Novel benzimidazole-based MCH R1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.07.054

The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.

Full text of DOI:10.1016/j.bmcl.2006.07.054

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4994–5000
Novel benzimidazole-based MCH R1 antagonists
Andrew J. Carpenter,* Kamal A. Al-Barazanji, Kevin K. Barvian,
Michael J. Bishop, Christy S. Britt, Joel P. Cooper, Aaron S. Goetz, Mary K. Grizzle,
Donald L. Hertzog, Diane M. Ignar, Ronda O. Morgan, Gregory E. Peckham,
Jason D. Speake and Will R. Swainà
Metabolic and Viral Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline, Five Moore Drive,
Research Triangle Park, NC 27709, USA
Received 2 June 2006; revised 13 July 2006; accepted 17 July 2006
Available online 9 August 2006
Abstract—The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based
MCH R1 antagonists. Structure–activity relationships and efforts to optimize pharmacokinetic properties are detailed along with
the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Obesity, characterized by excess body fat, is a chronic
disease that has dramatically increased in prevalence
over the past 30 years. The co-morbidities strongly asso-
ciated with obesity are numerous—diabetes, coronary
heart disease, hypertension, certain cancers, osteoarthri-
tis, and others—thus, obesity remains an increasingly
important medical and public health issue.1
tify antagonists of MCH R1 led to the discovery of a
series of thienopyrimidinones that are selective, orally
active compounds.7 This letter describes the extension
of the structure–activity relationships (SAR) to include
compounds containing a benzimidazole moiety.
Concomitant to the SAR exploration of the thienopyri-
midinone series, a screening hit was identified that con-
tained structural features (p-biphenyl amide) related to
the original hit (SB-282254). SB-282254 was the progen-
itor of the thienopyrimidinones, represented by GW
803430.7,8 A boost in potency had been realized when
the p-biphenyl amide group was replaced with the chlor-
ophenylthienopyrimidinone; therefore, it was reasoned
that a similar change in the new hit might produce more
potent compounds as well (Fig. 1).
Investigations into the factors that affect body weight
have led to the identification of a group of central tar-
gets for the potential treatment of obesity.2 Melanin-
concentrating hormone (MCH) is a 19-amino acid
peptide that signals through MCH R1 found in the
CNS and stimulates food intake in mammals.3 MCH
peptide knock-out animals are hypophagic and lean,
while MCH over-expressing animals are hyperphagic
and obese.4 Transgenic animals devoid of MCH R1
are resistant to diet-induced obesity and weigh less than
their wild type counterparts.5 These, and other data, are
supportive of MCH as a key mediator in the regulation
of energy balance and body weight.6 Our efforts to iden-
A general synthetic scheme for the preparation of thie-
nopyrimidinone derivatives is outlined in Scheme 1.
Amidine 2 was prepared by condensation of the com-
mercially available thiophene derivative 1 with dimeth-
ylformamide dimethylacetal in EtOH at reflux
followed by concentration and recrystallization of the
sample. The reaction of amidine 2 with a variety of
5-amino-1H-benzimidazoles 3 (or corresponding 6-ami-
no-1H-benzimidazoles) in refluxing ethanol under an
atmosphere of nitrogen provided thienopyrimidinones
4.9 An improvement in reproducibility of the condensa-
tion reaction involved rapidly heating the reactants in
phenol at 110–130 ꢁC over 5–60 min.9b
Keywords: Melanin-concentrating hormone; MCH; MCH R1; MCH
R1 antagonists; Obesity.
*
Corresponding author. Tel.: +1 919 483 9868; fax: +1 919 315
0430; e-mail: andrew.j.carpenter@gsk.com
Present address: Bayer, 400 Morgan Lane, West Haven, CT 06516,
USA.
à
Present address: GlaxoSmithKline, 1104 W. Greenfield Drive,
Peoria, IL 61614, USA.
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.07.054

