Discovery of novel phenylpyridone derivatives as potent and selective MCH1R antagonists

Article abstract of DOI:10.1016/j.bmc.2010.12.002

The design, synthesis and structure-activity relationships of a novel class of N-phenylpyridone MCH1R antagonists are described. The core part of the N-phenylpyridone structure was newly designed and the side chain moieties that were attached to the core part were extensively explored. As a result of optimization of the N-phenylpyridone leads, we successfully developed the orally available, and brain-penetrable MCH1R selective antagonist 7c, exhibiting excellent anti-obese effect in diet-induced obese (DIO) mice.

Full text of DOI:10.1016/j.bmc.2010.12.002

Bioorganic & Medicinal Chemistry 19 (2011) 883–893
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Discovery of novel phenylpyridone derivatives as potent and selective
MCH1R antagonists
⇑
Yuji Haga, Sayaka Mizutani, Akira Naya, Hiroyuki Kishino , Hisashi Iwaasa, Masahiko Ito, Junko Ito,
Minoru Moriya, Nagaaki Sato, Norihiro Takenaga, Akane Ishihara, Shigeru Tokita, Akio Kanatani,
Norikazu Ohtake
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co. Ltd, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The design, synthesis and structure–activity relationships of a novel class of N-phenylpyridone MCH1R
antagonists are described. The core part of the N-phenylpyridone structure was newly designed and
the side chain moieties that were attached to the core part were extensively explored. As a result of
optimization of the N-phenylpyridone leads, we successfully developed the orally available, and brain-
penetrable MCH1R selective antagonist 7c, exhibiting excellent anti-obese effect in diet-induced obese
(DIO) mice.
Received 22 September 2010
Revised 1 December 2010
Accepted 2 December 2010
Available online 6 December 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Melanin-concentrating hormone
MCH1R antagonist
Anti-obesity
N-Phenylpyridone
1. Introduction
rats and mice.8,9 These findings suggest that the MCH1 receptor
could be an attractive therapeutic target for the treatment of
Obesity is recently increasing in the developed countries and is
becoming recognized as an associated risk factor for type 2 diabe-
tes, stroke, hyperlipemia and cardiovascular disease. Consequently,
obesity.
There are a number of literature disclosures and patent applica-
tions describing potent small molecule MCH1R antagonists in a
variety of structure classes.10,11 T-226296 (1), which was first dis-
closed as a potent MCH1R antagonist by Takeda, suppressed MCH-
induced food intake at 30 mpk in rats (Fig. 1).12 GSK reported the
biphenylcarboxamide analog 2 was discovered with good binding
affinity for MCH1R and moderate brain penetrability in rats
(brain–blood ratio: 1).13 Abbott established that the indazole 3
exhibited significant in vitro and in vivo potency.14 From a view-
point of molecular profiling of current MCH1R lead structures,
compounds with potent binding activity for MCH1R had common
pharmacophore which consisted of three essential components
as follows: a distal hydrophobic aryl group (A), a central N-aryl car-
boxamide core connecting the distal aryl group with a pendant ba-
sic amine (B) and a basic amine substituent coupled through a
linker (C).
In order to discover structurally diverse molecules possessing
potent MCH1R antagonist activity, we focused our attention on
replacement of the central carboxamide moiety with a pyridone
scaffold as shown in Figure 2 in hopes of further improving
in vitro and in vivo potency. In this paper, we describe our efforts
on the design, synthesis and structure–activity relationships (SAR)
of a series of N-phenylpyridone derivatives and identification of
potent and selective MCH1R antagonists for the treatment of
obesity.
pharmaceutical companies have made
a concerted effort to
develop anti-obesity agents. There are several potential biological
targets for treatment of obesity,1 in particular central nervous sys-
tem including the neuropeptide-Y Y5 receptor, serotonin 5-HT2c
receptor, cannabinoid 1 (CB1) receptor and melanin-concentrating
hormone receptor 1 (MCH1R).
MCH is a cyclic 19-amino acid neuropeptide expressed through-
out the brain, predominantly in mammalian neurons in the lateral
hypothalamus and zona incerta region of the brain. Recent publica-
tions suggested that the MCH peptide plays a major role in the
regulation of food intake and energy homeostasis.2,3 Chronic intra-
cerebroventricular (icv) infusion of MCH stimulates food intake,
causing obesity with hyperphagia.4,5 MCH gene knock-out mice
are lean due to hypophagia and maintain elevated metabolic rate.6
In contrast, transgenic mice in which MCH is overexpressed are
susceptible to insulin resistance and prone to obesity.7 Further-
more, chronic administration of MCH1R antagonists suppresses
food intake and body weight gain in diet-induced obesity (DIO)
⇑
Corresponding author at present address: Clinical Science, MSD K.K. (Banyu
Pharmaceutical Co. Ltd), 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo 102-8667, Japan.
Tel.: +81 3 6272 2480; fax: +81 3 6238 9091.
E-mail address: hiroyuki.kishino@merck.com (H. Kishino).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.12.002

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Y. Haga et al. / Bioorg. Med. Chem. 19 (2011) 883–893
F
F3C
H
N
N
OMe
O
O
N
O
NEt2
1: Takeda (T-226296)
IC50=5.5 nM
2: GlaxoSmithKline
pKi=7.7
H
N
N
N
N
O
O
3: Abbott
IC50=1.4 nM
Figure 1. Structures of MCH1R antagonists.
A
A'
B
F3C
B'
R
Linker
C'
N
OMe
N
Aryl group
C
Aryl group
NEt2
NR1R2
O
O
O
O
N
-Aryl carboxamide
N-Phenylpyridone
Amine tail
Amine tail
2
5
Figure 2. Design of the N-phenylpyridone scaffold.
by Mitsunobu reaction with 2-(piperidin-1-yl)ethanol to afford
compound 5a in good yield (Scheme 1). Preparation of 5b is shown
in Scheme 2. Coupling reaction of 4-iodo-2-pyridone (13) with
4-(tert-butyldimethylsilyloxy)phenylboronic acid in the presence
of copper(II) acetate produced N-phenylpyridone derivative 14.
Subsequent treatment of 14 with 4-fluorophenol under Ullman
coupling conditions gave the deprotected phenol derivative 15 in
moderate yield. Phenol derivative 15 was alkylated with 2-(piper-
idin-1-yl)ethanol under Mitsunobu conditions to afford compound
5b. Derivatives at the right-hand amine part were prepared as out-
lined in Scheme 3. Coupling of commercially available pyridone
2. Chemistry
The synthesis of N-phenylpyridone MCH1R antagonists re-
ported herein is outlined in Schemes 1–5. Compound 5a was
prepared from commercially available 2-fluoro-4-iodopyridine
(8). Suzuki coupling reaction of (8) with 4-fluorophenylboronic
acid formed compound 9, followed by hydrolysis under acidic
conditions to afford pyridone derivative 10. Treatment of 10 with
1-benzyloxy-4-bromobenzene under Ullman coupling conditions
gave N-phenylpyridone derivative 11. Deprotection of the benzyl
group under acidic conditions produced phenol analog 12, followed
F
F
F
I
a
b
c
N
N
N
NH
F
O
F
O
OBn
8
9
10
11
F
F
d
e
N
N
O
O
N
OH
O
12
5a
Scheme 1. Reagents and conditions: (a) 4-Fluorophenylboronic acid, Pd(PPh3)4, 2 M Na2CO3, dimethoxyethane; (b) aq HCl; (c) 1-benzyloxy-4-bromobenzene, CuI, K2CO3,
DMF, 150 °C; (d) concd HCl, water–MeOH, reflux; (e) diethyl azodicarboxylate, PPh3, 2-(piperidin-1-yl)ethanol, THF.

Y. Haga et al. / Bioorg. Med. Chem. 19 (2011) 883–893
885
I
O
I
a
b
c
N
N
NH
F
O
O
O
OTBDMS
OH
13
14
15
O
N
F
O
N
O
5b
Scheme 2. Reagents and conditions: (a) 4-(tert-Butyldimethylsilyloxy)phenylboronic acid, Cu(OAc)2, molecular sieves 4A, pyridine, CH2Cl2; (b) 4-fluorophenol, CuI, K2CO3,
DMF, 150 °C; (c) diethyl azodicarboxylate, PPh3, 2-(piperidin-1-yl)ethanol, THF.
O
O
O
a
b
N
N
NH
O
O
O
O
O
OH
16
17
18
O
c
N
O
O
R
R =
N
N
N
N
N
O
5c
5i
5c d 5g p
−
5d
5g
5h
−
,
N
N
N
N
5j
5k
5l
5m
N
N
N
5o
5p
5n
Scheme 3. Reagents and conditions: (a) 2-(4-Iodophenoxy)tetrahydro-2H-pyran, CuI, K2CO3, DMF, 150 °C; (b) pyridinium p-toluenesulfonate, EtOH, reflux; (c) diethyl
azodicarboxylate, PPh3, ROH, THF.
(16) with 2-(4-iodophenoxy)tetrahydro-2H-pyran in the catalytic
amount of copper(I) iodide afforded the key intermediate N-phe-
nylpyridone derivative 17 in moderate yield. Compound 17 was
treated with a catalytic amount of pyridinium p-toluenesulfonate
in EtOH, followed by Mitsunobu reaction with 2-aminoethanol
derivatives to afford compounds 5c–d and 5g–p in moderate to
good yield. Compounds which have related substituents in lieu of
the left-hand benzyl group, different length linkers or other aryl
groups were synthesized as described in Scheme 4. Catalytic
hydrogenolysis of compound 5d under hydrogen atmosphere pro-
duced the phenol derivative 19, followed by Mitsunobu reaction to
give compounds 5e–f and 7a–j. Ullman coupling reaction of (16)
with 4-(methoxycarbonyl)phenylboronic acid produced compound
20, which was hydrolyzed to form carboxylic acid 21. Treatment of
21 with diphenylphosphoryl azide in MeOH–THF afforded
carbamate derivative 22, followed by alkylation with 2-(diethyl-
amino)ethyl bromide to give compound 6c. Removal of methoxy-
carbonyl group with lithium aluminum hydride afforded
compound 6a. Subsequent reductive amination with paraformal-
dehyde gave the N-methylated compound 6b.
