
N
toluene
reflux
H
R1
heat
3
5
OMe
R1
H
O
2R Cl
2R
NH2
N
AcHN
N
NH4OAc
o
O
N
R1
or
O
2R OH
1
50 C
6
7
Scheme 1. Standard synthesis of 2-alkyl-4-amino quinoline MCH1R
antagonist analogs. For full experimental details, see Ref. 9.

J. Jiang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5275–5279
5277
4
-substituents such as nitro, amino, acetoxy, and hydro-
Table 2. In vitro biological activity of 6-substituted-4-aminoquino-
a
lines
xy were deleterious to MCH1R binding affinity and
functional activity. The trifluoromethyl group (entry 9)
was selected for future analog work due to its excellent
binding and functional activity, presumed metabolic sta-
bility, and lipophilicity which might positively impact
access to MCH1R in the brain.
NH2
R
N
CH3
Entry
1
R
Binding IC50
Aeq. EC50
nd
We were interested in removing the cinnamide group
due to its potential reactivity with nucleophiles at the
b-position of the olefin. Table 2 shows analogs in which
the cinnamide has been replaced with other carboxa-
mides. A simple benzamide leads to an inactive analog
(entry 1). Incorporation of the biphenyl scaffold signifi-
cantly improves MCH1R activity (see Table 1, entry 16).
The 4 -trifluoromethyl biphenyl carboxamide (entry 2)
had comparable binding affinity but reduced functional
activity as compared to the unsubstituted biphenyl ana-
H
N
na
O
F3C
Cl
2
3
4
5
6
4.5
310
75
H
0
N
O
0
log. The 4 -chloro-biphenyl carboxamide (entry 3) had
0.7
H
subnanomolar binding affinity and improved functional
activity, while the 4-chlorophenyl-4-cyclohexyl analog
had somewhat reduced binding affinity. The 4-trifluoro-
methyl substituted benzamide and phenylacetamide
(entries 5, 6) were also much less active. The hydrocin-
namide entry 7 had improved binding affinity, however,
N
Cl
O
O
4.4
370
nd
H
N
incorporation of the 4-CF group (entry 8) provided a
3
F3C
H
N
compound with binding affinity of 13 nM and functional
activity of 110 nM. Other functional groups were ex-
plored as a linkage from the quinoline 6-position to
the preferred 4-trifluoromethylated phenyl pharmaco-
phore. For example, N-methylated carboxamide,
10,000
4000
O
H
N
nd
trifluoromethyl
benzyl
urea,
4-trifluoromethyl-
O
F3C
phenylpropylamine (removal of the carboxamide
carbonyl), and the ‘reversed’ carboxamide groups (en-
tries 9–12, respectively) were modifications that provid-
ed less active MCH1R antagonist analogs. These
structure–activity relationships demonstrate that rigid
H
7
8
9
N
8300
13
nd
O
0
F3C
F3C
F3C
scaffolds such as a trans-olefin, 4-4 -biphenyl, cyclo-
H
hexylphenyl or the proper alkyl chain length to the
phenyl substituent, linked to the quinoline 6-position,
are desired for improved MCH1R binding affinity and
functional antagonist activity.
N
120
nd
O
O
O
Me
N
1700
The analogs with modifications of the quinoline 2-sub-
stituent are shown in Table 3. Straight-chain and
branched alkyl groups are well tolerated and lead to
compounds with high binding affinities and less than
H
H
N
10
11
N
38
380
1
00 nM functional antagonist activities. Optimal ana-
F3C
F3C
logs included substituents such as the n-propyl (of the
original lead, entry 3), isobutyl (entry 7), and cyclopen-
tyl (entry 11) groups. The cyclohexyl group was also well
tolerated; however installation of a phenyl ring (entry
H
N
180
1000
O
1
2
2700
nd
1
3) provided a compound with reduced binding affinity
N
H
and minimal functional antagonist activity (albeit from
the 4-chlorocinnamide series—compare entries 3 and 9
from Table 1).
na, not active; <50%I at 10 lM. nd, not determined. Synthesis of
entries 10–12 described in Ref. 9.
a
In vitro data in nM are the average of at least two experiments.
The last area of structure modification to be explored
was the 4-position of the quinoline. The amine of the
original lead series was important for MCH1R binding
affinity as shown by lack of activity for the 4-hydroxy
analog (entry 2). The methyl ether analog (entry 3)
was much improved over the hydroxyl analog but still
possessed reduced binding affinity and functional activ-
ity as compared to the isosteric but basic N-methylamine
analog entry 4. Incorporation of larger monoalkyl
groups and dialkyl substituted amines led to analogs
with much reduced binding affinity and functional activ-

5278
J. Jiang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5275–5279
a
Table 3. In vitro biological activity of 2-substituted-4-aminoquino-
a
lines
Table 4. In vitro biological activity of 4-substituted quinolines
F3C
R
H
N
F3C
NH2
H
N
O
N
CH3
O
N
R
Entry
1
R
Binding IC50
Aeq. EC50
60
Entry
1
R
Binding IC50
8
Aeq. EC50
140
H
H
Me
1.3
na
N
H
2
3
4
5
6
7
8
9
Me
1.2
2
110
40
2
3
4
5
6
7
8
9
O
nd
Me
Me
26
360
150
340
nd
O
H
Me
Me
1.5
1.2
2.1
0.3
0.3
5.8
2.0
0.8
1.2
18.5
210
90
N
N
1.5
4.8
40
H
Et
Me
Me
Me
160
44
H
H
N
N
Me
18
2700
300
nd
Me
Me
Me
Me
Me
Et
Me
29
N
43
Me
Me
110
250
68
Et
N
1100
2.8
17
Me
1
1
1
0
1
1
1
1
0
1
2
2500
2800
nd
N
N
2
96
>4000
N
b
3
na, not active; <50I at 10 lM; nd, not determined. Entry 7, MCH2R
binding IC50 = 960 nM.
1
6600
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.
Entry 13, 4-chloro not 4-trifluoromethyl cinnamide.
b
more importantly, replacements for the potentially reac-
tive cinnamide moiety were identified such as biphenyl,
cyclohexyl phenyl, and hydrocinnamyl carboxamides.
Modifications of the 4-amino group were not well tolerat-
ed with the optimal substituent being the unsubstituted
amine identified from the original lead.
ity. In addition, cyclic amines such as azetidine, pyrrol-
idine, and piperidine were not advantageous for
MCH1R binding affinity. The analogs in Table 4 dem-
onstrate minimal tolerance for modifications at the
4-position with optimal substituents limited to the
unsubstituted amino group or small N-alkyl amines.
The inability to substantially modify this initial amino
quinoline MCH1R antagonist lead class, especially for
physical chemical properties, led us to explore other
permutations of the aminoquinoline substructure.
Ultimately, this led to the design of the isoelectronic
2-aminoquinoline series of MCH1R antagonists. The
development of this lead class is described in the subse-
The structure–activity relationships of 4-aminoquinoline
MCH1R antagonist lead series were explored by synthesis
of analogs with modifications at the 2-, 4-, and 6-positions
of the original HTS hit. Lipophilic groups were well toler-
ated at the 2-position, with n-propyl, tert-butyl, and
cyclopentylgroupsbeing optimal. 6-Aminocarboxamides
of the original lead were moderately improved upon, but
1
0b
quent paper.

J. Jiang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5275–5279
5279
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