Synthesis and evaluation of urea-based indazoles as melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity

Article abstract of DOI:10.1016/j.bmcl.2005.03.114

A series of urea-based N-1-(2-aminoethyl)-indazoles was synthesized and evaluated for melanin-concentrating hormone receptor 1 (MCHr1) antagonism in both binding and functional assays. Several compounds that acted as MCHr1 antagonists were identified, and optimization afforded a compound with excellent binding affinity, good functional potency, and oral efficacy in a chronic model for weight loss in diet-induced obese mice.

Full text of DOI:10.1016/j.bmcl.2005.03.114

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2752–2757
Synthesis and evaluation of urea-based indazoles as
melanin-concentrating hormone receptor 1 antagonists for
the treatment of obesity
Andrew J. Souers,* Ju Gao, Dariusz Wodka, Andrew S. Judd, Mathew M. Mulhern,
James J. Napier, Michael E. Brune, Eugene N. Bush, Sevan J. Brodjian, Brian D. Dayton,
Robin Shapiro, Lisa E. Hernandez, Kennan C. Marsh, Hing L. Sham,
Christine A. Collins and Philip R. Kym
Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
Received 10 February 2005; revised 4 March 2005; accepted 30 March 2005
Available online 29 April 2005
Abstract—A series of urea-based N-1-(2-aminoethyl)-indazoles was synthesized and evaluated for melanin-concentrating hormone
receptor 1 (MCHr1) antagonism in both binding and functional assays. Several compounds that acted as MCHr1 antagonists were
identified, and optimization afforded a compound with excellent binding affinity, good functional potency, and oral efficacy in a
chronic model for weight loss in diet-induced obese mice.
Ó 2005 Elsevier Ltd. All rights reserved.
Melanin-concentrating hormone (MCH) is a cyclic 19-
amino acid neuropeptide that serves as an important
mediator in the regulation of energy balance and food
intake in mammals.1,2 Transgenic mice overexpressing
the MCH gene are susceptible to insulin resistance and
obesity,3 while mice lacking the gene encoding MCH
are hypophagic, lean, and maintain elevated metabolic
rates.4 Similarly, genetically altered animals that lack
the gene encoding the MCH receptor maintain elevated
metabolic rates and remain lean despite hyperphagia on
a normal diet.5,6 This evidence suggests that antagonism
of MCH signaling could be an effective therapy for obes-
Figure 1. Indole-based MCHr1 antagonists. aValues represent an
average of at least two determinations where each determination is
within 35% of the mean value shown. b10 mg/kg, po in DIO mice,
interanimal variability was less than 25% for all values.
ity, and multiple reports of small molecule antagonists
of MCHr1 have appeared in the recent literature.7
A previous report8 from these laboratories described the
optimization of compound 1, which was identified via
high-throughput screening against MCHr1 (Fig. 1).
Substitution of the indole core with an indazole and re-
moval of the basic amine-containing side chain in favor
of 4-benzyloxyphenylacetic acid afforded a compound
(2) with significantly improved in vitro and in vivo prop-
erties. During the process of exploring the indazole
pharmacophore, we set out to investigate the struc-
ture–activity relationships (SARs) of analogs with
urea-based side chains. In this report, we disclose the
SAR of this series of MCHr1 antagonists, as well as
the identification of a compound with excellent binding
affinity, good functional activity, and efficient CNS pen-
etration upon oral dosing in diet-induced obese (DIO)
mice. Additionally, we describe the evaluation of this
Keywords: MCHR1; Obesity.
*
Corresponding author. Tel.: +1 847 937 5312; fax: +1 847 938
1674; e-mail: andrew.souers@abbott.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.114

A. J. Souers et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2752–2757
2753
compound in a two-week efficacy model for weight loss
in DIO mice.
were followed by iron-mediated reduction to afford the
diamine intermediates 5. Reaction with phenyl carbon-
ate afforded the intermediate carbamates, and subse-
quent derivitization with various amines under
microwave heating conditions afforded the final analogs
6. Alternatively, the appropriate isocyanates could be di-
rectly reacted with the diamine intermediates 5 to afford
the final products.
To explore the urea-based side chain SAR around the
indazole pharmacophore, we initially synthesized a set
of 6-substituted analogs with side chains that were
biased to contain the extended aromatic ethers necessary
for activity in the indazole amide-based series as exem-
plified by 2. To investigate the positional requirements
of the side chain, indazoles substituted at the 4- and 5-
positions were also prepared.