3. Results and discussion
3.1. In vitro evaluation
The primary screening of compounds were evaluated for their
binding affinity to the membranes of CHO cells expressing human
MCH1R in a competition binding assay with [125I]-MCH as the
radioligand. Subsequently, antagonistic activity was estimated by
the inhibitory effect of compounds on intracellular calcium release
induced by MCH using FLIPR in CHO cells expressing human
MCH1R.9 Furthermore, selected compounds were evaluated for
hERG K+ channel inhibitory activity using the [35S]N-[(4R)-10-
[(2R)-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl]-3,4-dihydro-4-
hydroxyspiro-[2H-1-benzopyran-2,40-piperidin]-6-yl]methanesul-
fonamide binding assay to assess QTc prolongation liability.15

886
Y. Haga et al. / Bioorg. Med. Chem. 19 (2011) 883–893
O
HO
O
R
a
b
N
N
N
O
N
O
N
O
N
O
O
O
5d
19
5e−f 7a−j
,
F
F
R =
F
F
O
F
Cl
7d
5e
5f
7a
7b
7c
Cl
MeO
F C
3
Cl
7e
7f
7g
7h
7i
7j
Scheme 4. Reagents and conditions: (a) Pd on carbon, H2, MeOH, THF; (b) 1,10-(azodicarbonyl)dipiperidine, PBu3, ROH, THF.
O
O
O
a
c
N
N
NH
O
O
O
CO2
R
NHCO2Me
22
16
20
R = Me
b
21 R = H
O
d
N
O
NEt
2
N
R'
6c
6c
R' = CO2Me
e
6a R' = H
f
6b R' = Me
Scheme 5. Reagents and conditions: (a) 4-(Methoxycarbonyl)phenylboronic acid, Cu(OAc)2, molecular sieves 4A, pyridine, CH2Cl2; (b) 4 N NaOH, MeOH, THF; (c)
diphenylphosphoryl azide, triethylamine, MeOH, THF; (d) 2-(diethylamino)ethyl bromide hydrobromide, potassium tert-butoxide, THF; (e) LiAlH4, THF; (f) paraformaldehyde,
ZnCl2, NaB(CN)H3, MeOH.
Our initial modification of the length of linker which connected
the N-phenylpyridone analog and the distal aryl group is outlined
in Table 1. Direct attachment of the terminal phenyl group to the
pyridone analog as in 5a was detrimental to MCH1R potency.
Introduction of oxygen atom between distal phenyl group and
pyridone analog as in 5b resulted in no improvement in potency.
Interestingly, incorporation of a methyleneoxy spacer as a linker
provided compounds with good binding affinities for MCH1R
receptor (IC50 values of 4.4 and 5.8 nM for 5c and 5d, respectively).
In addition, both compounds 5c and 5d exhibited good functional
activities with IC50 values of 19 and 27 nM, respectively. However,
further elongation of the spacer, as exemplified by 5e and 5f, led to
decreases in potency with IC50 values of 650 and 150 nM, respec-
tively. These results suggest that compounds with good binding
affinity for MCH1R in the N-phenylpyridone series require a meth-
yleneoxy spacer which probably arranges the distal aryl group and
the pyridone moiety to an appropriate spatial region in MCH1R
pharmacophore.
Based on the observation that compounds with a methyleneoxy
spacer as a linker significantly exhibited MCH1R potency, further
optimization at the right-hand amine part was explored using 4-
benzyloxy-N-phenylpyridone scaffold as a template. Table 2 out-
lines the SAR of N-phenylpyridone derivatives with a variety of
amine moieties with regard to MCH1R and hERG inhibitory activ-
ities. Replacement of piperidine with morpholine (as in 5g) de-
creased hERG inhibitory activity (IC50 >10 lM), however this
change resulted in 5-fold less potent MCH1R binding affinity than
5c. Compounds with acyclic amines such as dimethylamine (5h),
diethylamine (5i) and di-isopropylamine (5j) showed comparable
MCH1R binding affinity to 5c and 5d (IC50 values of 9.5, 6.6 and
5.1 nM for 5h, 5i and 5j, respectively). Furthermore, the smallest
dimethyl amine moiety as in 5h led to a decrease in hERG inhibi-
tory activity. Incorporation of bulky benzyl group on the nitrogen
atom as in 5k was also well tolerated but increased in hERG inhib-
itory activity significantly (IC50 = 0.81
lM). Introduction of methyl
or dimethyl groups into the ethylene spacer provided compounds

Y. Haga et al. / Bioorg. Med. Chem. 19 (2011) 883–893
887
Table 1
Table 2
hMCHIR binding affinity of compounds 5a–5f
Profiles of compounds 5c–d, 5g–p and 6a–c
X
O
N
R
N
O
NR1R2
O
O
a
a
R3
Compd
R
F
X (Linker)
Null
NR1R2
IC50 (nM)
FLIPR IC50 (nM)
Compd
R3
hMCH1R
FLIPR
hERG
5a
>1000
nt
nt
19
a
a
b
IC50 (nM)
IC50 (nM)
IC50
(l
M)
N
N
5b
5c
F
O
>1000
4.4
5c
5d
5g
4.4
5.8
24
19
27
34
5.8
8.1
>10
N
N
O
H
CH2O
N
N
N
N
O
5d
5e
5f
H
F
CH2O
5.8
27
nt
nt
O
N
O
O
O
CH2CH2O
OCH2CH2O
650
150
NMe2
NEt2
5h
5i
9.5
6.6
5.1
3.8
18
24
22
nt
>10
9.8
F
NiPr2
Values are means of two experiments. Compounds competed with [125I]-MCH
for binding at the human MCH1 receptor. nt = not tested.
a
5j
4.3
O
O
NMeBn
5k
0.81
5l and 5m, but with a drop in intrinsic MCH1R potency (IC50 values
of 51 and 180 nM for 5l and 5m, respectively). Immobilization of
the amine side chain onto the ethylene spacer via cyclization
provided piperidinyl (5n) and pyrrolidinyl analogs (5o and 5p)
with a slight decrease in MCH1R potency. Replacement of the oxy-
gen atom, which had connected the N-phenylpyridone analog and
the amine tail, with a nitrogen atom, led to compound 6a with
comparable MCH1R binding affinity and hERG inhibitory activity
to 5d. Subsequently, methyl substitution on the proximal nitrogen
atom of 6a provided compound 6b with a slight loss in MCH1R po-
tency with IC50 values of 16 nM and increase in hERG inhibitory
5l
51
nt
nt
nt
nt
NMe2
NMe2
N
O
O
5m
180
O
5n
5o
18
12
nt
5.8
9.3
N
23
O
O
5p
6a
6b
18
6.8
16
nt
nt
nt
>10
7.0
1.7
N
activity with IC50 values of 1.7 lM. Moreover, the methyl carba-
mate 6c was devoid of MCH1R activity.
NEt2
N
H
In an attempt to further enhance the MCH1R in vitro profiles,
we investigated the development of SAR of the distal phenyl group
as outlined in Table 3. Substitution with fluorine or chlorine atom
on the distal phenyl ring provided compounds (7a–7f) with good
MCH1R binding activities. Among these compounds, substitution
at the para-position exhibited significantly excellent potency
(IC50 values of 5.6 and 1.4 nM for fluoro 7c and chloro 7f, respec-
tively). In addition, 7c and 7f were comparable functional activity
to 5d. The relatively small fluoro derivative 7c showed less potent
hERG inhibitory activity than 7f (hERG inhibitory IC50 values of 9.0
NEt2
NEt2
N
N
6c
>1000
nt
nt
O
OMe
Values are means of two experiments. Compounds competed with [125I]-MCH
for binding at the human MCH1 receptor.
a
b
Inhibition of
[
35S]N-[(4R)-10-[(2R)-6-cyano-1,2,3,4-tetrahydro-2-naphthyl]-3,
4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,40-piperidin]-6-yl]methanesulfon-
amide binding to hERG in HEK293 cells. nt = not tested.
and 1.7 lM for 7c and 7f, respectively). Incorporation of electron
donating methoxy (7g) and electron withdrawing trifluoromethyl
(7h) at the para-position were also tolerated but both resulted in
increase in hERG inhibitory activities as compared to fluoro
compound 7c. Incorporation of a biphenyl moiety (7i) led to a
significant drop in potency, whereas the naphthyl derivative 7j
retained MCH1R binding affinity but without improving hERG
inhibitory activity.
penetrability with brain concentration of 2.4 lM and besides CSF
exposure of 7c is much higher than that of 7f. In addition, com-
pound 7c was confirmed to have excellent selectivity over not only
hERG inhibitory activity but also a panel of 150 diverse, unrelated
binding sites (500-fold less affinity than MCH 1R binding affinity).
