Synthesis and SAR investigations for novel melanin-concentrating hormone 1 receptor (MCH1) antagonists part 2: A hybrid strategy combining key fragments of HTS hits

Article abstract of DOI:10.1021/jm060383x

A novel series of melanin-concentrating hormone (MCH₁) receptor antagonists based on combining key fragments from the high-throughput screening (HTS) hits compound 2 (SNAP 7941) and compound 5 (chlorohaloperidol) are described. The resultant analogs, exemplified by compounds 11a-11h, 15a-15h, and 16a-16g, were evaluated in in vitro and in vivo assays for their potential in treatment of mood disorders. From further SAR investigations, N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl) -2-methylpropanamide (16g, SNAP 94847) was identified to be a high affinity and selective ligand for the MCH₁ receptor. Compound 16g also shows good oral bioavailability (59%) and exhibits a brain/plasma ratio of 2.3 in rats. Compound 16g showed in vivo inhibition of a centrally induced MCH-induced drinking effect and exhibited a dose-dependent anxiolytic effect in the rat social interaction model.

Full text of DOI:10.1021/jm060383x

J. Med. Chem. 2007, 50, 3883-3890
3883
Synthesis and SAR Investigations for Novel Melanin-Concentrating Hormone 1 Receptor
(MCH1) Antagonists Part 2: A Hybrid Strategy Combining Key Fragments of HTS Hits
Chien-An Chen, Yu Jiang, Kai Lu, Irena Daniewska, Christine G. Mazza, Leonardo Negron, Carlos Forray, Tony Parola,
Boshan Li, Laxminarayan G. Hegde, Toni D. Wolinsky, Douglas A. Craig, Ron Kong, John M. Wetzel, Kim Andersen, and
Mohammad R. Marzabadi*
Departments of Chemistry, Cellular Science and Target DiscoVery and Assessment, Lundbeck Research USA, Inc.,
215 College Road, Paramus, New Jersey 07652-1413
ReceiVed March 31, 2006
A novel series of melanin-concentrating hormone (MCH1) receptor antagonists based on combining key
fragments from the high-throughput screening (HTS) hits compound 2 (SNAP 7941) and compound 5
(chlorohaloperidol) are described. The resultant analogs, exemplified by compounds 11a-11h, 15a-15h,
and 16a-16g, were evaluated in in vitro and in vivo assays for their potential in treatment of mood disorders.
From further SAR investigations, N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-
2-methylpropanamide (16g, SNAP 94847) was identified to be a high affinity and selective ligand for the
MCH1 receptor. Compound 16g also shows good oral bioavailability (59%) and exhibits a brain/plasma
ratio of 2.3 in rats. Compound 16g showed in vivo inhibition of a centrally induced MCH-induced drinking
effect and exhibited a dose-dependent anxiolytic effect in the rat social interaction model.
Introduction
Synthetic Chemistry
The synthesis of N-(3-piperidin-4-yl-phenyl)-acetamide (8)
and 3-piperidin-4-yl-phenylamine (9) have been described
previously.10e The N-alkylation of compound 8 with various
commercially available substituted 4-chloro-1-aryl-butan-1-ones
7a-7e in DMF using potassium carbonate at 80-100 °C
afforded the desired compounds 11a-11e (Scheme 1).
The N-alkylation of 3-piperidin-4-yl-phenylamine (9) with
commercially available 4-chloro-1-(4-chloro-phenyl)-butan-1-
one (7b) in toluene in the presence of K2CO3 and 18-crown-6
at 110 °C gave the intermediate, 4-[4-(3-amino-phenyl)-piperi-
din-1-yl]-1-(4-chloro-phenyl)-butan-1-one (10). Compound 10
reacted with a variety of acid chlorides to afford compounds
11f-11h.
The synthesis of compounds 15a-15h and 16a-16g is
depicted in Scheme 2. The starting materials, 3-aryloxybenzal-
dehydes (12a-12h), are commercially available from Sigma-
Aldrich, while the 4-aryloxybenzaldehydes (13a-13e) are either
commercially available from Sigma-Aldrich (13a) or prepared
via an Ullmann-type reaction (13b-e).12 The syntheses of
piperidines 14a-14c have been described previously.10e The
reductive amination of piperidines 14a-14c with appropriately
substituted 3-aryloxybenzaldehydes 12a-12h and 4-aryloxy-
benzaldehydes 13a-13e using sodium triacetoxyborohydride
in 1,2-dichloroethane gave the desired products 15a-15h and
16a-16g.13
The melanin-concentrating hormone (MCH), a cyclic 19-
amino-acid polypeptide,1,2 has been reported to participate in a
varietyofprocesses,includingfeedingandpsychiatricdisorders.3-6
The effects of deletion or overexpression of MCH were
summarized in the preceding paper.7-9,10e The effects of MCH
are mediated through two distinct receptors in the rhodopsin
superfamily of 7-transmembrane G-protein-coupled receptors,
MCH1 and MCH2 receptors. MCH1 receptor has been isolated
in humans and rodents, whereas functional MCH2 receptor have
not been found in rats and mice.3,4 The effects of small molecule
MCH1 receptor antagonists in rodent feeding models have been
described by several groups,10,11 and the results support the
hypothesis that MCH1 receptor antagonists are potentially useful
agents in the treatment of obesity. Compound 1 (T-226296)
exhibited >90% suppression of MCH-stimulated food intake
at 30 mg/kg in lean rats.10a Compound 2 was used as an in
vivo tool to demonstrate that an MCH1 receptor antagonist may
be useful for the treatment of depression and anxiety as well as
for the management of obesity.10b In addition to the confirmation
of the anxiolytic results of compound 2 by Millan’s group,12a
Taisho/Arena have recently reported on MCH1 receptor an-
tagonist 4 (ATC0175, Figure 1), which possess antidepressant
and anxiolytic properties.10d More recent MCH1 receptor
publications have described additional pharmacological evalu-
ations and use of MCH1 antagonists in control of food intake
and mood disorders.12b-d
Results and Discussion
In the preceding paper,10e modifications of the dihydropyri-
midinone moiety of a high-throughput screening (HTS) lead
compound 2 resulted in compound 6 (SNAP 102739) with
improved pharmacokinetic and pharmacodynamic properties.