The corresponding indazole urea analog of 2 (Table 1,
compound 7) showed a dramatic decrease in both bind-
ing affinity and functional potency. Contraction of the
terminal ether portion of the side chain from a benzyl-
oxy to a phenoxy substituent afforded compound 8,
which had similar discouraging activity. However, inser-
tion of a methylene unit prior to the phenoxyphenyl sub-
stituent proved to be beneficial, as homologated analog
9 was significantly more potent in the functional assay
than both 7 and 8, and showed greater binding affinity.
The presence of an additional methylene unit (10)
brought an additive increase in activity, affording the
most potent 6-substituted analog from this set. Replac-
ing either of the phenyl portions of the extended aro-
matic ether side chain with other heterocycles or alkyl
chains afforded predominantly inactive compounds, as
exemplified by the 1-N-benzyl-4-amino-piperidinyl con-
taining analog 11. Side chains with other polar function-
ality in this region were also inactive (data not shown).
As shown in Scheme 1, 4-nitro indazole was synthesized
from 3-nitro-o-tolylamine (3), while the 5- and 6-nitroin-
dazoles were obtained from commercial sources. Alkyl-
ation of the individual nitroindazoles (4) and
purification of the corresponding N-1-alkylated isomers
A similar set of analogs was prepared starting from
5-nitroindazole in order to probe the effects of
moving the side chain around the core. The 4-benzyloxy-
phenyl-substituted urea 12 showed a considerable in-
crease in binding affinity relative to the corresponding
6-substituted analog 7, but no improvement in func-
tional potency. Contraction of the terminal benzyloxy
Scheme 1. Reagents and conditions: (a) NaNO2, AcOH, rt, 95%; (b)
chloroethylpyrrolidine hydrochloride, K2CO3, DMF, 60 °C, then SiO2
chromatography, 27–67%; (c) Fe, NH4Cl, 65 °C; (d) phenylcarbonate,
THF; or PhOC6H4NCO, THF, 60 °C, 90%; (e) R1R2NH, NMP,
220 °C, lw.
Table 1. Binding affinity and functional potency of MCHr1 antagonistsa
N
N
N
6
HN
5
RHN
4
O
Compd
R
Pos
MCHr1 binding IC50 (nM)b,d
Ca2+ release IC50 (lM)c,d
7
BnOC6H4–
PhOC6H4–
6
6
6
6
6
5
5
5
5
5
4
4
113
581
7.14
>10
0.626
0.178
>10
>10
0.104
>10
>10
>10
>10
>10
8
9
PhOC6H4CH2–
PhOC6H4(CH2)2–
(1-N-Bn-piperidin-4-yl)–
BnOC6H4–
78.5
34.3
4509
41.3
12.0
508
10
11
12
13
14
15
16
17
18
PhOC6H4–
PhOC6H4CH2–
PhOC6H4(CH2)2–
(1-N-Bn-piperidin-4-yl)–
BnOC6H4–
545
971
1053
1851
PhOC6H4–
a All compounds were >95% pure by HPLC and characterized by 1H NMR and HRMS.
b Displacement of [125I]-MCH from MCHr1 expressed in IMR-32 (I3.4.2) cells (MCH binding Kd = 0.66 0.25 nM, Bmax = 0.40 0.08 pmol/mg).
c
Inhibition of MCH-mediated Ca2+ release in whole IMR-32 cells (MCH EC50 = 62.0 3.6 nM).
d Values represent an average of at least two determinations where each determination is within 40% of the mean value shown.

2754
A. J. Souers et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2752–2757
ether to a phenoxy ether afforded compound 13, which
had excellent binding affinity and greatly improved
functional activity relative to any of the previously
tested urea-based compounds. In contrast to the trend
observed in the 6-substituted series, the addition of
one and two methylene unit spacers between the urea
nitrogen and phenoxyphenyl substituent (compounds
14 and 15, respectively) produced a decreasing trend
with respect to binding affinity. This is readily apparent
when comparing the decreasing affinities of analogs 13–
15 to the increasing affinities of the corresponding 6-
substituted analogs 8–10, and suggests that the addi-
tional two methylene units found in the 6-substituted
analog 10 may allow for the placement of the phenoxy-
phenyl substituent into similar space as that occupied in
the potent 5-substituted analog 13.
the hypothesis that reduced polarity within this region
of the molecule could improve the brain penetration. It
was further envisioned that an imidazolone could
achieve this task while introducing limited perturbation
to the molecule. To this end, N-1-alkylated indazole 5
was reductively aminated with dimethoxyglyoxal to
afford the secondary aniline 19 (Scheme 2). Reaction with
phenoxyphenyl isocyanate followed by acid treatment
under heated conditions afforded the 1,3-disubstituted
imidazolone 20. Subsequent reduction under a hydrogen
atmosphere afforded the saturated imidazolidinone 21.
