Substituted chromones and quinolones as potent melanin-concentrating hormone receptor 1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.05.075

A series of substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.

Full text of DOI:10.1016/j.bmcl.2006.05.075

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4237–4242
Substituted chromones and quinolones as potent
melanin-concentrating hormone receptor 1 antagonists
Brian Dyck,* Liren Zhao, Junko Tamiya, Joseph Pontillo, Sarah Hudson,
Brett Ching, Christopher E. Heise, Jenny Wen, Christi Norton, Ajay Madan,
David Schwarz, Warren Wade and Val S. Goodfellow
Departments of Medicinal Chemistry, Pharmacology and Molecular Biology, Neurocrine Biosciences Inc.,
12790 El Camino Real, San Diego, CA 92130, USA
Received 5 May 2006; revised 19 May 2006; accepted 22 May 2006
Available online 12 June 2006
Abstract—A series of substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrat-
ing hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.
Ó 2006 Elsevier Ltd. All rights reserved.
The epidemic spread of obesity throughout the devel-
oped world has given the pharmaceutical industry great
incentive to develop novel antiobesity medications.1
Many molecular targets for this disease are being pur-
sued, including the cannabinoid receptor 1, for which
the inverse agonist rimonabant is currently under review
by the FDA.2 Among the newer biological targets, mel-
anin-concentrating hormone receptor 1 (MCH1R) has
emerged at the forefront, demonstrating convincing pre-
clinical evidence that suggests the potential for efficacy
in humans. Central administration of melanin-concen-
trating hormone (MCH) produces hyperphagia upon
acute treatment and weight gain upon chronic exposure
in rodents.3,4 Mice deficient in MCH or its receptor are
lean and the latter are resistant to diet-induced obesi-
ty.5,6 A number of MCH1R antagonists are active in
rats and mice in various sub-chronic and chronic obesity
models and efficacy was also demonstrated in dogs
which, like humans, have a second functional MCH
receptor.7,8 Moreover, at least two companies have ad-
vanced MCH1R antagonists into clinical trials.9 There
is also a growing body of evidence suggesting a role
for MCH1R antagonists in the treatment of anxiety
and depression.7a,10,11
A number of structurally diverse MCH1R antagonists
have been patented and published, and this literature
was recently reviewed.12 Figure 1 shows three such
compounds (1–3), which have demonstrated efficacy
in preclinical obesity models and appear to have a
related pharmacophore. We discovered the pyridine
derivatives 3, which were designed in part based on
the first published MCH1R antagonist 1.7h,b In the
case of these pyridines, although they are potent in vitro
and show good oral bioavailability in rats, the lead
compound was rapidly cleared, which resulted in a ter-
minal half life of less than three hours. Our goal was to
improve the pharmacokinetics of these compounds
while maintaining high levels of brain penetration, an
essential feature of a drug for this CNS target. The
strategy used was to replace the metabolically labile
benzamide moiety with heterocyclic groups. The car-
bonyl group of compound 3 is essential for binding
affinity; therefore, the bicyclic group was designed such
that it would retain this feature. We envisaged that a
chromone- or quinolone-based molecule (i.e., 4 or 5)
would be active, and the fact that there are a number
of related molecules in various drug programs suggest-
ed the possibility of producing an orally absorbed com-
pound.13 The potential success of this strategy was
further supported by the activity of the putative clinical
compound 2, in which a carbonyl group is also con-
tained within a bicyclic ring system.8,12 An alternative
series of chromone-containing MCH1R antagonists
was recently reported.14
Keywords: MCH; Obesity; Anorectic; Anxiety; Depression; GPCR.
*
Corresponding author. Tel.: +1 858 617 7778; e-mail: bdyck@
neurocrine.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.05.075