Herein, a hybrid approach to the design and synthesis of a novel
series of MCH1 receptor antagonists is described based on
combining key fragments of initial HTS hits, compounds 2 and
5 (chlorohaloperidol17) shown in Figure 1.
Initial high-throughput screening of a GPCR-biased com-
pound collection against human MCH1 receptor in a functional
assay measuring intracellular Ca2+ mobilization resulted in the
identification of several hits with a common 4-arylpiperidine
scaffold. Among them, compound 2 has previously been
reported to have high affinity to and selectivity for the melanin-
concentrating hormone 1 receptor (MCH1 receptor).10b However,
the metabolic stability, in particular, of compound 2 is not
ideal.10j Compound 5 (chlorohaloperidol)17 has appropriate CNS
druglike properties, displays moderate affinity for the rat MCH1
* To whom correspondence should be addressed. Phone: +1 (201) 350-
0196. Fax: +1 (201) 261-0623. E-mail: moma@lundbeck.com.
10.1021/jm060383x CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/02/2007

3884 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16
Chen et al.
Figure 1. Representative nonpeptide MCH1 receptor antagonists.
Scheme 1a
a Reagents and conditions: (a) NaI, K2CO3, DMF, 80-100 °C overnight; (b) 18-crown-6, K2CO3, toluene, 110 °C, 48 h; (c) R2COCl, DIPEA, CH2Cl2, rt,
overnight.
receptor (Ki ) 346 nM), but displays cross-reactivities against
Modifications at the terminal aryl group R1 and the anilide
moiety is shown in Table 1. Compounds with R2 ) cyclohexyl
(11g) and benzyl (11h) substitution at the anilide position
showed MCH1 receptor affinities comparable to compound 11b.
Within compounds 11a-11h, described in Table 1, a dramatic
increase in MCH1 receptor affinity was observed by the
introduction of an isopropyl group at the anilide position (11f).
Compound 11f showed 5.0 nM affinity at the MCH1 receptor
and 120-fold selectivity over the human D2 receptor. The initial
improvements in MCH1 receptor binding affinity and the human
D2 selectivity of compounds 11a-11f prompted exploration of
the SAR of the N-alkyl linker moiety. The 3- and 4-aryloxy-
benzyl substitutions, shown in compounds 15a-15h and 16a-
16g, are particularly effective replacements (Tables 2-5).
Table 2 displays the MCH1 receptor and D2 receptor affinities
for 3-aryloxybenzyl-substituted analogs 15a-15h. Within com-
pounds 15a-15h, described in Table 2, compound 15c,
substituted with a bulky 4-t-Bu group showed poor MCH1
the hR1A and the hD2 receptors. This led us to prepare a hybrid
series of compounds, 11a-11h, by incorporating the key
fragments from compound 2 and compound 5.
Table 1 summarizes the rat MCH1 receptor binding affinities
and the human R1A and the human D2 receptor cross-reactivities
of the N-{3-[1-(4-oxo-4-aryl-butyl)-piperidin-4-yl]-phenyl}-
alkylamides 11a-11h. Compounds 11a, 11c, and 11d, contain-
ing an electron-neutral or electron-donating group at the para
position (R1 ) H, 4-Me, and 4-OPh) of the butyrophenone
group, showed MCH1 receptor affinities similar to chlorohalo-
peridol (5) in the range of 350-490 nM. Compound 11b, with
an electron-withdrawing group at the para position (R1 ) 4-Cl),
exhibited a Ki of 70 nM at the MCH1 receptor with greater than
20-fold selectivity over the human D2 receptor. The MCH1
receptor affinity and the hD2 selectivity of the disubstituted
analog 11e (R1 ) 3,4-dimethyl) is also improved when
compared with that shown by compound 5.

Melanin-Concentrating Hormone 1 Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16 3885
Scheme 2a
a Reagents: (a) NaBH(OAc)3, HOAc,DCM or 1,2-dichloroethane.
Table 1. Rat MCH1 Receptor, Human R1A, and Human D2 Binding Affinities for 11a-11h
affinity
cmpd
R1
NA
NA
H
R2
rMCH1a Ki ( SEM (nM)
hR1Ab Ki ( SEM (nM)
hD2c Ki ( SEM (nM)
2 (SNAP 7941)
5 (chlorohaloperidol)
NA
NA
Me
Me
Me
Me
Me
i-Pr
0.25 ( 0.01
350 ( 30
350 ( 30
70 ( 10
360 ( 30
490 ( 80
100 ( 30
5.0 ( 1.2
200 ( 30
84 ( 2
40 ( 10
150 ( 10
NDd
ND
ND
ND
ND
ND
ND
ND
2800 ( 300
190 ( 10
ND
11a
11b
11c
11d
11e
11f
4-Cl
1400 ( 100
4-Me
4-OPh
3,4-diMe
4-Cl
4-Cl
4-Cl
ND
ND
6100 ( 200
610 ( 150
ND
11g
11h
cyclohexyl
CH2Ph
780 ( 50
a Mean values ( standard error of the mean (SEM) determined in binding assays (n ) 3) to the recombinant rat MCH1. Binding assays were performed
by incubating membranes isolated from transfected cells with varying concentrations of [3H]-1 in binding buffer (50 mM Tris, 10 mM MgCl2, 0.16 mM
PMSF, 1 mM 1,10-phenanthroline, and 0.2% BSA, pH 7.4) at 25 °C for 90 min, as described previously.10b See the Experimental Section for details on
functional antagonism data of the compounds assessed using FLIPR calcium mobility assay in cells stably expressing rat MCH1. b Mean values ( standard
error of the mean (SEM) determined in binding assays (n ) 3) to the recombinant human R1A adrenoceptor using [125I]HEAT. c Mean values ( standard
error of the mean (SEM) determined in binding assays (n ) 3) to the recombinant human D2 dopamine receptor using [3H]spiperone. d ND ) not determined.
receptor binding affinity, while compounds with small electron-
neutral (R1 ) H, 15a; R1 ) 4-Me, 15b), electron-donating
groups (R1 ) 4-OMe, 15d), or electron-withdrawing groups (R1
) 4-Cl, 15e) showed favorable MCH1 receptor affinities. The
disubstituted analog 15g (R1 ) 3,4-diCl) exhibited a Ki of 18
nM at the MCH1 receptor.