The cyclic analogs 20 and 21 were evaluated in the
MCHr1 binding and functional assays (Table 3). Inter-
estingly, both compounds had binding affinities that
were very similar to 13, but functional potencies that de-
creased 6- and 10-fold for 20 and 21, respectively. The
more potent unsaturated analog 20 was further evalu-
ated in DIO mice to determine the effects of reducing
the hydrogen-bonding network of the urea on brain pen-
etration (Table 3). Interestingly, the CNS exposure was
modestly improved relative to parent compound 13, and
the distribution was biased in favor of the brain
(brainAUC:plasmaAUC = 1.3).
As observed with all isomers, attempt to incorporate
polarity within the side chain and/or replace the phenyl
substituents afforded significantly less active or inactive
compounds. This is exemplified by compound 16, which
showed improved binding affinity relative to the 6-
substituted derivative 11, but a similar lack of functional
activity. Finally, all of the 4-substituted analogs tested
showed poor binding affinities and functional potencies.
The two most potent compounds from this initial set, 10
and 13, were evaluated for plasma and brain exposure in
DIO mice (10 mg/kg, po). As shown in Table 2, the 6-
substituted analog 10 exhibited moderate plasma expo-
sure but negligible brain penetration. In contrast, the
5-substituted analog 13 showed excellent plasma expo-
sure and slightly improved brain penetration relative
to indazole amide 2.9
While compound 13 showed promising levels of
CNS penetration, the high plasma exposure afforded a
brainAUC:plasmaAUC ratio of 0.3. In an effort to improve
the brain to plasma ratio, we sought to limit the hydro-
gen-bonding ability of the urea pharmacophore with
Table 2. Selected pharmacokinetic parameters of 10 and 13 in DIO
mice (10 mg/kg po)a
Scheme 2. Reagents and conditions: (a) 1,1-dimethylglyoxal, 1:1 DCE/
MeOH (1% AcOH), NaBH3CN, 55 °C; (b) PhOC6H4NCO, THF,
60 °C; (c) p-TsOH, THF/H2O (4:1), 60 °C; (d) Pd(OH)2, H2, 60 psi.
Compd Plasma AUC Plasma Cmax Brain AUC Brain Cmax
(lg h/g)b
(ng/mL)b
(lg h/g)b
(ng/g)b
2
2.12
0.335
5.35
596
86.0
246
1.33
0.00
1.43
177
0.00
260
10
13
Table 3. Selected in vitro and pharmacokinetic properties of cyclic
ureasa
a All values are mean values (n = 3 unless specified otherwise). Inter-
animal variability was less than 30%. Compounds are dosed in DIO
mice at 10 mg/kg, po in a vehicle containing 1% Tween 80 and water.
b The three mice with highest plasma and brain concentrations were
averaged to provide the peak plasma and brain concentrations
(Cmax), respectively. The mean plasma or brain concentration data
were submitted to multi-exponential curve fitting using WinNonlin.
The area under the mean concentration–time curve from 0 to t h
20
21
MCHr1 binding IC50 (nM)b
Ca2+ release IC50 (lM)b
Plasma AUC (lg h/mL)c
Plasma Cmax (ng/mL)c
Brain AUC (lg h/g)c
5.90
0.654
1.35
543
19.8
1.12
NT
NT
NT
NT
1.71
183
Brain Cmax (ng/g)c
(time of the last measurable concentration) after dosing (AUC0–t
)
was calculated using the linear trapezoidal rule for the concentra-
tion–time profile. The residual area was extrapolated to infinity,
determined as the final measured mean concentration (Ct) divided by
the terminal elimination rate constant (b), and was added to AUC0–t
to produce the total area under the curve (AUC0–1).
NT, not tested.
a All compounds were >95% pure by HPLC and characterized by 1H
NMR and HRMS.
b See Table 1, footnote d.
c See Table 2, footnote b.