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B. Dyck et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4237–4242
CH3
O
N
N
O
O
N
CH3
S
O
N
H
N
Cl
CH3
T-226296 (1)
GW3430 (2)
F
R
H
N
N
N
N
N
O
X
O
R
CH3
N
N
H
3
4: X=O
5: X=NR'
Ar
Ph
Figure 1. Published and proposed MCH1R antagonists.
The synthesis of the chromone-based compounds
is shown in Scheme 1. The more active bromide
of 1,5-dibromopyridine (6) was displaced with
3-(dimethylamino)pyrrolidine to produce 7. This com-
pound was coupled with 20,40-dimethoxyacetophenone
using the conditions reported by Buchwald to afford
ketone 8.15 Reaction with boron tribromide allowed
for the chelation-controlled demethylation of the
methoxy group ortho to the carbonyl substituent, while
leaving the 4-methoxy group untouched.16 The resulting
phenol 9 underwent cyclization with dimethylformam-
ide dimethyl acetal thereby providing the chromone core
10. Demethylation of the remaining methoxy group
required more forcing conditions without the participa-
tion of an ortho acyl group, and so the material was
heated in concentrated hydrobromic acid. The resulting
phenol 11 was converted to the corresponding triflate,
and an ensuing Suzuki coupling provided target
compounds 12. Alternatively, the phenol 11 was also
subjected to Ullmann-type coupling with aryl halides
to provide the aryloxy derivatives 13.17
intermediate which, upon reaction with methylamine,
provided the quinolone core (15). Removal of the benzyl
protecting group gave the phenol, which was converted
to the triflate and coupled with aryl boronic acids as de-
scribed above to provide the target quinolones 16.
The binding affinity of the chromones and quinolones
for MCH1R is shown in Table 1, combined with the
data from a GTPcS functional assay, and intrinsic
clearance values obtained in vitro from human liver
microsomes (HLM). The parent chromone 17a demon-
strated potent binding and functional activity, thereby
indicating that the newly incorporated ring system is
well tolerated in vitro. With the exception of larger
groups such as the trifluoromethoxy group of 17h, sub-
stitution at the four position of the phenyl ring had min-
imal influence over affinity (17b–17g), and when this
substituent was halogen, a modest improvement in the
intrinsic clearance was afforded (17b–17d). Alkyl substi-
tution at the four position, as exemplified by ethyl deriv-
ative 17e, resulted in a loss of binding affinity and
functional activity relative to 17a, and led to more rapid
clearance in HLM. Not surprisingly, fluorination of the
alkyl group, as in 17f, reduced clearance to levels com-
parable to 17a, but the binding affinity of this compound
was still suboptimal. Introduction of a 4-methoxy group
provided 17g, which demonstrated a subnanomolar Ki
The synthesis of the quinolone derivatives is shown in
Scheme 2. Bromopyridine 7 was coupled to 40-benzyl-
oxy-20-fluoroacetophenone in the same manner as above
to provide 14. Aminomethylenation with dimethylform-
amide dimethyl acetal provided the pre-cyclization
CH3
O
Br
N
CH3O
Br
b
CH3
a
CH3
N
N
N
N
OR
N
N
6
Br
CH3
8: R = Me
9: R = H
7
c
CH3
O
N
Ar
CH3
f
N
CH3
N
O
O
N
RO
12
CH3
d
N
CH3
Ar
O
O
N
g
N
O
CH3
10: R = Me
11: R = H
e
N
O
N
13
Scheme 1. Reagents and conditions: (a) 3-Dimethylaminopyrrolidine, toluenesulfonic acid monohydrate, 130 °C; (b) 20,40-dimethoxyacetophenone,
sodium tert-butoxide, 2-(dicyclohexylphosphino)-20-methylbiphenyl, palladium(II) acetate, THF, 80 °C; (c) boron tribromide, DCM, ꢀ25 °C; (d)
dimethylformamide dimethyl acetal, DCM, 20 °C; (e) sodium iodide, 48% hydrobromic acid, 100 °C; (f) i—trifluoromethanesulfonic anhydride,
DIEA, DCM, 0 °C; ii—ArB(OH)2, Pd(dppf)2Cl2, potassium carbonate, aqueous DMF, 80 °C; (g) Ar-Br or Ar-I, copper(II) oxide, pyridine, 130 °C.