Encouraged by its good potency, selectivity and excellent brain
penetrability, further evaluation of compound 7c in an acute food
intake model was investigated. The food intake efficacy of 7c was
evaluated in established DIO mice fed a high-fat diet. Acute oral
administration of 7c dose-dependently suppressed spontaneous
food intake for 24 h in DIO mice as outlined in Figure 3 (6%, 13%
and 19% at 3, 10 and 30 mg/kg, respectively).16 The excellent
in vivo efficacy of 7c in the food intake model stimulated us to fur-
ther evaluate this antagonist in a chronic efficacy model. Chronic
oral administration of 7c at 3, 10 and 30 mg/kg once-daily for
1.5 months dose-dependently reduced the food intake and body
weight of established DIO mice. The reduction of the body weight
at the end of treatment was 4%, 11% and 21% loss in body weight at
3, 10 and 30 mpk, q.d., respectively (Fig. 4).17
3.2. In vivo evaluation
The representative compounds 5c, 7c and 7f were evaluated for
their ability to penetrate the CNS in rats. The brain and cerebrospi-
nal fluid (CSF) levels in SD rats were examined (2 h after 10 mg/kg
oral administration of these compounds) as compiled in Table 4. All
compounds in the N-phenylpyridone series exhibited good brain
penetrability with brain/plasma ratios of 3.8, 2.4 and 3.6 for 5c,
7c and 7f, respectively. The relatively low plasma level of 5c is prob-
ably attributable to its metabolical unstability in rats relative to 7c
(data was not shown). Compound 7c exhibited excellent brain

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Y. Haga et al. / Bioorg. Med. Chem. 19 (2011) 883–893
Table 3
Table 4
Profiles of compounds 7a–7j
Biological properties of the representative phenylpyridone compounds
R4
O
Compd
Brain penetration in SD rats 2 h @10 mpk
Plasma (
lM)
Brain (nmol/g)
CSF (l
M)
Brain/plasma ratio
N
5c
7c
7f
0.2
1.0
0.47
0.76
2.4
1.67
nd
0.055
0.01
3.8
2.4
3.6
O
N
O
Compd
R
hMCH1R
IC50 (nM)
FLIPR
IC50 (nM)
hERG
IC50
nd = Not detected.
a
a
b
(
lM)
7a
8.7
30
4.3
F
7b
7c
5.9
5.6
22
23
2.9
9.0
F
F
7d
12
nt
nt
Cl
7e
7f
4.2
1.4
7.0
6.7
nt
1.9
1.7
1.2
2.4
Cl
Cl
Figure 3. Effect of 7c on spontaneous food intake in DIO mice. Food intake was
measured 24 h after 7c was orally administrated. #P <0.05 versus vehicle treated
control group. ##P <0.01 versus vehicle treated control group.
17
11
49
MeO
7g
7h
F C
3
7i
7j
640
7.7
nt
nt
175
0.67
a
Values are means of two experiments. Compounds competed with [125I]-MCH
for binding at the human MCH1 receptor.
b
Inhibition of
[
35S]N-[(4R)-10-[(2R)-6-cyano-1,2,3,4-tetrahydro-2-naphthyl]-3,
4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,40-piperidin]-6-yl]methanesulfona-
mide binding to hERG in HEK293 cells. nt = not tested.
4. Conclusion
Figure 4. Body weight change in DIO mice with administration of compound 7c for
1.5 months (q.d). Data are mean SEM. #P <0.05 versus vehicle treated control
group. ##P <0.01 versus vehicle treated control group.
In conclusion, we designed the novel N-phenylpyridone struc-
ture as a central core, and explored the side chain moieties that
were attached to this core, aiming at identifying a potent MCH1R
antagonist. The structure–activity relationship and the subsequent
characterization of the selected compounds revealed that 7c was a
potent and selective MCH1R antagonist with excellent brain pene-
trability. Compound 7c exhibited excellent body weight reduction
in a dose-dependent manner in DIO mice model. Further develop-
ment of the N-phenylpyridone class is ongoing to evaluate their
potential as a clinical development candidate for the treatment
of obesity.
400 MHz on a Mercury-400 (Varian) or 400 MHz on a JMN-AL400
(JEOL) spectrometer, with chemical shifts (d, ppm) expressed rela-
tive to TMS as an internal standard. Mass spectra were recorded
with electron-spray ionization (ESI) or atmospheric pressure
chemical ionization (APCI) on a Waters micromass ZQ, micromass
Quattro II or micromass Q-TOF-2 instrument. TLC was performed
with Merck Silica Gel 60 F254 pre-coated plates. Flash chromatog-
raphy was carried out with Wakogel C-300 (mesh 45–75 lm) or
prepacked silica gel columns (KP-Sil silica) from Biotage. Prepara-
tive thin-layer chromatography (TLC) was performed with TLC Sil-
ica Gel 60 F (Merck KGaA). Preparative HPLC purification was
carried out on a YMC-Pack Pro C18 (YMC, 50 ꢀ 30 mm i.d.), eluting
with a gradient of CH3CN/aqueous CF3CO2H (0.1%) 10:90 to 50:50
over 8 min at a flow rate of 40 mL/min. High-resolution mass spec-
tra were recorded with electron-spray ionization on a micromass
Q-TOF-2 instrument. Melting points were determined on a Yanaco
MP-S3 melting point apparatus and are uncorrected.
5. Experimental
5.1. Chemistry
5.1.1. General procedures
In general, all reagents and solvents were obtained from com-
mercial suppliers and used without further purification. The 1H
NMR spectra were obtained at 300 MHz on
a Gemini-300,

Y. Haga et al. / Bioorg. Med. Chem. 19 (2011) 883–893
889
5.1.2. 1-[4-(Benzyloxy)phenyl]-4-(4-fluorophenyl)pyridin-
2(1H)-one (11)
Cu(OAc)2 (2.46 g, 13.6 mmol), pyridine (0.73 mL, 27.1 mmol),
molecular sieves 4A (2.0 g) in CH2Cl2 (40 mL) was stirred at room
temperature for 2.5 days. The mixture was filtrated and washed
with brine (100 mL). The organic fraction was dried over MgSO4
and the solvent was evaporated under reduced pressure. The resi-
due was purified by flash chromatography on silica gel (EtOAc/hex-
ane) and crystallized (hexane) to give compound 14 (439 mg, 11%)
as a white solid. 1H NMR (300 MHz, DMSO-d6) d: 0.22 (s, 6H), 0.96
(s, 9H), 6.60 (dd, J = 7.0, 1.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.01 (d,
J = 1.8 Hz, 1H) , 7.26 (d, J = 8.8 Hz, 2H) , 7.38 (d, J = 7.0 Hz, 1H).
A mixture of 2-fluoro-4-iodopyridine (8, 2.0 g, 8.97 mmol), (4-
fluorophenyl)boronic acid (1.4 g, 10.0 mmol), tetrakis(triphenyl-
phosphine)palladium (270 mg, 0.234 mmol), 2 M Na2CO3 (10 mL)
in DME (20 mL) was stirred at 80 °C overnight. The mixture was
cooled and diluted with EtOAc (20 mL), then washed with water
(20 mL) and brine (20 mL). The organic fraction was dried over
MgSO4 and the solvent was evaporated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(EtOAc/hexane) to give compound 9 (1.70 g, 99%) as a white solid.
A
mixture of 2-fluoro-4-(4-fluorophenyl)pyridine (9, 1.70 g,
5.1.6. 4-(4-Fluorophenoxy)-1-(4-hydroxyphenyl)pyridin-2(1H)-
one (15)
8.97 mmol) in concd HCl (5 mL) and water (10 mL) was refluxed
for 4hr and stirred at room temperature overnight. The precipitate
was collected and washed with water and acetone to afford com-
pound 10 (1.46 g, 87%) as a white solid. Compound 10 was used
without further purifications. A mixture of 4-(4-fluorophenyl)pyri-
din-2(1H)-one (10, 300 mg, 1.58 mmol), 1-(benzyloxy)-4-bromo-
benzene (500 mg, 1.90 mmol), CuI (90 mg, 0.48 mmol), K2CO3
(440 mg, 3.17 mmol) in DMF (6 mL) was stirred at 150 °C over-
night. Furthermore, 1-(benzyloxy)-4-bromobenzene (180 mg,
0.684 mmol) and CuI (150 mg, 0.80 mmol) were added to the mix-
ture and stirred at 150 °C for 6 h and then cooled. The mixture was
diluted with CHCl3 (200 mL), then washed with water (200 mL)
and brine (100 mL). The organic fraction was dried over MgSO4
and the solvent was evaporated under reduced pressure. The resi-
due was purified by flash chromatography on silica gel (EtOAc/hex-
ane) and crystallized (EtOAc/hexane) to provide compound 11
(458 mg, 78%) as a white solid. 1H NMR (300 MHz, DMSO-d6) d:
5.18 (s, 2H), 6.64 (dd, J = 7.2, 2.0 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H),
7.12 (d, J = 8.9 Hz, 2H), 7.28–7.51 (m, 9H), 7.69 (d, J = 7.2 Hz, 1H),
7.83 (dd, J = 8.9, 5.4 Hz, 2H).
A mixture of 1-[4-(tert-butyldimethylsilyloxy)phenyl]-4-iodo-
pyridin-2(1H)-one (14, 100 mg, 0.23 mmol), 4-fluorophenol
(29 mg, 0.26 mmol), CuI (50 mg, 0.26 mmol), K2CO3 (65 mg,
0.27 mmol) in DMF (1 mL) was stirred at 150 °C for 1.5 h. CHCl3
(20 mL) and water (20 mL) were added to the mixture, and then
the mixture was filtrated. The organic layer was washed with brine
(10 mL). The organic fraction was dried over MgSO4 and the sol-
vent was evaporated under reduced pressure. The residue was
purified by flash chromatography on silica gel (EtOAc/hexane)
and crystallized (EtOAc/hexane) to provide compound 15 (18 mg,
26%) as a white solid. 1H NMR (300 MHz, CDCl3) d: 5.84 (d,
J = 2.6 Hz, 1H), 6.19 (dd, J = 7.5, 2.6 Hz, 1H), 6.61 (d, J = 8.8 Hz,
2H), 6.98 (d, J = 8.8 Hz, 2H), 7.07–7.15 (m, 4H), 7.32 (d, J = 7.6 Hz,
1H); MS (ESI) m/z = 298 [M+H]+.