A. J. Souers et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2752–2757
2755
Table 4. Binding affinity and functional potency of MCHr1
antagonistsa
Compd
R
n
MCHr1 binding
IC50 (nM)c
Ca2+ release
IC50 (lM)c
13b
24b
1
1
12.0
305
0.104
>10
Scheme 3. Reagents and conditions: (a) 1,10-dimethoxy-2-bromo-
ethane, or 1,10-dimethoxy-3-bromopropane, K2CO3, DMF, 60 °C, then
SiO2 chromatography (41–57%); (b) Fe, NH4Cl, 65 °C, 90%; chloro-
ethylpyrrolidine hydrochloride, K2CO3, DMF, 60 °C, then SiO2
chromatography (32, 45%); (c) PhOC6H4NCO, THF, 85%; (d) 2/1
2 N HCl/acetone, 60 °C; (e) R1R2NH, MeOH (1% AcOH), MP-
CNBH3.
25
1
38.7 18.2
0.516 0.358
26
1
1
1
2.40 0.03
1.80 0.90
6130
0.147 0.044
0.751 0.195
>10
27
28b
Despite the enhanced brainAUC:plasmaAUC ratio of
compound 20, the deleterious effect of urea cyclization
on functional potency encouraged us to concentrate on
13 for additional SAR development. Since the phenoxy-
phenylurea represented the preferred side chain for opti-
mal potency, we retained this substituent while altering
the tertiary amine and linker length of the 1-(2-pyrroli-
din-1-yl-ethyl) portion of the molecule. A panel of
hydrophobic and hydrophilic amines was selected, along
with two and three carbon linkers. As shown in Scheme
3, 5-nitro indazole (4) was alkylated with 1,10-dime-
thoxy-2-bromoethane or 1,10-dimethoxy-3-bromopro-
pane and the desired N-1-functionalized isomer 22
separated via chromatography. Following iron-medi-
ated reduction and amide bond formation, the latent
aldehyde was liberated with aqueous acid. Reductive
amination with various primary and secondary amines
afforded the final compounds 23.
29
1
134 64
0.171 0.089
30b
31
2
2
2
82.9
1.177
8.50 1.20
40.6 15.6
0.275 0.116
2.88 1.21
32
33b
2
91.5
0.894
a All values are mean values SEM (n = 3 unless specified otherwise).
b Values represent an average of at least two determinations where
each determination is within 45% of the mean value shown.
c See Table 1, footnote c.
both assays. Additionally, the 4-amido-piperidine ana-
log 32 showed a 3-fold improvement in binding affinity
relative to the two-carbon linked derivative 29, yet dem-
onstrated a significant loss of functional activity. A
notable exception was 4-hydroxy-piperidine analog 33,
which showed greater than 65-fold improvement in
binding affinity and a significant increase in functional
potency relative to 28.
As displayed in Table 4, substituted pyrrolidine analogs
24 and 25 showed decreased functional potency as com-
pared to parent analog 13, although the 2-methoxym-
ethyl analog 25 had similar binding affinity. The
secondary and tertiary amines 26 and 27, respectively,
demonstrated excellent binding affinities, both improv-
ing approximately 10-fold. Interestingly, the methyl-
isobutylamine analog 27 showed a 7-fold decrease in
functional potency, while 26 was comparable to 13.
Nearly all of the piperidine analogs evaluated (repre-
sented by analog 28) were weak binders of MCHr1, with
the exception of amide-substituted piperidine analog 29,
which showed good binding affinity and nearly equipo-
tent functional antagonism. Incorporation of larger cyc-
lic amines such as hexamethyleneamine afforded
compounds that demonstrated no improvement relative
to 13 (data not shown).
The SAR from this focused batch of compounds re-
vealed some interesting trends, yet no analogs offered
a significant improvement in functional potency relative
to parent 13. Therefore, we selected this compound for
evaluation in an in vivo efficacy model in order to assess
the potential of the urea-based pharmacophore. For a
two-week period, DIO mice fed a high-fat diet ad libi-
tum were dosed orally with 13 (10, 30, and 100 mg/kg,
bid), D-fenfluramine10 (10 mg/kg, qd) as a drug-treat-
ment control, or vehicle. Food intake and body weight
were measured at days 1, 5, 7, 11, and 14 for each group.