A. J. Carpenter et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4994–5000
4995
Figure 1. Structural similarity between the progenitor of the thienopyrimidinone series and the screening hit.
O
O
N
R
N
S
S
a
OMe
NH2
OMe
R1
Cl
Cl
+
N
H2N
NMe2
1
2
3
b
R
N
O
N
R1
S
N
N
Cl
4
Scheme 1. Reagents and conditions: (a) DMF–DMA, EtOH, reflux; (b) EtOH, reflux or PhOH, 110–130 ꢁC.
The synthesis of the various 5- and 6-amino-1H-benz-
imidazole derivatives10 was achieved through several
complementary methods, some achieving regioselective
access to N1-versus N3-substitution (yielding 5-amino-
1H-benzimidazoles and 6-amino-1H-benzimidazoles,
respectively), while others simply gave mixtures that re-
quired separation.11
The exploration of the benzimidazole-based antagonists
also focused on appending solubilizing groups at the
N1-, N3-, or C2-positions. To this end, 2-dimethylamino
analogs were also prepared from the dinitro intermedi-
ate (Scheme 2). After introduction of the requisite ani-
line, a moderately selective reduction with sodium
dithionite was performed (purification required) and
the resultant 2-amino-1-anilino-4-nitrobenzene deriva-
tive 9 was treated with phosgene iminium chloride to
directly provide the 2-dimethylamino-1H-benzimid-
azole. Nitro reduction as before completed the synthesis
of this fragment.
Selective introduction of an N1-aryl group was achieved
by treating 2,4-dinitrofluorobenzene (5) with the appro-
priate aniline (Scheme 2). Reduction of the nitro groups
with palladium on carbon under an atmosphere of
hydrogen generated the unstable diamino derivative 7
that was immediately treated with acetyl chloride and
Et3N in DMF. Acid catalyzed cyclization to the benz-
imidazole with concomitant deacylation provided the
5-amino-1-aryl-1H-benzimidazole coupling partner 8.
The same protocol was also used to introduce alkyl sub-
stitution at the N1-position by treating 2,4-dinitroflu-
orobenzene with alkyl amines.
An alternative route to the 2-dimethylamino-1H-benz-
imidazoles 10, which provided the 5-amino-N1-substi-
tuted benzimidazole regioisomer, employed
a
modification of the palladium-mediated intramolecular
cyclization as reported by Brain and Brunton.12 As
depicted in Scheme 3, commercially available 2-bromo-
5-nitroaniline (11) was treated with phosgene iminium

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A. J. Carpenter et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4994–5000
NHR
NO2
NHR
NH2
F
a
b
O2N
NO2
O2N
H2N
5
6
7
e
c, d
R
N
R
N
NHR
NH2
f, g
N
N
N
H2N
O2N
H2N
10
9
8
Scheme 2. Reagents and conditions: (a) ArNH2 or RNH2, K2CO3, DMF, 80 ꢁC; (b) Pd/C, H2, EtOAc; (c) AcCl, Et3N, DMF; (d) concentrated HCl,
100 ꢁC; (e) Na2S2O4; (f) phosgene iminium chloride, DCM; (g) Pd/C, H2, EtOH.
Br
N
Br
N
Br
a
b
O2N
NH2
O2N
O2N
NHR
N
Cl
N
11
12
13
c
R
R
N
N
d
N
N
N
N
H2N
O2N
10
14
Scheme 3. Reagents and conditions: (a) phosgene iminium chloride, DCM, reflux; (b) RNH2, Et3N, THF, reflux; (c) Pd(OAc)2, BINAP, Cs2CO3,
THF, reflux; (d) Pd/C, H2, EtOH.
chloride and the resultant dimethylcarbamimidic chlo-
ride intermediate 12 was then treated with a variety of
primary amines to afford the guanidinyl derivatives 13.
Palladium-mediated cyclization in the presence of BIN-
AP afforded the 5-nitrobenzimidazole derivatives 14.
Nitro reduction completed the synthesis of these
fragments.
The 2-dimethylamino-1H-benzimidazole analogs could
also be conveniently prepared by a three-step sequence
starting with commercially available 3,4-diaminonitro-
benzene (22) (Scheme 5). Treatment of the diamine with
phosgene iminium chloride followed by non-selective
alkylation provided a mixture of 1-substituted benzimid-
azoles that were separated and carried into the nitro
reduction step.
The preparation of other 2-dialkylamino-1H-benzimid-
azoles 20 and 21 could be performed by either starting
with the alkylation of 2-chlorobenzimidazole (15) fol-
lowed by a non-selective nitration of the 6-membered
ring with HNO3 and H2SO4, or switching the order of
the sequence, depending on the nature of the R group.
After separation of the regioisomers, introduction of
an amine via thermally induced nucleophilic aromatic
substitution followed by nitro reduction completed the
synthesis of this coupling partner (Scheme 4). In this
divergent synthesis, a variety of nucleophilic secondary
amines could be introduced by treating the chloro deriv-
ative with an amine in an alcohol solvent in a sealed tube.
Gratifyingly, our initial foray into the series of thieno-
pyrimidinones containing a 1-aryl-1H-benzimidazole
moiety produced antagonists with improved potency13
over the screening hit. The potency was improved with
selected substitution at the para position on the aryl
ring; for example, H versus ethoxy (compounds 24 and
27, respectively) produced a full log improvement in
potency. Unfortunately, these analogs suffered from
poor solubility, and one representative compound, 26
(Table 1), showed undesirable bioavailability14 in rats.
The hypothesis that the N-aryl substituent was primarily
responsible for diminished oral absorption was tested by
replacing the aryl groups with hydrogen, alkyl or substi-
tuted alkyl groups (Table 2). Completely removing the
aryl group did result in a slight loss of potency, but
replacing the aryl group with the cyclohexyl retained
almost all activity. While the fully saturated cyclohexyl
The N-unsubstituted 2-dialkylamino-1H-benzimidazoles
could be prepared by foregoing the alkylation step,
nitrating, reducing the nitro group, and then introduc-
ing the dialkylamino group in a similar fashion (steps
b and c).