5.1.7. 4-(4-Fluorophenoxy)-1-{4-[2-(piperidin-1-yl)ethoxy]
phenyl}pyridin-2(1H)-one (5b)
Compound 5b was prepared from 15 and 2-(piperidin-1-yl)eth-
anol using the procedure described for 5a with 55% as a white so-
lid. 1H NMR (300 MHz, DMSO-d6) d: 1.31–1.40 (m, 2H), 1.42–1.52
(m, 4H), 2.36–2.43 (m, 4H), 2.65 (t, J = 6.0 Hz, 2H), 4.09 (t,
J = 6.0 Hz, 2H), 5.45 (d, J = 2.9 Hz, 1H), 6.14 (dd, J = 7.6, 2.9 Hz,
1H), 7.01 (d, J = 8.9 Hz, 2H), 7.24 (d, J = 8.9 Hz, 2H), 7.27–7.37 (m,
4H), 7.65 (d, J = 7.6 Hz, 1H); MS (ESI) m/z = 409 [M+H]+; HRMS
(ESI) calcd for C24H26FN2O3 409.1927; found 409.1922 [M+H]+.
5.1.3. 4-(4-Fluorophenyl)-1-(4-hydroxyphenyl)pyridin-2(1H)-
one (12)
A mixture of 1-[4-(benzyloxy)phenyl]-4-(4-fluorophenyl)pyri-
din-2(1H)-one (11, 200 mg, 0.539 mmol) in concd HCl (2 mL)–
water (2 mL)–MeOH (2 mL) was refluxed for 1 h. Concd H2SO4
(0.5 mL) was added to the mixture and the mixture was refluxed
for 3 h. The mixture was diluted with water (5 mL) and cooled to
room temperature with stirring. The precipitate was collected
and washed with water and MeOH to afford compound 12
(141 mg, 93%) as a pale yellow solid. The solid was used without
further purifications.
5.1.8. 4-(Benzyloxy)-1-[4-(tetrahydro-2H-pyran-2-yloxy)-
phenyl]pyridin-2(1H)-one (17)
A
mixture of 4-(benzyloxy)pyridin-2(1H)-one (16, 26.06 g,
129.5 mmol), 2-(4-iodophenoxy)tetrahydro-2H-pyran (50.3 g,
165.4 mmol), CuI (7.78 g, 40.85 mmol), K2CO3 (38.12 g, 275.8
mmol) in DMF (500 mL) was stirred at 150 °C for 24 h. The mixture
was cooled and poured into water (3.0 L) to appear a precipitate.
The precipitate was collected and then the precipitate was dis-
solved in CHCl3 (1 L). The organic layer was washed with brine
(500 mL) and dried over MgSO4. The solvent was evaporated under
reduced pressure and the residue was crystallized (EtOAc) to give
compound 17 (28.12 g, 60%) as a white solid. 1H NMR (300 MHz,
DMSO-d6) d: 1.46–1.58 (m, 3H), 1.58–1.93 (m, 3H), 3.50–3.60 (m,
1H), 3.70–3.81 (m, 1H), 5.12 (s, 2H), 5.52 (s, 1H), 5.95 (d,
J = 2.7 Hz, 1H), 6.06 (dd, J = 7.7, 2.7 Hz, 1H), 7.09 (d, J = 8.8 Hz,
2H), 7.25 (d, J = 8.8 Hz, 2H), 7.32–7.49 (m, 5H), 7.53 (d, J = 7.7 Hz,
1H); MS (ESI) m/z = 378 [M+H]+.
5.1.4. 4-(4-Fluorophenyl)-1-{4-[2-(piperidin-1-
yl)ethoxy]phenyl}pyridin-2(1H)-one (5a)
To a solution of 4-(4-fluorophenyl)-1-(4-hydroxyphenyl)pyri-
din-2(1H)-one (12, 40 mg, 0.142 mmol), PPh3 (56 mg, 0.213 mmol),
2-(piperidin-1-yl)ethanol (0.025 mL, 0.170 mmol) in THF (2 mL)
was added diethyl azodicarboxylate (37 mg, 0.213 mmol). The
mixture was stirred at room temperature for 4 h and concentrated
under reduced pressure. The residue was purified by flash chroma-
tography on silica gel (MeOH/CHCl3) and crystallized (EtOAc/hex-
ane) to give compound 5a (41 mg, 73%) as a white solid. 1H NMR
(300 MHz, DMSO-d6) d: 1.32–1.42 (m, 2H), 1.43–1.54 (m, 4H),
2.38–2.46 (m, 4H), 2.66 (t, J = 5.9 Hz, 2H), 4.11 (t, J = 5.9 Hz, 2H),
6.63 (dd, J = 7.2, 2.0 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 7.05 (d,
J = 8.9 Hz, 2H), 7.29–7.37 (m, 4H), 7.68 (d, J = 7.2 Hz, 1H), 7.83
(dd, J = 8.9, 5.5 Hz, 2H); MS (ESI) m/z = 393 [M+H]+; HRMS (ESI)
calcd for C24H26FN2O2 393.1978; found 393.1977 [M+H]+.
5.1.9. 4-(Benzyloxy)-1-(4-hydroxyphenyl)pyridin-2(1H)-one (18)
A
mixture of 4-(benzyloxy)-1-[4-(tetrahydro-2H-pyran-2-
yloxy)phenyl]pyridin-2(1H)-one (17, 982 mg, 2.60 mmol), pyridi-
nium p-toluenesulfonate (65 mg, 0.26 mmol) in EtOH (16 mL)
was refluxed for 1 h. The mixture was cooled and water (60 mL)
was added to the mixture to appear a precipitate. The precipitate
was collected and washed with water and EtOAc to afford com-
pound 18 (746 mg, 98%) as a white solid. 1H NMR (300 MHz, CDCl3)
5.1.5. 1-[4-(tert-Butyldimethylsilyloxy)phenyl]-4-iodopyridin-
2(1H)-one (14)
A mixture of 4-iodepyridin-2(1H)-one (13, 2.0 g, 9.05 mmol), 4-
(tert-butyldimethylsilyloxy)phenylboronic acid (6.8 g, 27.1 mmol),
d: 5.06 (s, 2H), 6.08–6.15 (m, 2H), 6.73 (d, J = 8.8 Hz, 2H), 7.07 (d,

890
Y. Haga et al. / Bioorg. Med. Chem. 19 (2011) 883–893
J = 8.8 Hz, 2H), 7.23 (d, J = 7.5 Hz, 1H), 7.38–7.44 (m, 5H); MS (ESI)
m/z = 294 [M+H]+.
J = 5.9 Hz, 2H), 5.12 (s, 2H), 5.94 (d, J = 2.7 Hz, 1H), 6.05 (dd, J = 7.6,
2.7 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 7.23 (d, J = 8.9 Hz, 2H), 7.32–
7.48 (m, 5H), 7.50 (d, J = 7.6 Hz, 1H); MS (ESI) m/z = 421 [M+H]+;
HRMS (ESI) calcd for C26H33N2O3 421.2491; found 421.2490 [M+H]+.
5.1.10. 4-(Benzyloxy)-1-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-
pyridin-2(1H)-one (5c)
Compound 5c was prepared from 18 and 2-(piperidin-1-yl)eth-
anol using the procedure described for 5a with 72% as a white so-
lid. 1H NMR (300 MHz, DMSO-d6) d: 1.32–1.42 (m, 2H), 1.43–1.55
(m, 4H), 2.38–2.47 (m, 4H), 2.66 (t, J = 5.5 Hz, 2H), 4.09 (t,
J = 5.9 Hz, 2H), 5.12 (s, 2H), 5.94 (d, J = 2.6 Hz, 1H), 6.05 (dd,
J = 7.7, 2.6 Hz, 1H), 7.00 (d, J = 8.9 Hz, 2H), 7.23 (d, J = 8.9 Hz, 2H),
7.32–7.47 (m, 5H), 7.50 (d, J = 7.6 Hz, 1H); MS (ESI) m/z = 405
[M+H]+; HRMS (ESI) calcd for C25H29N2O3 405.2178; found
405.2177 [M+H]+.
5.1.16. 1-(4-{2-[Benzyl(methyl)amino]ethoxy}phenyl)-4-
(benzyloxy)pyridin-2(1H)-one (5k)
Compound 5k was prepared from 18 and 2-[benzyl(methyl)-
amino]ethanol using the procedure described for 5a with 70% as
a white solid. 1H NMR (300 MHz, DMSO-d6) d: 2.23 (s, 3H), 2.75
(t, J = 5.9 Hz, 2H), 3.57 (s, 2H), 4.13 (t, J = 5.9 Hz, 2H), 5.12 (s, 2H),
5.94 (d, J = 2.8 Hz, 1H), 6.06 (dd, J = 7.6, 2.8 Hz, 1H), 7.00 (d,
J = 8.9 Hz, 2H), 7.23 (d, J = 8.9 Hz, 2H), 7.20–7.48 (m, 10H), 7.51
(d, J = 7.6 Hz, 1H); MS (ESI) m/z = 441 [M+H]+; HRMS (ESI) calcd
for C28H29N2O3 441.2178; found 441.2180 [M+H]+.