The three carbon linked analogs were generally less ac-
tive than the corresponding two carbon linked com-
pounds. Analogs 30 and 31 were approximately 2-fold
less than the corresponding compounds 25 and 26 in
As indicated in Figure 2, the vehicle group continued to
gain weight throughout the study. D-Fenfluramine

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A. J. Souers et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2752–2757
Figure 2. Effect of compound 13 (dosed at 30 and 100 mg/kg, po, bid
in 1% Tween 80 in water) and D-fenfluramine (D-fen, 10 mg/kg, po, qd)
on the body weight of DIO mice. Change is registered as the number of
grams of body weight difference for each measurement time point
relative to day zero. All values are mean values SEM for n = 12. (**)
p <0.05 for comparisons against vehicle group.
Figure 3. Effect of compound 13 (dosed at 30 and 100 mg/kg, po, bid
in 1% Tween 80 in water) and D-fenfluramine (D-fen, 10 mg/kg, po, qd)
on daily and cumulative food intake of DIO mice. All values are mean
values SEM for n = 12. (*) p <0.05 for comparisons against vehicle
group.
absorptiometry11 (DEXA). No significant decrease in
fat mass or lean mass was apparent upon chronic oral
treatment of 13 at 30 mg/kg, bid, while fat mass was sig-
nificantly reduced in mice treated with the higher dose of
100 mg/kg, bid (16.6 1.7 g vs 22.1 0.1 g for vehicle-
treated controls, p <0.05). No significant loss of lean
mass was apparent for either dose group. Administra-
tion of D-fenfluramine also resulted in a significant de-
crease in fat mass (12.3 1.0 g, p <0.05) with no
change in lean mass. Finally, no significant changes in
locomotor activity were observed upon administration
with 13 at either dose, indicating that treatment did
not cause any overt behavioral effects (data not shown).
caused a rapid decrease in body weight followed by a re-
bound that started on day 8 and continued until day 14.
Compound 13 showed no statistically significant effect
on body weight at 30 mg/kg, while treatment with
100 mg/kg caused a decrease in body weight that was
observed at day 1 and continued throughout the dura-
tion of the study. At day 14, mice dosed with indazole
13 (100 mg/kg, po, bid) and D-fenfluramine (10 mg/kg,
po, qd) weighed 17.1% and 9.12% less (p <0.01), respec-
tively, than the vehicle control group (Table 5).
The cumulative food intake was decreased in both dos-
ing groups of mice treated with 13 (Fig. 3), although the
reduction observed in the lower dose group was not sta-
tistically significant. Treatment with 100 mg/kg 13 re-
sulted in a significant reduction in food intake by day
5 (Table 6) and a significant cumulative reduction by
day 14. Treatment with D-fenfluramine also caused a de-
crease in food intake that was significant by day 5 and
continued through the duration of the study.
The significant reduction in food intake observed in the
mice treated with 13 (100 mg/kg, po, bid) indicates that
the measured weight loss is primarily mediated by a neg-
ative energy balance. Interestingly, while this is consis-
tent with the MCHr1 antagonist-mediated weight loss
reported for other small molecule MCHr1 antagonists,12
it is in contrast to our findings with the related amide-
based indazole antagonist 2 (Fig. 1).8 Upon chronic
administration of 2, no decrease in food consumption
was observed in the face of significant loss of body fat,
indicating that increased energy expenditure was the pri-
mary component of the observed weight loss. Since both
compounds selectively reduced body fat and had no
effect on lean mass, and that no overt toxicity was ob-
served upon chronic treatment with these compounds,
it is likely that the pharmacological effect is at least par-
tially mediated by antagonism of the targeted receptor.
In light of the different effects upon food intake by these
two efficacious compounds, it is possible that the in-
creased energy expenditure component yields to signifi-
cant effects on food intake with increasing receptor
blockade. Further studies are needed to fully investigate
the disparate effects of these MCHr1 antagonists.
In order to determine the contributions of changes in fat
and lean mass relative to the observed decrease in body
weight following the two-week study, analysis of body
composition was performed with dual-energy X-ray
Table 5. Body weight (BW) of all animal groups at day0, day14, and %
change of the drug-treatment groups vs vehiclea
Groupb
BWday0 (g) BWday14 (g) % Change from
vehicle
Lean
Vehicle
31.7 0.8
45.0 0.7
D-Fen 10 mg/kg 42.7 0.7
31.8 0.8
46.9 0.8
39.8 0.8
42.3 1.1
36.3 1.3
—
—
ꢀ9.12 0.0
ꢀ3.41 0.00
ꢀ17.1 0.0
13 30 mg/kg
13 100 mg/kg
42.3 0.9
42.5 1.0
a All values are mean values SEM (n = 12).
b All doses were given in 4-mL/kg body weight volume of vehicle (1%
Tween 80 in water). Compound 13 was administered po by gavage, at
doses of 30 and 100 mg/kg, bid, and D-fenfluramine at a dose of
10 mg/kg, po, qd. Food and body weights were determined on the
first day and periodically thereafter for 14 days.