Table 3 shows the MCH1 receptor affinities and R1A receptor
selectivities for the 4-aryloxybenzyl analogs 16a-16e. A
comparison of compounds 15 and 16, described in Tables 2
and 3, showed that the 4-substituted compounds 16a-16e
showed better MCH1 receptor affinity profiles than the corre-
sponding 3-aryloxybenzyl analogs 15a-15h. The 3,4-dichloro

3886 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16
Table 2. The SAR for 3-Aryloxybenzyl Analogs 15a-15h
Chen et al.
Table 4. The SAR of the 4-Arylpiperidine Moiety
affinity
affinity
cmpd
R1
rMCH1a Ki ( SEM (nM)
hD2b Ki ( SEM (nM)
rMCH1a Ki ( hR1Ab Ki (
hD2c Ki (
15a
15b
15c
15d
15e
15f
H
28 ( 4
31 ( 3
NDc
1300 ( 400
ND
1000 ( 400
ND
ND
ND
ND
cmpd
R2
SEM (nM)
SEM (nM)
SEM (nM)
4-Me
4-t-Bu
4-OCH3
4-Cl
3-CF3
3,4-di-Cl
3,5-di-Cl
540 ( 140
43 ( 1
16e
16f
H
4-Me
1.8 ( 0.2
27 ( 1
2.2 ( 0.4
200 ( 20
1010 ( 10
180 ( 20 7400 ( 2400
470 ( 70
400 ( 100
23 ( 1
16g (SNAP 94847) 6-Me
65 ( 3
a Mean values ( standard error of the mean (SEM) determined in binding
assays (n ) 3) to the recombinant rat MCH1. Binding assays were performed
by incubating membranes isolated from transfected cells with varying
concentrations of [3H]-1 in binding buffer (50 mM Tris, 10 mM MgCl2,
0.16 mM PMSF, 1 mM 1,10-phenanthroline, and 0.2% BSA, pH 7.4) at 25
°C for 90 min, as described previously.10b See the Experimental Section
for details on functional antagonism data of the compounds assessed using
FLIPR calcium mobility assay in cells stably expressing rat MCH1. b Mean
values ( standard error of the mean (SEM) determined in binding assays
(n ) 3) to the recombinant human R1A adrenoceptor using [125I]HEAT.
c Mean values ( standard error of the mean (SEM) determined in binding
assays (n ) 3) to the recombinant human D2 dopamine receptor using
[3H]spiperone.
15g
15h
18 ( 1
140 ( 20
a Mean values ( standard error of the mean (SEM) determined in binding
assays (n ) 3) to the recombinant rat MCH1. Binding assays were performed
by incubating membranes isolated from transfected cells with varying
concentrations of [3H]-1 in binding buffer (50 mM Tris, 10 mM MgCl2,
0.16 mM PMSF, 1 mM 1,10-phenanthroline, and 0.2% BSA, pH 7.4) at 25
°C for 90 min, as described previously.10b See the Experimental Section
for details on functional antagonism data of the compounds assessed using
FLIPR calcium mobility assay in cells stably expressing rat MCH1. b Mean
values ( standard error of the mean (SEM) determined in binding assays
(n ) 3) to the recombinant human D2 dopamine receptor using [3H]spip-
erone. c ND ) not determined.
significant cross-reactivity for anxiety related targets in an in-
house panel of 18 receptors as well as a broad CRO cross-
reactivity panel.
Table 3. The SAR for 4-Aryloxybenzyl Analogs 16a-e
Pharmacokinetic (PK) properties of compound 16g in rats
are shown in Table 5. Compound 16g exhibited good bioavail-
ability (59%), low plasma and blood clearances of 4.2 L/hr/kg
and 3.3 L/hr/kg, respectively, and the half-life was shown to
be 5.2 h in rats. Furthermore, the brain levels in rats at 4 h
were determined to be 2.3 times higher than the plasma levels
at 10 mg/kg oral dosing.
affinity
rMCH1a Ki (
SEM (nM)
hR1Ab Ki (
SEM (nM)
hD2c Ki (
SEM (nM)
cmpd
R1
MCH was recently reported to stimulate water intake
independent of food intake.16 As a measure of centrally mediated
MCH1 receptor antagonism, we examined the effects of
compound 16g on basal and MCH-stimulated water intake in
rats. Compound 16g (10 mg/kg, p.o.) had no effect on basal
water consumption measured over 2 h: vehicle-treated (2.0 (
0.0 mL, N ) 4); 16g-treated (2.3 ( 0.25 mL; N ) 4). A dramatic
increase in 2 h water consumption was produced in response
to centrally administered MCH peptide (10 µg, icv; Figure 2).
MCH-evoked water intake was inhibited significantly by
compound 16g at doses of 1.0, 2.5, and 10 mg/kg. To examine
whether this effect was likely to result from selective MCH-1
receptor antagonism or a nonspecific effect on water intake in
general, we examined the effect of 16g on a dose of angiotensin-
II (100ng, icv) that evoked a similar degree of water consump-
tion.18 Water intake in response to angiotensin-II was not
affected significantly by 16g. We conclude, therefore, that
significant occupancy of 16g at central MCH1 receptors occurs
at oral doses of 1 mg/kg and above.
The rat social interaction animal model is used as a predictive
tool for anxiolytic activity.14 The design and procedure for the
social interaction test was modified from that previously
described by Kennett et al.15 Animals were treated with either
vehicle (20% cyclodextrin), chlordiazepoxide (CDP; 5 mg/kg
p.o.), or various concentrations of compound 16g. In this test,
compound 16g, administered orally 1 h prior to test, produced
a significant increase in social interaction time relative to
vehicle-treated rats, with a minimally effective dose ) 0.3 mg/
kg (basal, 58.6 ( 3.4 s; chlordiazepoxide, 99.3 ( 1.4 s; 16g,
16a
16b
16c
16d
16e
H
4-Cl
4-OCH3
3,4-di-Cl
3,4-di-F
10 ( 3
NDd
ND
ND
120 ( 20
110 ( 30
1400 ( 400
2900 ( 1700
470 ( 70
5.3 ( 0.6
35 ( 3
8.2 ( 1.2
1.8 ( 0.2
34 000 ( 2100
200 ( 20
a Mean values ( standard error of the mean (SEM) determined in binding
assays (n ) 3) to the recombinant rat MCH1. Binding assays were performed
by incubating membranes isolated from transfected cells with varying
concentrations of [3H]-1 in binding buffer (50 mM Tris, 10 mM MgCl2,
0.16 mM PMSF, 1 mM 1,10-phenanthroline, and 0.2% BSA, pH 7.4) at 25
°C for 90 min, as described previously.10b See the Experimental Section
for details on functional antagonism data of the compounds assessed using
FLIPR calcium mobility assay in cells stably expressing rat MCH1. b Mean
values ( standard error of the mean (SEM) determined in binding assays
(n ) 3) to the recombinant human R1A adrenoceptor using [125I]HEAT (
0.1 nM. c Mean values ( standard error of the mean (SEM) determined in
binding assays (n ) 3) to the recombinant human D2 dopamine receptor
using [3H]spiperone. d ND ) not determined.
and 3,4-difluoro analogs, 16d and 16e, in particular, showed
high MCH1 receptor affinity and human R1A and D2 receptor
selectivity profiles.