5.1.11. 4-(Benzyloxy)-1-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-
pyridin-2(1H)-one (5d)
5.1.17. 4-(Benzyloxy)-1-(4-{[1-(dimethylamino)propan-2-yl]-
oxy}phenyl)pyridin-2(1H)-one (5l)
Compound 5d was prepared from 18 and 2-(pyrrolidin-1-
yl)ethanol using the procedure described for 5a with 85% as a
white solid. 1H NMR (300 MHz, DMSO-d6) d: 1.80–1.85 (m, 4H),
2.62–2.67 (m, 4H), 2.93 (t, J = 6.3 Hz, 2H), 4.15 (t, J = 6.3 Hz,2H),
5.03 (s, 2H), 6.03 (dd, J = 7.8, 2.4 Hz, 1H), 6.06 (d, J = 2.4 Hz, 1H),
6.99 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 8.6 Hz,
2H), 7.40 (dd, J = 13.7, 4. 3 Hz, 5H); MS (ESI) m/z = 391 [M+H]+;
HRMS (ESI) calcd for C24H27N2O3 391.2022; found 391.2021
[M+H]+; mp 109–111 °C.
Compound 5l was prepared from 18 and 1-(dimethyl-
amino)propan-2-ol (racemate) using the procedure described for
5a with 9% as a white solid. 1H NMR (300 MHz, DMSO-d6) d: 1.24
(d, J = 6.0 Hz, 3H), 2.19 (s, 6H), 2.36 (dd, J = 12.7, 5.5 Hz, 1H),
2.45–2.55 (m, 1H), 4.61 (m, 1H), 5.12 (s, 2H), 5.95 (d, J = 2.7 Hz,
1H), 6.05 (dd, J = 7.5, 2.7 Hz, 1H), 7.00 (d, J = 8.9 Hz, 2H), 7.22 (d,
J = 8.9 Hz, 2H), 7.32–7.48 (m, 5H), 7.52 (d, J = 7.5 Hz, 1H); MS
(ESI) m/z = 379 [M+H]+; HRMS (ESI) calcd for C23H27N2O3
379.2022; found 379.2031 [M+H]+.
5.1.12. 4-(Benzyloxy)-1-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-
pyridin-2(1H)-one (5g)
5.1.18. 4-(Benzyloxy)-1-(4-{[1-(dimethylamino)-2-methyl-
propan-2-yl]oxy}phenyl)pyridin-2(1H)-one (5m)
Compound 5g was prepared from 18 and 2-(morpholin-4-
yl)ethanol using the procedure described for 5a with 82% as a
white solid. 1H NMR (300 MHz, DMSO-d6) d: 2.40–2.55 (m, 4H),
2.70 (t, J = 5.6 Hz, 2H), 3.53–3.60 (m, 4H), 4.12 (t, J = 5.6 Hz, 2H),
5.12 (s, 2H), 5.94 (d, J = 2.6 Hz, 1H), 6.06 (dd, J = 7.6, 2.6 Hz, 1H),
7.01 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.32–7.48 (m, 5H),
7.50 (d, J = 7.6 Hz, 1H); MS (ESI) m/z = 407 [M+H]+; HRMS (ESI)
calcd for C24H27N2O4 407.1971; found 407.1974 [M+H]+.
Compound 5m was prepared from 18 and 2-(dimethylamino)-
2-methylpropan-1-ol using the procedure described for 5a with
61% as a white solid. 1H NMR (300 MHz, DMSO-d6) d: 1.27 (s,
6H), 2.29 (s, 6H), 2.47 (s, 2H), 5.12 (s, 2H), 5.96 (d, J = 2.8 Hz, 1H),
6.06 (dd, J = 7.6, 2.8 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 7.23 (d,
J = 8.8 Hz, 2H), 7.32–7.48 (m, 5H), 7.54 (d, J = 7.6 Hz, 1H); MS
(ESI) m/z = 393 [M+H]+; HRMS (ESI) calcd for C24H29N2O3
393.2178; found 393.2181 [M+H]+.
5.1.13. 4-(Benzyloxy)-1-{4-[2-(dimethylamino)ethoxy]phenyl}-
pyridin-2(1H)-one (5h)
5.1.19. 4-(Benzyloxy)-1-{4-[(1-methylpiperidin-2-yl)methoxy]-
phenyl}pyridin-2(1H)-one (5n)
Compound 5h was prepared from 18 and 2-(dimethyl-
amino)ethanol using the procedure described for 5a with 60% as
a white solid. 1H NMR (300 MHz, DMSO-d6) d: 2.21 (s, 6H), 2.63
(t, J = 5.8 Hz, 2H), 4.08 (t, J = 5.8 Hz, 2H), 5.12 (s, 2H), 5.94 (d,
J = 2.6 Hz, 1H), 6.06 (dd, J = 7.6, 2.6 Hz, 1H), 7.01 (d, J = 8.9 Hz,
2H), 7.23 (d, J = 8.9 Hz, 2H), 7.32–7.48 (m, 5H), 7.51 (d, J = 7.6 Hz,
1H); MS (ESI) m/z = 365 [M+H]+; HRMS (ESI) calcd for
Compound 5n was prepared from 18 and (1-methylpiperidin-2-
yl)methanol (racemate) using the procedure described for 5a with
16% as a white solid. 1H NMR (300 MHz, DMSO-d6) d: 1.10–1.85 (m,
6H), 2.00–2.90 (m, 6H), 3.90–4.15 (m, 2H), 5.12 (s, 2H), 5.94 (d,
J = 2.7 Hz, 1H), 6.06 (dd, J = 7.6, 2.6 Hz, 1H), 7.01 (d, J = 8.7 Hz,
2H), 7.24 (d, J = 8.7 Hz, 2H), 7.32–7.48 (m, 5H), 7.51 (d, J = 7.6 Hz,
1H); MS (ESI) m/z = 405 [M+H]+; HRMS (ESI) calcd for C25H29N2O3
405.2178; found 405.2177 [M+H]+.
C
22H25N2O3 365.1865; found 365.1863 [M+H]+.
5.1.14. 4-(Benzyloxy)-1-{4-[2-(diethylamino)ethoxy]phenyl}-
pyridin-2(1H)-one (5i)
5.1.20. 4-(Benzyloxy)-1-{4-[(1-methylpyrrolidin-2-yl)methoxy]-
phenyl}pyridin-2(1H)-one (5o)
Compound 5i was prepared from 18 and 2-(diethylamino)etha-
nol using the procedure described for 5a with 73% as a white solid.
1H NMR (300 MHz, DMSO-d6) d: 0.97 (t, J = 7.1 Hz, 6H), 2.54 (q,
J = 7.1 Hz, 4H), 2.78 (t, J = 5.9 Hz, 2H), 4.04 (t, J = 5.9 Hz, 2H), 5.12
(s, 2H), 5.94 (d, J = 2.7 Hz, 1H), 6.05 (dd, J = 7.6, 2.6 Hz, 1H), 7.00
(d, J = 8.9 Hz, 2H), 7.23 (d, J = 8.9 Hz, 2H), 7.32–7.48 (m, 5H), 7.51
(d, J = 7.6 Hz, 1H); MS (ESI) m/z = 393 [M+H]+; HRMS (ESI) calcd
for C24H29N2O3 393.2178; found 393.2171 [M+H]+.
Compound 5o was prepared from 18 and (1-methylpyrrolidin-2-
yl)methanol (racemate) using the procedure described for 5a with
17% as a white solid. 1H NMR (300 MHz, DMSO-d6) d: 1.50–1.75
(m, 3H), 1.90–2.05 (m, 1H), 2.13–2.28 (m, 1H), 2.37 (s, 3H), 2.53–
2.63 (m, 1H), 2.92–3.00 (m, 1H), 3.82–3.90 (m, 1H), 3.97–4.05 (m,
1H), 5.12 (s, 2H), 5.94 (d, J = 2.9 Hz, 1H), 6.06 (dd, J = 7.6, 2.9 Hz,
1H), 7.01 (d, J = 8.9 Hz, 2H), 7.23 (d, J = 8.9 Hz, 2H), 7.32–7.48 (m,
5H), 7.51 (d, J = 7.6 Hz, 1H); MS (ESI) m/z = 391 [M+H]+; HRMS
(ESI) calcd for C24H27N2O3 391.2022; found 391.2022 [M+H]+.
5.1.15. 4-(Benzyloxy)-1-{4-[2-(diisopropylamino)ethoxy]-
phenyl}pyridin-2(1H)-one (5j)
Compound 5j was prepared from 18 and 2-(diisopropyl-
amino)ethanol using the procedure described for 5a with 73% as a
white solid. 1H NMR (300 MHz, DMSO-d6) d: 0.98 (d, J = 6.5 Hz,
12H), 2.79 (t, J = 6.9 Hz, 2H), 3.01 (h, J = 6.5 Hz, 2H), 3.90 (t,
5.1.21. 4-(Benzyloxy)-1-{4-[(1-methylpyrrolidin-3-yl)oxy]-
phenyl}pyridin-2(1H)-one (5p)
Compound 5p was prepared from 18 and 1-methylpyrrolidin-3-
ol (racemate) using the procedure described for 5a with 28% as a

Y. Haga et al. / Bioorg. Med. Chem. 19 (2011) 883–893
891
white solid. 1H NMR (300 MHz, DMSO-d6) d: 1.70–1.85 (m, 1H),
2.25 (s, 3H), 2.25–2.40 (m, 2H), 2.53–2.81 (m, 3H), 4.85–4.95 (m,
1H), 5.12 (s, 2H), 5.94 (d, J = 2.7 Hz, 1H), 6.05 (dd, J = 7.6, 2.7 Hz,
1H), 6.94 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.9 Hz, 2H), 7.32–7.48 (m,
5H), 7.51 (d, J = 7.6 Hz, 1H); MS (ESI) m/z = 377 [M+H]+; HRMS
(ESI) calcd for C23H25N2O3 377.1865; found 377.1866 [M+H]+.