B. Dyck et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4237–4242
4239
CH3
O
Br
N
BnO
CH3
b
CH3
N
CH3
a
N
N
N
F
N
14
7
CH3
N
O
CH3
N
O
Ar
CH3
BnO
CH3
N
N
c
N
N
N
N
H3C
16
H3C
15
Scheme 2. Reagents and conditions: (a) 20-Fluoro,40-benzyloxyacetophenone, sodium tert-butoxide, 2-(dicyclohexylphosphino)-20-methylbiphenyl,
palladium(II) acetate, THF, 65 °C; (b) i—dimethylformamide dimethyl acetal, DCM; ii—aqueous methylamine, ethanol; (c) i—10% palladium on
carbon, hydrogen, 40 psi; ii—trifluoromethanesulfonic anhydride, TEA, DCM, 0 °C; iii—ArB(OH)2, Pd(dppf)2Cl2, potassium carbonate, aqueous
DMF, 80 °C.
Table 1. In vitro data for 17–19
CH3
N
N
O
Y
CH3
N
17: X=CH, Y=O
18: X=N, Y=O
R
X
19: X=CH, Y=NCH3
Clearanceb (mL/min/kg)
a
IC50 (nM)
Compound
R
Kia (nM)
3c
N.A.
5.2
4.1
2.0
2.1
3.0
8.8
10
12
15
17a
17b
17c
H
4-F
22
16
8.4
10
4-Cl
4-Br
16
18
17d
17e
20
44
4-C2H5
4-CF3
36
24
17f
59
17g
17h
17i
4-CH3O
4-CF3O
2,4-Cl2
4-Cl,3-CH3
4-Cl,2-CH3
2-CH3,4-CH3O
2,4-(CH3O)2
3,4-OCH2O
3,4-O(CH2)2O
4-CH3O
4-CF3
0.6
24
7.8
N.D.d
30
258
N.D.d
12
14
10
17j
59
24
22
24
17k
17l
7.1
3.3
16
12
60
66
38
17m
17n
17o
18a
18b
(R)-17c
(S)-17c
19a
19b
4.7
5.4
18
33
112
65
120
55
22
29
130
20
37
4-Cl
4-Cl
1.6
1.4
24
N.D.d
N.D.d
53
12
41
N.D.d
4-Cl
4-CF3
120
49
a Values are averaged from at least two experiments. Observed values typically fell within a 2-fold range of this mean. See Refs. 7n and 18 for assay
details.
b Intrinsic hepatic clearance measured in human liver microsomes.19
c Ref. 7h.
d Not determined.
for MCH1R and the most potent functional activity of
the group. However, the inherent metabolic lability of
a methoxy substituent was apparent from the very rapid
HLM clearance of this compound. Compounds with
additional substitution on this phenyl ring exhibited
substantial loss of binding affinity and functional poten-
cy when compared to analogs which were exclusively
substituted at the four position (17i–17o). In the case
of the most potent analog 17g, even though the addition
of the 2-methyl group to give 17l resulted in a 3-fold
drop in binding affinity, the molecule was still one of
the more potent analogs. Although some other varia-
tions on alkoxy-substituted phenyl derivatives, including
the dimethoxy compound 17m and the fused dioxacycles
17n and 17o, provided sufficient in vitro potency, none
of these compounds had HLM clearance values