The SAR of the 4-arylpiperidine modification, in compounds
16e-16g, is depicted in Table 4. Within this series of
compounds, the introduction of a methyl group in the 4-position
of the aromatic ring (16f) resulted in 13-fold loss of MCH1
receptor potency. Compound 16g, with a methyl group in the
6-position, showed a favorable combination of MCH1 receptor
affinity (Ki ) 2.2 nM) and human R1A receptor (>80-fold) and
D2 (>500-fold) selectivity and was chosen for further in vivo
evaluation. Furthermore, compound 16g did not show any

Melanin-Concentrating Hormone 1 Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16 3887
Table 5. The PK Properties of Compound 16g in Rats
a,c
a,d
a,e
g
CLb
CLp
T1/2
brain levelsf
(ng/g)
Vss
%Fa,b
(L/hr/kg)
(L/hr/kg)
(hrs)
(L/kg)
[brain]/[plasma]f
2.3
59
3.3
4.2
5.2
184 ( 2h
29
a The rats were dosed at 2 mg/kg po (n ) 2) and 1 mg/kg iv (n ) 2). b F% ) rat bioavailability. c CLb ) blood clearance. d CLp ) plasama clearance.
e T1/2 ) half-life. f In a separate experiment, the rats were dosed at 10 mg/kg po, and the brain and the plasma exposures were determined 4 h after dosing
g
(n ) 2). Vss ) volume of distribution at steady state. h The analytical limit of quantitation for compounds 16g was determined to be (2 ng/mL for plasma
measurements and (2 ng/g for brain measurements.
N-{3-[1-(4-Oxo-4-phenylbutyl)-4-piperidinyl]phenyl}-
acetamide (11a). The desired product was obtained according to
method I (16 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 8.10-6.80
(m, 10 H), 3.40-2.95 (m, 4 H), 2.85-2.20 (m, 3 H), 2.19 (s, 3 H),
2.15-1.70 (m, 8 H); ESMS m/e 365.3 (M + H)+; exact mass calcd
for C23H29N2O2 (M + H), 365.2229; found, 365.2231.
N-(3-{1-[4-(4-Chlorophenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-
acetamide (11b). The desired product was obtained according to
method I (11 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J
) 8.8 Hz, 2 H), 7.55-7.40 (m, 3 H), 7.35 (m, 2 H), 7.22 (t, J )
8.0 Hz, 1 H), 6.92 (d, J ) 8.0 Hz, 1 H), 3.30-3.27 (m, 2 H), 3.09
(t, J ) 7.0 Hz, 2 H), 2.76-2.39 (m, 5 H), 2.20 (s, 3 H), 2.17-1.85
(m, 6 H); ESMS m/e 399.3 (M + H)+; exact mass calcd for C23H28-
ClN2O2 (M + H), 399.1839; found, 399.1841.
N-(3-{1-[4-(4-Methylphenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-
acetamide (11c). The desired product was obtained according to
method I (13 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 7.90-6.80
(m, 9 H), 3.10-2.45 (m, 7 H), 2.32 (S, 3 H), 2.02 (s, 3 H), 2.01-
1.68 (m, 8 H); ESMS m/e 379.3 (M + H)+; exact mass calcd for
Figure 2. Compound 16g antagonism of MCH-evoked drinking. MCH
(10 ug, icv) produced a robust increase in water consumption in rats
over a 2 h period. Compound 16g, given orally 1 h before MCH,
produced a significant reduction in the response to MCH. In contrast,
compound 16g failed to significantly modify drinking in response to
cording to method I (15 mg, 69%). 1H NMR (400 MHz, CDCl3) δ
angiotensin-II (100ng, icv). ***p < 0.001 vs MCH alone (Newman-
8.15-6.75 (m, 14 H), 3.30-2.80 (m, 4 H), 2.75-2.10 (m, 5 H),
Keuls post hoc test; N values in parentheses).
C24H31N2O2 (M + H), 379.2385; found, 379.2384.
N-(3-{1-[4-Oxo-4-(4-phenoxyphenyl)butyl]-4-piperidinyl}-
phenyl)acetamide (11d). The desired product was obtained ac-
2.03 (s, 3 H), 2.00-1.60 (m, 6 H); ESMS m/e 457.3 (M + H)+;
exact mass calcd for C29H33N2O3 (M + H), 457.2491; found,
81.0 ( 4.4 s; p < 0.05; Newman-Keuls post hoc test). In the
social interaction study, no effect on the locomotor activity was
observed upon administration of compound 16g.
457.2496.
N-(3-{1-[4-(3,4-Dimethylphenyl)-4-oxobutyl]-4-piperidinyl}-
phenyl)acetamide (11e). The desired product was obtained ac-
cording to method I (11 mg, 41%). 1H NMR (CDCl3) δ 7.75 (s, 1
H), 7.71 (d, J ) 7.6 Hz, 1 H), 7.45 (d, J ) 7.2 Hz, 2 H), 7.35 (s,
1 H), 7.26-7.22 (m, 2 H), 6.93 (d, J ) 7.6 Hz, 1 H), 3.24-3.21
(m, 2 H), 3.04 (t, J ) 7.0 Hz, 2 H), 2.67-2.63 (m, 2 H), 2.59-
2.48 (m, 1 H), 2.32 (s, 6 H), 2.30-2.27 (m, 2 H), 2.18 (s, 3 H),
2.14-2.06 (m, 2 H), 2.00-1.80 (m, 4 H); ESMS m/e 393.3 (M +
H)+; exact mass calcd for C25H33N2O2 (M + H), 393.2542; found,
393.2539.