MS (ESI) m/z = 409 [M+H]+; HRMS (ESI) calcd for C24H26FN2O3
409.1927; found 409.1931 [M+H]+.
5.1.27. 4-[(4-Fluorobenzyl)oxy]-1-{4-[2-(pyrrolidin-1-yl)ethoxy]-
phenyl}pyridin-2(1H)-one (7c)
Compound 7c was prepared from 19 and 4-fluorophenylmetha-
nol using the procedure described for 5e with 48% as a white solid.
1H NMR (400 MHz, CDCl3) d: 1.81–1.86 (m, 4H), 2.64–2.70 (m, 4H),
2.95 (t, J = 5.9 Hz, 2H), 4.16 (t, J = 5.9 Hz, 2H), 4.99 (s, 2H), 6.01 (dd,
J = 7.4, 2.9 Hz, 1H), 6.04 (d, J = 2.9 Hz, 1H), 6.99 (d, J = 8.6 Hz, 2H),
7.10 (t, J = 8.6 Hz, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.25 (d, J = 8.6 Hz,
2H), 7.40 (dd, J = 8.6, 5.5 Hz, 2H); MS (ESI) m/z = 409 [M+H]+; HRMS
(ESI) calcd for C24H26FN2O3 409.1927; found 409.1933 [M+H]+; mp
124–126 °C.
5.1.22. 4-Hydroxy-1-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-
pyridin-2(1H)-one (19)
To
a solution of 4-(benzyloxy)-1-{4-[2-(pyrrolidin-1-yl)eth-
oxy]phenyl}pyridin-2(1H)-one (5d, 395 mg, 1.01 mmol) in THF
(5 mL) and MeOH (5 mL) was added Pd (10 wt % on activated car-
bon, 200 mg). The mixture was stirred at room temperature under
H2 atmosphere for 2 h. The mixture was filtrated and washed with
MeOH. The filtrate was concentrated to give compound 19
(303 mg, 99%) as a white solid. 1H NMR (400 MHz, DMSO-d6) d:
1.82–1.87 (m, 4H), 2.68–2.74 (m, 4H), 2.96 (t, J = 5.8 Hz, 2H), 4.12
(t, J = 5.8 Hz, 2H), 5.84 (d, J = 2.4 Hz, 1H), 5.92 (dd, J = 7.8, 2.4 Hz,
1H), 6.98 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 7.8 Hz, 1H), 7.17 (d,
J = 8.8 Hz, 2H); MS (ESI) m/z = 301 [M+H]+.
5.1.28. 4-[(2-Chlorobenzyl)oxy]-1-{4-[2-(pyrrolidin-1-yl)ethoxy]-
phenyl}pyridin-2(1H)-one (7d)
Compound 7d was prepared from 19 and 2-chlorophenylmeth-
anol using the procedure described for 5e with 42% as a white so-
lid. 1H NMR (400 MHz, DMSO-d6) d: 1.66–1.69 (m, 4H), 2.45–2.55
(m, 4H), 2.79 (t, J = 5.9 Hz, 2H), 4.10 (t, J = 5.9 Hz, 2H), 5.17 (s,
2H), 5.98 (d, J = 2.6 Hz, 1H), 6.06 (dd, J = 7.6, 2.6 Hz, 1H), 7.01 (d,
J = 9.0 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H), 7.39–7.45 (m, 2H), 7.51–
7.55 (m, 2H), 7.61 (d, J = 7.6 Hz, 1H); MS (ESI) m/z = 425 [M+H]+;
HRMS (ESI) calcd for C24H26ClN2O3 425.1632; found 425.1628
[M+H]+.
5.1.23. 4-[2-(4-Fluorophenyl)ethoxy]-1-{4-[2-(pyrrolidin-1-yl)-
ethoxy]phenyl}pyridin-2(1H)-one (5e)
To a solution of 4-hydroxy-1-{4-[2-(pyrrolidin-1-yl)ethoxy]-
phenyl}pyridin-2(1H)-one (19, 30 mg, 0.10 mmol), PBu3 (0.075
mL, 0.30 mmol), 2-(4-fluorophenyl)ethanol (0.025 mL, 0.20 mmol)
in THF (1 mL) was added 1,10-(azodicarbonyl)dipiperidine (76 mg,
0.30 mmol). The mixture was stirred at room temperature over-
night. The mixture was concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(MeOH/CHCl3) to give compound 5e (24 mg, 57%) as a white solid.
1H NMR (400 MHz, CDCl3) d: 1.82–1.86 (m, 4H), 2.65–2.71 (m, 4H),
2.95 (t, J = 5.9 Hz, 2H), 3.07 (t, J = 6.7 Hz, 2H), 4.12–4.18 (m, 4H),
5.92–5.96 (m, 2H), 6.97–7.04 (m, 4H), 7.27–7.16 (m, 5H); MS
(ESI) m/z = 423 [M+H]+; HRMS (ESI) calcd for C25H28FN2O3
423.2084; found 423.2081 [M+H]+.
5.1.29. 4-[(3-Chlorobenzyl)oxy]-1-{4-[2-(pyrrolidin-1-yl)ethoxy]-
phenyl}pyridin-2(1H)-one (7e)
Compound 7e was prepared from 19 and 3-chlorophenylmeth-
anol using the procedure described for 5e with 45% as a white so-
lid. 1H NMR (400 MHz, DMSO-d6) d: 1.64–1.70 (m, 4H), 2.44–2.54
(m, 4H), 2.78 (t, J = 5.9 Hz, 2H), 4.09 (t, J = 5.9 Hz, 2H), 5.12 (s,
2H), 5.93 (d, J = 2.8 Hz, 1H), 6.05 (dd, J = 7.6, 2.8 Hz, 1H), 7.00 (d,
J = 8.9 Hz, 2H), 7.23 (d, J = 8.9 Hz, 2H), 7.40–7.48 (m, 3H), 7.52
(m, 2H); MS (ESI) m/z = 425 [M+H]+; HRMS (ESI) calcd for
C
24H26ClN2O3 425.1632; found 425.1630 [M+H]+.
5.1.24. 4-[2-(4-Fluorophenoxy)ethoxy]-1-{4-[2-(pyrrolidin-1-yl)-
ethoxy]phenyl}pyridin-2(1H)-one (5f)
5.1.30. 4-[(4-Chlorobenzyl)oxy]-1-{4-[2-(pyrrolidin-1-yl)ethoxy]-
phenyl}pyridin-2(1H)-one (7f)
Compound 5f was prepared from 19 and 2-(4-fluorophen-
oxy)ethanol using the procedure described for 5e with 7% as a
white solid. 1H NMR (400 MHz, CDCl3) d: 1.32–1.43 (m, 2H),
1.44–1.55 (m, 4H), 1.82–1.93 (m, 2H), 2.28–2.47 (m, 6H), 4.05 (t,
J = 6.3 Hz, 2H), 6.64 (dd, J = 7.2, 2.0 Hz, 1H), 6.75 (d, J = 2.0 Hz,
1H), 7.03 (d, J = 8.9 Hz, 2H), 7.29–7.37 (m, 4H), 7.69 (d, J = 7.2 Hz,
1H), 7.83 (dd, J = 7.8, 5.3 Hz, 2H); MS (ESI) m/z = 439 [M+H]+;
HRMS (ESI) calcd C25H28FN2O4 439.2033; found 439.2025 [M+H]+.
Compound 7f was prepared from 19 and 4-chlorophenylmeth-
anol using the procedure described for 5e with 46% as a white so-
lid. 1H NMR (400 MHz, DMSO-d6) d: 1.62–1.73 (m, 4H), 2.45–2.55
(m, 4H), 2.78 (t, J = 6.0 Hz, 2H), 4.09 (t, J = 6.0 Hz, 2H), 5.14 (s,
2H), 5.94 (d, J = 2.9 Hz, 1H), 6.08 (dd, J = 7.8, 2.9 Hz, 1H), 7.00 (d,
J = 9.0 Hz, 2H), 7.23 (d, J = 9.0 Hz, 2H), 7.39–7.48 (m, 3H), 7.50–
7.56 (m, 2H); MS (ESI) m/z = 425 [M+H]+; HRMS (ESI) calcd for
C
24H26ClN2O3 425.1632; found 425.1630 [M+H]+.
5.1.25. 4-[(2-Fluorobenzyl)oxy]-1-{4-[2-(pyrrolidin-1-yl)ethoxy]-
phenyl}pyridin-2(1H)-one (7a)
5.1.31. 4-[(4-Methoxybenzyl)oxy]-1-{4-[2-(pyrrolidin-1-yl)-
ethoxy]phenyl}pyridin-2(1H)-one (7g)
Compound 7a was prepared from 19 and 2-fluorophenylmeth-
anol using the procedure described for 5e with 41% as a white so-
lid. 1H NMR (400 MHz, CDCl3) d: 1.93–1.99 (m, 4H), 2.88–3.04 (m,
4H), 3.14–3.20 (m, 2H), 4.28–4.33 (m, 2H), 5.10 (s, 2H), 6.04 (dd,
J = 7.8, 2.4 Hz, 1H), 6.08 (d, J = 2.4 Hz, 1H), 6.95–7.49 (m, 9H); MS
(ESI) m/z = 409 [M+H]+; HRMS (ESI) calcd for C24H26FN2O3
409.1927; found 409.1932 [M+H]+.