In summary, exploration of urea-based side chains upon
the previously identified N-1-pyrrolidinyl-ethyl-indazole
core led to the identification of 13. This compound binds
with high affinity to the MCHr1 receptor, potently

A. J. Souers et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2752–2757
2757
Table 6. Cumulative food intake of mice treated with compound 13, D-fenfluramine, or vehiclea
Group
Day 1
Day 5
Day 7
Day 11
Day 14
Leanb
3.10 0.11
4.36 0.87
0.89 0.7
3.00 0.83
2.17 0.50
11.8 0.3
14.3 1.6
8.44 1.40
11.2 1.1
7.86 0.85
20.3 0.4
23.1 2.2
17.8 2.0
20.1 1.4
13.6 1.1
31.9 0.6
37.0 2.9
31.1 2.4
32.4 2.0
23.6 1.9
40.6 0.6
44.1 3.5
39.9 3.1
39.8 2.1
29.4 2.1
Vehiclec
D-Fen 10 mg/kgc
13 30 mg/kgc
13 100 mg/kgc
a All values are mean values SEM (n = 12).
b Lean mice were administered a purified low fat diet (D12450Bi, 10 kcal % fat, 3.8 kcal/g).
c Vehicle and drug-treated animal groups were fed a high fat content diet (D12492i, 60 kcal % fat, 5.2 kcal/g), both obtained from Research Diets Inc.
(New Brunswick, NJ) for approximately 16 weeks. The fat content of these diets was a mixture of lard and soybean oil.
inhibits Ca2+ mobilization in IMR-32 cells, and shows
6. 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.;
good brain exposure upon oral dosing in DIO mice.
Furthermore, chronic oral treatment with 13 at
100 mg/kg, bid, exerts a significant anorectic effect on
Gopal-Truter, S.; MacNeil, D. J.; Strack, A. M.; MacIn-
DIO mice that appears to be the result of decreased food
intake. Studies are ongoing to fully explore the pharma-
tyre, D. E.; Van der Ploeg, L. H. T.; Qian, S. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 3240–3245.
cological effects of treatment with this compound, and
7. Multiple patents describing small molecule MCHr1 antag-
further optimization of the urea-based indazole class
of MCHr1 antagonists for binding affinity and func-
tional potency, brain penetration, and oral efficacy will
be reported in due course.
onists have been published recently. For excellent reviews
on the subject, see the following: (a) Kowalski, T. J.;
McBriar, M. D. Expert Opin. Invest. Drugs 2004, 13,
1113–1122; (b) Browning, A. Expert Opin. Ther. Pat.
2004, 14, 313–325; (c) Collins, C. A.; Kym, P. R. Curr.
Opin. Invest. Drugs 2003, 4, 386–394.
8. Souers, A. J.; Gao, J.; Brune, M.; Bush, E.; Wodka, D.;
Vasudevan, A.; Judd, A.; 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, ASAP.
9. Similar results were obtained in the previous study (Ref.
8), as 5-substituted indazoles consistently showed better
oral exposure than 6-substituted indazoles.
10. Bickerdike, M. J. Curr. Top. Med. Chem. 2003, 3, 885–897.
11. Sjogren, K.; Hellberg, N.; Bohlooly, Y. M.; Savendahl, L.;
Johansson, M. S.; Berglindh, T.; Bosaeus, I.; Ohlsson, C.
J. Nutr. 2001, 131, 2963–2966.
Acknowledgments
The authors thank Christopher Ogiela, Dennis Fry, and
Doug Falls for preparing the IMR-32 cells and aiding
with the execution of the binding and functional assays,
Paul Richardson and J. J. Jiang for MCH production,
Seble Wagaw, Xiu Wang, Lei Wang, Su Yu, and Ken-
neth Engstrom for process support, and Brian Droz
and Victoria Knourek-Segel for help with compound
dosing.
12. (a) Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marza-
badi, M. R.; DeLeon, J.; Lagu, B.; Heurich, R.; Lichtblau,
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