4-[4-(3-Aminophenyl)-1-piperidinyl]-1-(4-chlorophenyl)-1-bu-
tanone (10). A mixture of 3-piperidin-4-yl-phenylamine (2.0 mmol),
4-chloro-1-(4-chloro-phenyl)-butan-1-one (2.4 mmol), potassium
carbonate (3.0 mmol), and 18-crown-6 (10 mg) in 5 mL of toluene
were heated at 110 °C for 2.5 days. The reaction mixture was
concentrated and chromatographed on silica (5% methanol in
Conclusions
In summary, lead optimization of the initial high-throughput
screening based on a strategy of combining key fragments from
compounds 2 and 5 led to the identification of N-(3-{1-[4-(3,4-
difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-me-
thylpropanamide (16g). Compound 16g is a novel high affinity
and highly selective MCH1 receptor antagonist with good
physicochemical properties in rats. Compound 16g shows high
brain-to-plasma exposure levels (2.3-fold) 4 h after oral dosing
in rats. Compound 16g showed inhibition of a centrally induced
MCH effect and is orally efficacious in the rat social interaction
assay, an acute model of anxiety. Additional studies of
compound 16g and related compounds in other animal models
of anxiety and depression will be reported in due course.
1
dichloromethane) to give the desired product (428 mg, 60%). H
NMR (400 MHz, CDCl3) δ 7.94 (d, J ) 8.4 Hz, 2 H), 7.44 (d, J
) 8.8 Hz, 2 H), 7.08 (t, J ) 7.6 Hz, 1 H), 6.60 (d, J ) 7.6 Hz, 1
H), 6.53 (m, 2 H), 3.61 (s, 2 H), 3.01-2.97 (m, 4 H), 2.45-2.33
(m, 3 H), 2.05-1.94 (m, 4 H), 1.78-1.75 (m, 2 H), 1.69-1.59
(m, 2 H); ESMS m/e 357.3 (M + H)+.
General Procedure for the Acylation of 4-[4-(3-Aminophe-
nyl)-1-piperidinyl]-1-(4-chlorophenyl)-1-butanones (Method II,
11f-h). A mixture of 1 equiv of 4-[4-(3-aminophenyl)-1-piperidi-
nyl]-1-(4-chlorophenyl)-1-butanone, 1.5 equiv of an acid chloride,
and 5 equiv of diisopropylethylamine in dichloromethane was stirred
at room temperature for 2 days. The reaction mixture was applied
to a preparative TLC plate and eluted with dichloromethane/
methanol (15:1, containing 1% isopropyl amine) to give the desired
product.
Experimental Section
See part 1, the preceding paper for a description of the general
synthetic methods.10e
General Procedure for the Preparation of the Substituted
4-N-(3-{1-[4-(Phenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-
acetamides (Method I, 11a-e). A mixture of N-[3-(4-piperidinyl)-
phenyl]acetamide (1.0 equiv) and an aryl-substituted chlorobuty-
rophenone (2.0 equiv), K2CO3 (5.0 equiv), diisopropylethylamine
(3.0 equiv), and tetrabutylammonium iodide (cat. 5-10%) in
dioxane (0.5 to 1.0 M) were heated at reflux temperature for 16 h.
The reaction mixture was filtered and concentrated in vacuo. The
crude product was chromatographed using silica preparative TLC
(chloroform/methanol containing 0.5% isopropyl amine) to give
the desired product.
N-(3-{1-[4-(4-Chlorophenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-
2-methylpropanamide (11f). The desired product was obtained
according to method II (13 mg, 54%). 1H NMR (400 MHz, CDCl3)

3888 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16
Chen et al.
δ 7.93 (d, J ) 8.6 Hz, 2 H), 7.45 (d, J ) 8.6 Hz, 2 H), 7.39 (d, J
) 7.2 Hz, 1 H), 7.32 (m, 2 H), 7.24 (t, J ) 7.8 Hz, 1 H), 6.94 (d,
J ) 8.4 Hz, 1 H), 3.21-3.18 (m, 2 H), 3.05 (t, J ) 7.0 Hz, 2 H),
2.64-2.51 (m, 4 H), 2.28-1.86 (m, 8 H), 1.26 (d, J ) 6.8 Hz, 6
H); ESMS m/e 427.3 (M + H)+; exact mass calcd for C25H32ClN2O2
(M + H), 427.2152; found, 427.2153.
N-(3-{1-[4-(4-Chlorophenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-
cyclohexanecarboxamide (11g). The desired product was obtained
according to method II (17 mg, 64%). 1H NMR (400 MHz, CDCl3)
δ 7.93 (d, J ) 8.4 Hz, 2 H), 7.55-7.19 (m, 6 H), 6.93 (d, J ) 7.6
Hz, 1 H), 3.25-3.00 (m, 4 H), 2.65-2.45 (m, 4 H), 2.30-1.50
(m, 18 H); ESMS m/e 467.3 (M + H)+; exact mass calcd for C28H36-
ClN2O2 (M + H), 467.2465; found, 467.2469.
N-(3-{1-[4-(4-Chlorophenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-
2-phenylacetamide (11h). The desired product was obtained
according to method II (17 mg, 64%). 1H NMR (400 MHz, CDCl3)
δ 7.92 (d, J ) 8.4 Hz, 2 H), 7.46-7.26 (m, 10 H), 7.20 (t, J ) 7.6
Hz, 1 H), 6.92 (d, J ) 7.6 Hz, 1 H), 3.75 (s, 2 H), 3.15-3.13 (m,
2 H), 3.03 (t, J ) 7.0 Hz, 2 H), 2.64-2.46 (m, 3 H), 2.22-1.60
(m, 8 H); ESMS m/e 475.3 (M + H)+; exact mass calcd for C29H32-
ClN2O2 (M + H), 475.2152; found, 475.2166.
General Reductive Amination Procedure for Compounds
15a-h and 16a-g (Method III). A mixture of the aldehyde (1
mol equiv), the piperidine (1 mol equiv), and the acetic acid (1
mol equiv) in 1,2-dichloroethane is stirred with 1.3-1.6 equiv of
sodium triacetoxyborohydride under a nitrogen atmosphere at room
temperature overnight. The reaction mixture was neutralized with
saturated NaHCO3 aqueous solution, and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were washed with brine, dried over MgSO4, concentrated in vacuo,
and purified by preparative TLC using 5% of NH3 (2.0 M in
methanol) in CH2Cl2 to give the desired products 15a-h and
16a-g.