Compound 7g was prepared from 19 and 4-methoxyphenyl-
methanol using the procedure described for 5e with 34% as a white
solid. 1H NMR (400 MHz, DMSO-d6) d: 1.64–1.70 (m, 4H), 2.44–
2.54 (m, 4H), 2.78 (t, J = 5.9 Hz, 2H), 3.76 (s, 3H), 4.09 (t,
J = 5.9 Hz, 2H), 5.03 (s, 2H), 5.94 (d, J = 2.8 Hz, 1H), 6.02 (dd,
J = 7.8, 2.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H),
7.23 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 7.8 Hz,
1H); MS (ESI) m/z = 421 [M+H]+; HRMS (ESI) calcd for
C25H29N2O4 421.2127; found 421.2130 [M+H]+.
5.1.26. 4-[(3-Fluorobenzyl)oxy]-1-{4-[2-(pyrrolidin-1-yl)ethoxy]-
phenyl}pyridin-2(1H)-one (7b)
Compound 7b was prepared from 19 and 3-fluorophenylmeth-
anol using the procedure described for 5e with 29% as a white so-
lid. 1H NMR (400 MHz, CDCl3) d: 1.90–1.94 (m, 4H), 2.82–2.90 (m,
4H), 3.08 (t, J = 5.3 Hz, 2H), 4.26 (t, J = 5.3 Hz, 2H), 5.04 (s, 2H), 6.01
(d, J = 2.7 Hz, 1H), 6.05 (dd, J = 7.7, 2.7 Hz, 1H), 6.97–7.41 (m, 9H);
5.1.32. 1-{4-[2-(Pyrrolidin-1-yl)ethoxy]phenyl}-4-{[4-(trifluoro-
methyl)benzyl]oxy}pyridin-2(1H)-one (7h)
Compound 7h was prepared from 19 and 4-trifluoromethylphe-
nylmethanol using the procedure described for 5e with 54% as a
white solid. 1H NMR (400 MHz, CDCl3) d: 1.83–1.88 (m, 4H),

892
Y. Haga et al. / Bioorg. Med. Chem. 19 (2011) 883–893
2.68–2.75 (m, 4H), 2.98 (t, J = 5.5 Hz, 2H), 4.18 (t, J = 5.5 Hz, 2H),
5.10 (s, 2H), 6.02 (d, J = 2.4 Hz, 1H), 6.05 (dd, J = 7.8, 2.4 Hz, 1H),
6.99 (d, J = 9.4 Hz, 2H), 7.22–7.27 (m, 3H), 7.54 (d, J = 7.8 Hz, 2H),
7.67 (d, J = 7.8 Hz, 2H); MS (ESI) m/z = 459 [M+H]+; HRMS (ESI)
calcd for C25H26F3N2O3 459.1896; found 459.1904 [M+H]+.
tert-butoxide (86 mg, 0.766 mmol) in THF (10 mL) was added 2-
(diethylamino)ethyl bromide hydrobromide (135 mg, 0.517 mmol)
and the mixture was stirred at room temperature for 1.5 h. The
mixture was diluted with sat. NaHCO3 (20 mL) and extracted with
CHCl3 (20 mL). The organic fraction was dried over MgSO4. The sol-
vent was evaporated under reduced pressure. The residue was
purified by flash chromatography on silica gel (MeOH/CHCl3) to
give compound 6c (107 mg, 93%) as a yellow oil. 1H NMR
(300 MHz, CDCl3) d: 1.00 (t, J = 7.1 Hz, 6H), 2.48–2.60 (m, 4H),
2.62–2.74 (m, 2H), 3.71 (s, 3H), 3.68–3.80 (m, 2H), 5.05 (s, 2H),
6.02–6.10 (m, 2H), 7.21–7.48 (m, 10H); MS (ESI) m/z = 450 [M+H]+.
5.1.33. 4-(Biphenyl-4-ylmethoxy)-1-{4-[2-(pyrrolidin-1-yl)-
ethoxy]phenyl}pyridin-2(1H)-one (7i)
Compound 7i was prepared from 19 and biphenyl-4-ylmetha-
nol using the procedure described for 5e with 38% as a white solid.
1H NMR (400 MHz, DMSO-d6) d: 1.81–1.86 (m, 4H), 2.64–2.70 (m,
4H), 2.95 (t, J = 5.9 Hz, 2H), 4.16 (t, J = 5.9 Hz, 2H), 5.08 (s, 2H), 6.05
(dd, J = 7.8, 2.3 Hz, 1H), 6.09 (d, J = 2.3 Hz, 1H), 7.00 (d, J = 8.6 Hz,
2H), 7.22 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 7.35–7.40 (m,
1H), 7.43–7.51 (m, 4H), 7.65–7.59 (m, 4H); MS (ESI) m/z = 467
[M+H]+; HRMS (ESI) calcd for C30H31N2O3 467.2335; found
467.2326 [M+H]+.
5.1.39. 4-(Benzyloxy)-1-(4-{[2-(diethylamino)ethyl]amino}-
phenyl)pyridin-2(1H)-one (6a)
To a solution of methyl N-{4-[4-(benzyloxy)-2-oxopyridin-
1(2H)-yl]phenyl}-N-[2-(diethylamino)ethyl]carbamate (6c, 100 mg,
0.222 mmol) in THF (10 mL) was added lithium aluminum hydride
(LiAlH4: 10 mg, 0.264 mmol), and the mixture was stirred at room
temperature for 1 h. Additional LiAlH4 (10 mg, 0.264 mmol) was
added to the mixture and stirred for 1.5 h. The reaction mixture
was quenched by Na2SO4ꢁ10H2O, EtOAc were added to the mixture
and stirred overnight. The precipitate was removed by filtration
and the solvent was evaporated under reduced pressure. The residue
was purified by preparative HPLC to give compound 6a (8 mg, 9%) as
a white solid. 1H NMR (300 MHz, CDCl3) d: 1.03 (t, J = 7.1 Hz, 6H),
2.57 (q, J = 7.1 Hz, 4H), 2.71 (t, J = 5.9 Hz, 2H), 3.08–3.19 (m, 2H),
4.50–4.67 (m, 1H), 5.03 (s, 2H), 6.00 (dd, J = 7.6, 2.6 Hz, 1H), 6.06
(d, J = 2.6 Hz, 1H), 6.66 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H),
7.22 (d, J = 7.6 Hz, 1H), 7.30–7.48 (m, 5H); MS (ESI) m/z = 392
[M+H]+.
5.1.34. 4-(Naphthalen-2-ylmethoxy)-1-{4-[2-(pyrrolidin-1-yl)-
ethoxy]phenyl}pyridin-2(1H)-one (7j)
Compound 7j was prepared from 19 and naphthalen-2-ylmeth-
anol using the procedure described for 5e with 43% as a white so-
lid. 1H NMR (400 MHz, DMSO-d6) d: 1.66–1.69 (m, 4H), 2.47–2.53
(m, 4H), 2.78 (t, J = 6.1 Hz, 2H), 4.09 (t, J = 5.9 Hz, 2H), 5.30 (s,
2H), 6.01 (d, J = 2.6 Hz, 1H), 6.10 (dd, J = 7.6, 2.6 Hz, 1H), 7.00 (d,
J = 8.9 Hz, 2H), 7.23 (d, J = 8.9 Hz, 2H), 7.51–7.58 (m, 4H), 7.91–
8.01 (m, 4H); MS (ESI) m/z = 441 [M+H]+; HRMS (ESI) calcd for
C
28H29N2O3 441.2178; found 441.2170 [M+H]+.
5.1.35. Methyl 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]benzo-
ate (20)
Compound 20 was prepared from 16 using the procedure de-
5.1.40. 4-(Benzyloxy)-1-(4-{[2-(diethylamino)ethyl](methyl)-
amino}phenyl)pyridin-2(1H)-one (6b)
scribed for 14 with 80% as a white solid. 1H NMR (300 MHz, CDCl3)
d
:
3.93 (s, 3H), 5.05 (s, 2H),6.04–6.13 (m, 2H), 7.21–7.25 (m, 1H),
To a solution of 4-(benzyloxy)-1-(4-{[2-(diethylamino)ethyl]-
amino}phenyl)pyridin-2(1H)-one (6a, 7 mg, 0.018 mmol) and
paraformaldehyde (1 mg) in MeOH (1 mL) was added ZnCl2
(41 mg, 0.3 mmol) and NaB(CN)H3 (23 mg, 0.6 mmol). The mixture
was stirred at room temperature for 1 h. The mixture was diluted
with CHCl3 (20 mL), washed with 1 N NaOH (10 mL) and brine
(10 mL). The organic fraction was dried over MgSO4 and the sol-
vent was evaporated under reduced pressure to give compound
6b (2.8 mg, 39%) as a white solid. 1H NMR (300 MHz, CDCl3) d:
1.06 (t, J = 7.1 Hz, 6H), 2.52–2.72 (m, 2H), 2.61 (q, J = 7.1 Hz, 4H),
3.42–3.52 (m, 2H), 2.99 (s, 3H), 5.03 (s, 2H), 6.00 (dd, J = 7.6,
2.7 Hz, 1H), 6.06 (d, J = 2.7 Hz, 1H), 6.72 (d, J = 9.0 Hz, 2H), 7.17
(d, J = 9.0 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.32–7.45 (m, 5H); MS
(ESI) m/z = 406 [M+H]+.
7.33–7.50 (m, 7H), 8.12–8.18 (m, 2H); MS (ESI) m/z = 336 [M+H]+.