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B. Dyck et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4237–4242
consistent with reasonable plasma levels upon oral
administration. Replacement of the terminal phenyl ring
with various heterocycles was detrimental as is exempli-
fied by the two 2-pyridyl derivatives 18a and 18b, which
were substantially less potent than their phenyl counter-
parts 17g and 17f, respectively.
study in rats. The chloro-substituted derivative 17c was
chosen because it is one of the most potent examples,
while still demonstrating low intrinsic clearance in
HLM. There was little difference in the in vitro data
for the two enantiomers of 17c; the (R)-isomer was arbi-
trarily chosen for testing. The hydrochloride salt of this
compound was administered orally and intravenously to
Notably, in terms of in vitro potency, this compound
class did not demonstrate a significant stereochemical
preference as enantiomers (R)-17c and (S)-17c had near-
ly identical binding affinities and similar activity in the
GTPcS assay.
1000
Plasma (IV: 2.5 mg/kg)
Plasma (PO: 10 mg/kg)
The quinolones synthesized in Scheme 2 showed some
affinity for MCH1R, but were not as potent as their oxy-
gen-containing analogs. The 4-chloro quinolone 19a had
a Ki of 24 nM and a GTPcS IC50 of 41 nM. In addition,
19a showed higher clearance in HLM relative to the
analogous chromone 17c.
100
10
In an attempt to incorporate some flexibility into an
otherwise rigid molecule, the ether-derived compounds
20 were also tested and the in vitro data are collected
in Table 2. The phenoxy compound 20a showed slightly
less binding affinity and functional activity than the
phenyl compound 17a and demonstrated an intrinsic
clearance of 31 mL/min/kg. Unlike the analogs with the
phenyl ring directly attached to the fused bicyclic core,
the in vitro affinity of the phenoxy compounds
appeared to be sensitive to the sterics of the phenyl sub-
stituent. Hence, the unsubstituted compound 20a
(Ki = 7.2 nM) was the most potent, followed by the
4-fluoro analog 20b (Ki = 13 nM), the 4-methyl analog
20d (Ki = 19 nM), and the 4-chloro analog 20c
(Ki = 28 nM). Larger substituents such as trifluorometh-
yl (20e), methoxy (20f), and a fused furyl ring (20g)
resulted in substantial loss in binding affinity. The 4-flu-
oro analog was by far the most stable compound tested
in HLM with an intrinsic clearance of only 3 mL/min/kg.
1
0
5
10
15
20
25
Time (h)
Figure 2. Concentration of (R)-17c in rats after a po (10 mg/kg) or iv
(2.5 mg/kg) dose.20
Table 3. Pharmacokinetic values of (R)-17c in rats20
Parameter
Value SD
a
Vd (L/kg)
58 13
133 9.7
5.0 0.9
CLa (mL/min-kg)
a
t1/2 (h)
AUC-poa,b (ng h/mL)
Fa (%)
859 210
66 16
9.5 2.5, 25 2.8
Brain/plasmaa (1 h, 4 h)
a Determined by administering 2.5 mg/kg iv and 10 mg/kg po to
Sprague–Dawley rats.
b Plasma area under the curve upon oral dosing.
Due to the excellent in vitro profile of several of the chr-
omones, one analog was evaluated in a pharmacokinetic
Table 2. In vitro data for 20
CH3
N
N
O
CH3
N
R
O
O
20
Clearanceb (mL/min/kg)
a
IC50 (nM)
Compound
R
Kia (nM)
20a
20b
20c
20d
20e
20f
20g
H
4-F
7.2
13
24
35
31
3
17
4-Cl
4-Me
28
19
90
58
28
4-CF3
4-MeO
2,3-Dihydrobenzo-furan-5-yl
(60%)
138
78
N.D.c
N.D.c
350
N.D.c
N.D.c
N.D.c
a Values are averaged from at least two experiments. Observed values typically fell within a 2-fold range of this mean. See Refs. 7n and 18 for assay
details.
b Intrinsic hepatic clearance measured in human liver microsomes.19
c Not determined.

B. Dyck et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4237–4242
4241
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rats and the results from this study are presented in
Figure 2 and Table 3. In rats, (R)-17c demonstrated
clearance of 133 mL/kg/min and 66% oral bioavailabili-
ty. The plasma half life of (R)-17c was 5.0 h and the
compound showed very high brain penetration, which
increased from nearly 10-fold at one hour to 25-fold at
4 h.
In summary, we have described the design and synthesis
of a novel class of potent MCH1R antagonists which
demonstrate very good oral bioavailability and other
pharmacokinetic parameters in rats. The remarkably
high brain penetration of these compounds makes them
useful tools in the study of centrally acting anorectic
agents operating through the MCH1R mechanism.
Acknowledgments
The authors thank John Saunders, Paul Conlon, and
Rich Maki for helpful discussions concerning the dis-
covery of these compounds and the preparation of the
manuscript.
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added internal standard consisted of precipitation with
200 lL of acetonitrile from 50 lL of plasma, centrifuga-
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vacuum then reconstitution in acetonitrile–water solutions
before introducing into an LC-MS/MS system for analy-
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analytical methods was 5 ng/mL of test article in plasma.
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centrifugation and recovery of the supernatant before
introducing into an LC-MS/MS system for analysis.
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