1.72 (m, 4 H), 1.24 (d, J ) 6.8 Hz, 6 H); ESMS m/e 459.2 (M +
H)+; exact mass calcd for C29H35N2O3 (M + H), 459.2647; found,
459.2660.
N-(3-{1-[3-(4-Chlorophenoxy)benzyl]-4-piperidinyl}phenyl)-
2-methylpropanamide (15e). The desired product was obtained
according to method III (82 mg, 33%). 1H NMR (400 MHz, CDCl3)
δ 7.48 (s, 1 H), 7.38 (s, 1 H), 7.33-7.25 (m, 4 H), 7.21 (t, J ) 8.0
Hz, 1 H), 7.11 (d, J ) 7.6 Hz, 1 H), 7.03 (s, 1 H), 6.96-6.91 (m,
3 H), 6.87 (dd, J ) 8.0, 2.4 Hz, 1 H), 3.50 (s, 2 H), 2.96 (d, J )
11.2 Hz, 2 H), 2.53-2.42 (m, 2 H), 2.08-2.01 (m, 2 H), 1.79-
1.72 (m, 4 H), 1.23 (d, J ) 6.8 Hz, 6 H); ESMS m/e 463.2 (M +
H)+; exact mass calcd for C28H32ClN2O2 (M + H), 463.2152; found,
463.2156.
2-Methyl-N-[3-(1-{3-[3-(trifluoromethyl)phenoxy]benzyl}-4-
piperidinyl)phenyl]propanamide (15f). The desired product was
1
obtained according to method III (64 mg, 24%). H NMR (400
MHz, CDCl3) δ 7.48 (s, 1 H), 7.43 (t, J ) 8.0 Hz, 1 H), 7.32 (t, J
) 7.6 Hz, 3 H), 7.24 (t, J ) 7.6 Hz, 3 H), 7.18-7.14 (m, 2 H),
7.08 (s, 1 H), 6.96 (d, J ) 7.6 Hz, 1 H), 6.92 (dd, J ) 8.0, 2.0 Hz,
1 H), 3.53 (s, 2 H), 2.98 (d, J ) 11.2 Hz, 2 H), 2.53-2.43 (m, 2
H), 2.10-2.03 (m, 2 H), 1.80-1.74 (m, 4 H), 1.24 (d, J ) 6.8 Hz,
6 H); ESMS m/e 497.2 (M + H)+; exact mass calcd for
C29H32F3N2O2 (M + H), 497.2416; found, 497.2420.
N-(3-{1-[3-(3,4-Dichlorophenoxy)benzyl]-4-piperidinyl}phenyl)-
2-methylpropanamide (15g). The desired product was obtained
according to method III (268 mg, 48%). 1H NMR (400 MHz,
CDCl3) δ 7.49 (s, 1 H), 7.38 (d, J ) 8.8 Hz, 1 H), 7.32 (t, J ) 8.0
Hz, 2 H), 7.24 (t, J ) 7.6 Hz, 1 H), 7.15 (d, J ) 7.6 Hz, 1 H), 7.09
(d, J ) 2.8 Hz, 2 H), 7.06 (s, 1 H), 6.97 (d, J ) 7.6 Hz, 1 H), 6.90
(dd, J ) 7.6, 2.0 Hz, 1 H), 6.86 (dd, J ) 8.8, 2.8 Hz, 1 H), 3.52
(s, 2 H), 2.98 (d, J ) 11.2 Hz, 2 H), 2.53-2.45 (m, 2 H), 2.11-
2.02 (m, 2 H), 1.82-1.79 (m, 4 H), 1.26 (d, J ) 6.8 Hz, 6 H);
ESMS m/e 497.2 (M + H)+; exact mass calcd for C28H31Cl2N2O2
(M + H), 497.1762; found, 497.1763.
N-(3-{1-[3-(3,5-Dichlorophenoxy)benzyl]-4-piperidinyl}phenyl)-
2-methylpropanamide (15h). The desired product was obtained
according to method III (56 mg, 21%). 1H NMR (400 MHz, CDCl3)
δ 7.49 (s, 1 H), 7.35-7.30 (m, 2 H), 7.26-7.16 (m, 3 H), 7.08-
7.05 (m, 2 H), 6.96 (d, J ) 7.6 Hz, 1 H), 6.92 (dd, J ) 8.0, 2.4 Hz,
1 H), 6.87-6.86 (m, 2 H), 3.53 (s, 2 H), 2.98 (d, J ) 11.2 Hz, 2
H), 2.55-2.44 (m, 2 H), 2.10-2.04 (m, 2 H), 1.81-1.75 (m, 4 H),
1.24 (d, J ) 6.8 Hz, 6 H); ESMS m/e 497.2 (M + H)+; exact mass
calcd for C28H31Cl2N2O2 (M + H), 497.1762; found, 497.1770.
2-Methyl-N-{3-[1-(4-phenoxybenzyl)-4-piperidinyl]phenyl}-
propanamide (16a). The desired product was obtained according
2-Methyl-N-{3-[1-(3-phenoxybenzyl)-4-piperidinyl]phenyl}-
propanamide (15a). The desired product was obtained according
to method III (81 mg, 65%). H NMR (400 MHz, CDCl3) δ 7.46
1
(s, 1 H), 7.35-7.19 (m, 6 H), 7.11-7.00 (m, 5 H), 6.95 (d, J )
7.6 Hz, 1 H), 6.89 (dd, J ) 8.0, 2.4 Hz, 1 H), 3.51 (S, 2 H), 2.97
(d, J ) 11.2 Hz, 2 H), 2.53-2.41 (m, 2 H), 2.08-1.99 (m, 2 H),
1.79-1.73 (m, 4 H), 1.23 (d, J ) 6.8 Hz, 6 H); ESMS m/e 429.2
(M + H)+; exact mass calcd for C28H33N2O2 (M + H), 429.2542;
found, 429.2549.