5.1.36. 4-[4-(Benzyloxy)-2-oxopyridin-1(2H)-yl]benzoic acid (21)
A mixture of methyl 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-
benzoate (20, 0.39 g, 1.16 mmol), 4 N NaOH (3.2 mL, 12.8 mmol),
MeOH (20 mL) and THF (20 mL) was stirred at 90 °C for 5 h. The
mixture was cooled and 1 N HCl was added until the mixture
was adjusted to PH 2–3. The mixture was extracted with EtOAc
(100 mL). The organic fractions were dried over MgSO4. The sol-
vent was evaporated under reduced pressure to afford compound
21 (0.31 g, 83%) as a white solid. 1H NMR (300 MHz, CD3OD) d:
5.15 (s, 2H), 6.08–6.10 (m, 1H), 6.25–6.30 (m, 1H), 7.30–7.56 (m,
8H), 8.11–8.16 (m, 2H); MS (ESI) m/z = 322 [M+H]+.
5.1.37. Methyl N-{4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-
phenyl}carbamate (22)
5.2. Biology
A mixture of 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]benzoic
acid (21, 0.31 g, 0.97 mmol), diphenylphosphoryl azide (0.11 mL,
1.15 mmol), triethylamine (0.16 mL, 1.15 mmol), MeOH (0.2 mL)
and DMF (5 mL) was stirred at 100 °C overnight. The mixture was
cooled and brine (20 mL) was added. The mixture was extracted
with CHCl3 (40 mL). The organic fractions were dried over MgSO4.
The solvent was evaporated under reduced pressure. The residue
was purified by flash chromatography on silica gel (MeOH/CHCl3)
to provide compound 22 (203 mg, 60%) as a white solid. 1H NMR
(300 MHz, CDCl3) d: 3.99 (s, 3H), 5.05 (s, 2H),6.04–6.08 (m, 2H),
6.86 (brs, 1H), 7.17–7.50 (m, 10H); MS (ESI) m/z = 351 [M+H]+.
5.2.1. In vivo efficacy in diet-induced obese mice
C57BL/6J mice were fed moderately high-fat diet for about
10 months before the experiment was initiated. The mice were
then divided into three groups, and each group was orally admin-
istrated either vehicle (0.5% methylcellulose in water) or com-
pound 7c at doses of 3, 10 and 30 mg/kg once-daily for
1.5 month. Compound 7c was administered after measurement of
daily food intake and body weight, 1–2 h before the beginning of
the dark period.
Acknowledgments
5.1.38. Methyl N-{4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-
phenyl}-N-[2-(diethylamino)ethyl]carbamate (6c)
To a solution of methyl N-{4-[4-(benzyloxy)-2-oxopyridin-
1(2H)-yl]phenyl}carbamate (22, 90 mg, 0.257 mmol), potassium
We thank Hirokazu Ohsawa for collecting the high-resolution
mass spectral data, Mioko Hirayama for the hERG binding assay.
Special thanks are given to all the team members of the Tsukuba
Research Institute who dedicated their efforts towards this project.

Y. Haga et al. / Bioorg. Med. Chem. 19 (2011) 883–893
893
F. X.; Zhou, H. Q. Bioorg. Med. Chem. Lett. 2006, 16, 4723; (c) Kanuma, K.;
Omodera, K.; Nishiguchi, M.; Funakoshi, T.; Chaki, S.; Nagase, Y.; Iida, I.;
Yamaguchi, J.; Semple, G.; Tran, T. A.; Sekiguchi, Y. Bioorg. Med. Chem. 2006, 14,
3307; (d) Tavares, F. X.; Al Barazanji, K. A.; Bishop, M. J.; Britt, C. S.; Carlton, D.
L.; Cooper, J. P.; Feldman, P. L.; Garrido, D. M.; Goetz, A. S.; Grizzle, M. K.;
Hertzog, D. L.; Ignar, D. M.; Lang, D. G.; McIntyre, M. S.; Ott, R. J.; Peat, A. J.;
Zhou, H. Q. J. Med. Chem. 2006, 49, 7108; (e) Zhang, M. Z.; Tamiya, J.; Nguyen, L.;
Rowbottom, M. W.; Dyck, B.; Vickers, T. D.; Grey, J.; Schwarz, D. A.; Heise, C. E.;
Haelewyn, J.; Mistry, M. S.; Goodfellow, V. S. Bioorg. Med. Chem. Lett. 2007, 17,
2535.
We also thank Peter T. Meinke (Merck Research Laboratories,
Rahway, NJ) for the editing of this manuscript.
References and notes
1. Mancini, M. C.; Halpern, A. Expert Opin. Invest. Drugs 2006, 15, 897.
2. Saito, Y.; Nothacker, H. P.; Civelli, O. Trends Endocrinol. Metab. 2000, 11, 299.
3. Schwartz, M. W.; Woods, S. C.; Porte, D.; Seeley, R. J.; Baskin, D. G. Nature 2000,
404, 661.
4. Marsh, D. J.; Weingarth, D. T.; Novi, D. E.; Chen, H. Y.; Trumbauer, M. E.; Chen,
A. S.; Guan, X. M.; Jiang, M. M.; Feng, Y.; Camacho, R. E.; Shen, Z.; Frazier, E. G.;
Yu, H.; Metzger, J. M.; Kuca, S. J.; Shearman, L. P.; Gopal-Truter, S.; MacNeil, D.
J.; Strack, A. M.; MacIntyre, D. E.; Van der Ploeg, L. H. T.; Qian, S. Proc. Natl. Acad.
Sci. U.S.A. 2002, 99, 3240.
5. Gomori, A.; Ishihara, A.; Ito, M.; Mashiko, S.; Matsushita, H.; Yumoto, M.; Ito,
M.; Tanaka, T.; Tokita, S.; Moriya, M.; Iwaasa, H.; Kanatani, A. Am. J. Physiol.
Endocrinol. Metab. 2003, 284, E583.
6. Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, L. S.; Maratos-Flier, E. Nature
1998, 396, 670.
11. For reviews on MCH 1R antagonists, please see: (a) Dyke, H. J.; Ray, N. C.
Expert Opin. Ther. Patents 2005, 15, 1303; (b) McBriar, M. D. Curr. Opin.
Drug Discov. Dev. 2006, 9, 496; (c) Rokosz, L. L. Expert Opin. Drug Discov.
2007, 2, 1301.
12. Takekawa, S.; Asami, A.; Ishihara, Y.; Terauchi, J.; Kato, K.; Shimomura, Y.; Mori,
M.; Murakoshi, H.; Kato, K.; Suzuki, N.; Nishimura, O.; Fujino, M. Eur. J.
Pharmacol. 2002, 438, 129.
13. Witty, D. R.; Bateson, J. H.; Hervieu, G. J.; Jeffrey, P.; Johnson, C. N.; Muir, A. I.;
O’Hanlon, P. J.; Stemp, G.; Stevens, A. J.; Thewlis, K. M.; Wilson, S.; Winborn, K.
Y. Bioorg. Med. Chem. Lett. 2006, 16, 4865.
14. Souers, A. J.; Gao, J.; Brune, M.; Bush, E.; Wodka, D.; Vasudevan, A.; Judd, A. S.;
Mulhern, M.; Brodjian, S.; Dayton, B.; Shapiro, R.; Hernandez, L. E.; Marsh, K. C.;
Sham, H. L.; Collins, C. A.; Kym, P. R. J. Med. Chem. 2005, 48, 1318.
15. For hERG binding assay protocol, please see: Butcher, J. W.; Claremon, D. A.;
Connolly, T. M.; Dean, D. C.; Karczewski, J.; Koblan, K. S.; Kostura, M. J.;
Liverton, N. J.; Melillo, D. G. Radioligand and binding assay. PCT Int. Appl.
WO2002005860, 2002.
16. Ito, M.; Ishihara, A.; Gomori, A.; Egashira, S.; Matsushita, H.; Mashiko, S.; Ito, J.;
Ito, M.; Nakase, K.; Haga, Y.; Iwaasa, H.; Suzuki, T.; Ohtake, N.; Moriya, M.; Sato,
N.; MacNeil, D. J.; Takenaga, N.; Tokita, S.; Kanatani, A. Eur. J. Pharmacol. 2009,
624, 77.
7. Ludwig, D. S.; Tritos, N. A.; Mastaitis, J. W.; Kulkarni, R.; Kokkotou, E.; Elmquist,
J.; Lowell, B.; Flier, J. S.; Maratos-Flier, E. J. Clin. Invest. 2001, 107, 379.
8. 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, 8, 825.
9. Mashiko, S.; Ishihara, A.; Gomori, A.; Moriya, R.; Ito, M.; Iwaasa, H.; Matsuda,
M.; Feng, Y.; Shen, Z.; Marsh, D. J.; Bednarek, M. A.; MacNeil, D. J.; Kanatani, A.
Endocrinology 2005, 146, 3080.
10. (a) Carpenter, A. J.; Al Barazanji, K. A.; Barvian, K. K.; Bishop, M. J.; Britt, C. S.;
Cooper, J. P.; Goetz, A. S.; Grizzle, M. K.; Hertzog, D. L.; Ignar, D. M.; Morgan, R.
O.; Peckham, G. E.; Speake, J. D.; Swain, W. R. Bioorg. Med. Chem. Lett. 2006, 16,
4994; (b) Hertzog, D. L.; Al Barazanji, K. A.; Bigharn, E. C.; Bishop, M. J.; Britt, C.
S.; Carlton, D. L.; Cooper, J. P.; Daniels, A. J.; Garrido, D. M.; Goetz, A. S.; Grizzle,
M. K.; Guo, Y. C.; Handlon, A. L.; Ignar, D. M.; Morgan, R. O.; Peat, A. J.; Tavares,
17. Ito, M.; Ishihara, A.; Gomori, A.; Matsushita, H.; Ito, M.; Metzger, J. M.; Marsh,
D. J.; Haga, Y.; Iwaasa, H.; Tokita, S.; Takenaga, N.; Sato, N.; MacNeil, D. J.;
Moriya, M.; Kanatani, A. Br. J. Pharmacol. 2010, 159, 374.