2-Methyl-N-(3-{1-[3-(4-methylphenoxy)benzyl]-4-piperidinyl}-
phenyl)propanamide (15b). The desired product was obtained
according to method III (62 mg, 26%). 1H NMR (400 MHz, CDCl3)
δ 7.45 (s, 1 H), 7.34-7.19 (m, 4 H), 7.14 (d, J ) 8.8 Hz, 2 H),
7.06 (d, J ) 8.0 Hz, 1 H), 7.02-7.01 (m, 1 H), 6.96 (d, J ) 7.6
Hz, 1 H), 6.92 (d, J ) 8.8 Hz, 2 H), 6.85 (dd, J ) 8.4, 2.4 Hz, 1
H), 3.50 (s, 2 H), 2.98 (d, J ) 11.2 Hz, 2 H), 2.53-2.42 (m, 2 H),
2.34 (s, 3 H), 2.09-2.01 (m, 2 H), 1.80-1.74 (m, 4 H), 1.25 (d, J
) 6.8 Hz, 6 H); ESMS m/e 443.2 (M + H)+; exact mass calcd for
C29H35N2O2 (M + H), 443.2698; found, 443.2697.
N-(3-{1-[3-(4-tert-Butylphenoxy)benzyl]-4-piperidinyl}phenyl)-
2-methylpropanamide (15c). The desired product was obtained
according to method III (63 mg, 24%). 1H NMR (400 MHz, CDCl3)
δ 7.45 (s, 1 H), 7.35-7.32 (m, 3 H), 7.28-7.20 (m, 3 H), 7.07 (d,
J ) 7.6 Hz, 1 H), 7.05 (m, 1 H), 6.97-6.92 (m, 3 H), 6.88 (dd, J
) 8.0, 2.4 Hz, 1 H), 3.51 (s, 2 H), 2.98 (d, J ) 11.2 Hz, 2 H),
2.53-2.42 (m, 2 H), 2.09-2.02 (m, 2 H), 1.80-1.71 (m, 4 H),
1.32 (s, 9 H), 1.24 (d, J ) 6.8 Hz, 6 H); ESMS m/e 485.3 (M +
H)+; exact mass calcd for C32H41N2O2 (M + H), 485.3168; found,
485.3182.
N-(3-{1-[3-(4-methoxyphenoxy)benzyl]-4-piperidinyl}phenyl)-
2-methylpropanamide (15d). The desired product was obtained
according to method III (77 mg, 31%). 1H NMR (400 MHz, CDCl3)
δ 7.45 (s, 1 H), 7.35-7.31 (m, 2 H), 7.26-7.20 (m, 2 H), 7.03 (d,
J ) 7.6 Hz, 1 H), 7.00-6.95 (m, 4 H), 6.90-6.86 (m, 2 H), 6.81
(dd, J ) 8.0, 2.4 Hz, 1 H), 3.80 (s, 3 H), 3.49 (s, 2 H), 2.97 (d, J
) 11.2 Hz, 2 H), 2.53-2.41 (m, 2 H), 2.08-2.01 (m, 2 H), 1.79-
1
to method III (81 mg, 87%). H NMR (400 MHz, CDCl3) δ 7.47
(s, 1 H), 7.36-7.29 (m, 6 H), 7.23 (dd, J ) 13.6, 6 Hz, 1 H), 7.10
(t, J ) 7.6 Hz, 1 H), 7.03-6.94 (m, 5 H), 3.58 (s, 2 H), 3.07 (d,
J ) 11.6 Hz, 2 H), 2.54-2.45 (m, 2 H), 2.17-2.09 (m, 2 H), 1.87-
1.80 (m, 4 H), 1.24 (d, J ) 6.8 Hz, 6 H); ESMS m/e 429.2 (M +
H)+; exact mass calcd for C28H33N2O2 (M + H), 429.2542; found,
429.2548.
N-(3-{1-[4-(4-Chlorophenoxy)benzyl]-4-piperidinyl}phenyl)-
2-methylpropanamide (16b). The desired product was obtained
according to method III (151 mg, 65%). 1H NMR (400 MHz,
CDCl3) δ 7.50 (s, 1 H), 7.34-7.19 (m, 7 H), 6.98-6.87 (m, 5 H),
3.50 (s, 2 H), 2.98 (d, J ) 11.8 Hz, 2 H), 2.58-2.44 (m, 2 H),
2.10-1.98 (m, 2 H), 1.83-1.76 (m, 4 H), 1.24 (d, J ) 6.8 Hz, 6
H); ESMS m/e 463.2 (M + H)+; exact mass calcd for C28H32ClN2O2
(M + H), 463.2152; found, 463.2150.
N-(3-{1-[4-(4-Methoxyphenoxy)benzyl]-4-piperidinyl}phenyl)-
2-methylpropanamide (16c). The desired product was obtained
according to method III (167 mg, 73%). 1H NMR (400 MHz,
CDCl3) δ 7.48 (s, 1 H), 7.31-7.20 (m, 4 H), 7.12 (s, 1 H), 7.00-
6.96 (m, 3 H), 6.91-6.86 (m, 4 H), 3.80 (s, 3 H), 3.49 (s, 2 H),
2.99 (d, J ) 11.6 Hz, 2 H), 2.53-2.44 (m, 2 H), 2.08-2.01 (m, 2
H), 1.82-1.72 (m, 4 H), 1.25 (d, J ) 6.8 Hz, 6 H); ESMS m/e
459.2 (M + H)+; exact mass calcd for C29H35N2O3 (M + H),
459.2647; found, 459.2657.
N-(3-{1-[4-(3,4-Dichlorophenoxy)benzyl]-4-piperidinyl}phenyl)-
2-methylpropanamide (16d). The desired product was obtained

Melanin-Concentrating Hormone 1 Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16 3889
according to method III (422 mg, 85%). 1H NMR (400 MHz,
CDCl3) δ 7.53 (s, 1 H), 7.36-7.18 (m, 6 H), 7.08 (d, J ) 1.8 Hz,
1 H), 6.96 (d, J ) 6.8 Hz, 3 H), 6.84 (dd, J ) 2.8, 8.9 Hz, 1 H),
3.51 (s, 2 H), 2.99 (d, J ) 11.5 Hz, 2 H), 2.55-2.42 (m, 2 H),
2.12-2.02 (m, 2 H), 1.84-1.73 (m, 4 H), 1.24 (d, J ) 7.0 Hz, 6
H); ESMS m/e 497.1 (M + H)+; exact mass calcd for C28H31-
Cl2N2O2 (M + H), 497.1762; found, 497.1767.
Groblewski, T.; O’Donnell, D.; Payza, K.; Ahmad, S.; Walker, P.
The receptor for the orexigenic peptide melanin-concentrating
hormone is a G-protein-coupled receptor. Nat. Cell. Biol. 1999, 1
(5), 267-271. (d) Saito, Y.; Nothacker, H. P.; Wang, Z.; Lin, S. H.;
Leslie, F.; Civelli, O. Molecular characterization of the melanin-
concentrating-hormone receptor. Nature 1999, 400 (6741), 265-269.
(e) Shimomura, Y.; Mori, M.; Sugo, T.; Ishibashi, Y.; Abe, M.;
Kurokawa, T.; Onda, H.; Nishimura, O.; Sumino, Y.; Fujino, M.
Isolation and identification of melanin-concentrating hormone as the
endogenous ligand of the SLC-1 receptor. Biochem. Biophys. Res.
Commun. 1999, 261 (3), 622-626.
N-(3-{1-[4-(3,4-Difluorophenoxy)benzyl]-4-piperidinyl}phenyl)-
2-methylpropanamide (16e). The desired product was obtained
according to method III (255 mg, 69%). 1H NMR (400 MHz,
CDCl3) δ 7.52 (s, 1H), 7.32 (d, J ) 8.4 Hz, 2 H), 7.28-7.21 (m,
2 H), 7.14-7.06 (m, 2 H), 6.98-6.94 (m, 3 H), 6.86-6.79 (m, 1
H), 6.76-6.69 (m, 1 H), 3.51 (s, 2 H), 2.99 (d, J ) 11.7 Hz, 2 H),
2.55-2.44 (m, 2 H), 2.12-2.02 (m, 2 H), 1.86-1.74 (m, 4 H),
1.25 (d, J ) 7.0 Hz, 6 H); ESMS m/e 465.2 (M + H)+; exact mass
calcd for C28H31F2N2O2 (M + H), 465.2353; found, 465.2356.
N-(5-{1-[4-(3,4-Difluorophenoxy)benzyl]-4-piperidinyl}-2-me-
thylphenyl)-2-methylpropanamide (16f). The desired product was
(4) (a) An, S. Z.; Cutler, G.; Zhao, J. J.; Huang, S. G.; Tian, H.; Li, W.;
Liang, L.; Rich, M.; Bakleh, A.; Du, J.; Chen, J. L.; Dai, K.
Identification and characterization of a melanin-concentrating hor-
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David, C.; Ames, R. S.; Szekeres, P.; Wilson, S.; Bergsma, D. J.;
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cloning and functional characterization of MCH2, a novel human
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Mori, M.; Harada, M.; Terao, Y.; Sugo, T.; Watanabe, T.; Shimo-
mura, Y.; Abe, M.; Shintani, Y.; Onda, H.; Nishimura, O.; Fujino,
M. Cloning of a novel G protein-coupled receptor, SLT, a subtype
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Sadowski, S. J.; Ito, M.; Ito, M.; Bansal, A.; Ky, B.; Figueroa, D. J.;
Jiang, Q.; Austin, C. P.; MacNeil, D. J.; Ishihara, A.; Ihara, M.;
Kanatani, A.; Van der Ploeg, L. H.; Howard, A. D.; Liu, Q.
Identification and characterization of a second melanin-concentrating
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Ito, M.; Guan, X. M.; MacNeil, D. J.; Kanatani, A.; Van der Ploeg,
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Flier, E. Mice lacking melanin-concentrating hormone are hypophagic
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1
obtained according to method III (22 mg, 28%). H NMR (400
MHz, CDCl3) δ 7.82 (s, 1 H), 7.36 (d, J ) 8.4 Hz, 2 H), 7.13 (q,
J ) 9.2 Hz, 2 H), 6.97-6.93 (m, 4 H), 6.86-6.80 (m, 1 H), 6.74-
6.70 (m, 1 H), 3.54 (s, 2 H), 3.03 (d, J ) 10.8 Hz, 2 H), 2.61-
2.50 (m, 2 H), 2.24 (s, 3 H), 2.20-2.04 (m, 2 H), 1.85-1.83 (m,
4 H), 1.30 (d, J ) 6.8 Hz, 6 H); ESMS m/e 479.2 (M + H)+; exact
mass calcd for C29H33F2N2O2 (M + H), 479.2510; found, 479.2520.
N-(3-{1-[4-(3,4-Difluorophenoxy)benzyl]-4-piperidinyl}-4-me-
thylphenyl)-2-methylpropanamide (16g). The desired product was
1
obtained according to method III (220 mg, 43%). H NMR (400
MHz, CDCl3) δ 7.42 (d, J ) 2 Hz, 1 H), 7.38-7.31 (m, 2 H), 7.27
(dd, J ) 8.8, 2.0 Hz, 1 H), 7.14-7.06 (m, 3 H), 7.00-6.93 (m, 2
H), 6.86-6.79 (m, 1 H), 6.75-6.69 (m, 1 H), 3.52 (s, 2 H), 3.01
(d, J ) 11.2 Hz, 2 H), 2.73-2.65 (m, 1 H), 2.52-2.43 (m, 1 H),
2.28 (s, 3 H), 2.10 (dt, J ) 11.6, 2.8 Hz, 2 H), 1.88-1.71 (m, 4
H), 1.24 (d, J ) 6.8 Hz, 6 H); ESMS m/e 479.1 (M + H)+; exact
mass calcd for C29H33F2N2O2 (M + H), 479.2510; found, 479.2518.
In Vitro, In Vivo and DMPK Procedures: See part 1, the
preceding paper, for a description of the in vitro binding assays;10e
see part 1, the preceding paper, for a description of the in vivo
assays: social interaction test (SIT);10e see part 1, the preceding
paper, for a description of the MCH-induced water intake;10e see
part 1, the preceding paper, for a description of the rat pharmaco-
kinetic assay;10e and see part 1, the preceding paper, for a description
of the rat pharmacokinetic screening.10e
Acknowledgment. We would like to thank QingPing Han
for mass spectra and analytical support and Jignesh G. Patel
and Xioali Ping for in vivo support. We also thank Carsten H.
Petersen (Valby, Denmark) for high-resolution MS data.
Supporting Information Available: IC50 values, LCMS purity
checks, and high-resolution mass spectrum data for compounds of
interest. This material is available free of charge via the Internet at
http://pubs.acs.org.
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