A. J. Carpenter et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4994–5000
4997
R1
N
N
R2
N
H2N
c, d
R
20
R
N
R
N
b
a
a
b
O2N
Cl
Cl
N
N
H
N
18
16
17
+
Cl
R
N
N
H
15
N
Cl
Cl
N
O2N
N
19
O2N
c, d
R
N
R1
R2
when R = H
b, d, c
N
N
H2N
21
Scheme 4. Reagents and conditions: (a) RX, K2CO3, DMF, 60 ꢁC; (b) HNO3, H2SO4; (c) R1R2NH, sealed tube, reflux; (d) Pd/C, H2, EtOH.
R
N
H2N
N
N
H
N
NH2
NH2
a
b, c
23
N
+
N
O2N
O2N
R
N
22
14a
N
N
H2N
10
Scheme 5. Reagents and conditions: (a) phosgene iminium chloride, DCM, reflux; (b) RX, K2CO3, DMF, 60 ꢁC; (c) Pd/C, H2, EtOH; (14a = 14,
R = H).
Table 1. SAR and bioavailability of 2-methyl-1-aryl-1H-benzimidazoles (compounds 24–29)
R
N
O
S
N
N
Cl
N
% Fb
a
Compound
R
pIC50
24
25
26
27
28
29
Ph
4-Toluyl
7.5
7.7
8.3
8.5
8.1
8.3
nd
nd
3
4-Methoxyphenyl
4-Ethoxyphenyl
4-Isopropoxyphenyl
nd
nd
nd
4-Dimethylaminophenyl
a Values are means of greater than three experiments; pIC50 = Àlog(IC50).
b Bioavailability (nd, not determined).
was clearly not an improvement with respect to oral bio-
availability, introduction of the aminoethyl substituents
produced compounds with improved bioavailabilities
(compounds 32 and 33) while retaining potency. In the
2-methyl-1H-benzimidazole series, the best improve-
ments in bioavailability were found with alkoxy- and
hydroxypropyl substituents (compounds 34 and 35).
Encouraged by the improvements in oral bioavailability
by the incorporation of tethered amino functionality, a
series of 2-amino-1H-benzimidazoles was investigated
(Table 3). In general, this series exhibited acceptable
potency. Increasing the bulk on the exocyclic nitrogen
appeared to have a beneficial effect (compounds 36 vs.
37, 38 and 42). The limit appeared to be reached with

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A. J. Carpenter et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4994–5000
Table 2. SAR and bioavailability of 2-methyl-1-substituted-1H-benzimidazoles (compounds 26, 30–35)
R
N
O
S
N
N
Cl
N
% Fb
a
Compound
R
pIC50
26
30
31
32
33
34
35
4-Methoxyphenyl
H
Cyclohexyl
8.3
7.6
8.2
8.2
8.7
8.3
8.8
3
nd
0
24
2-(4-Morpholinyl)ethyl
2-(1-Pyrrolidinyl)ethyl
3-Methoxypropyl
3-Hydroxypropyl
31
40
P10014b
a Values are means of greater than 3 experiments; pIC50 = Àlog(IC50).
b Bioavailability (nd, not determined).
Table 3. SAR and bioavailability of N-unsubstituted 2-aminobenzimidazoles (compounds 36–47)
H
R1
N
O
N
R2
S
N
N
Cl
N
a
Compound
R1
R2
H
pIC50
% Fb
36
37
38
39
40
41
42
43
44
45
46
47
H
7.5
8.4
8.6
8.1
7.8
8.5
8.3
7.8
7.0
7.5
8.2
8.3
nd
0
H
Me
Me
i-Pr
c-Pr
Me
H
4
nd
nd
76
31
nd
nd
nd
0
H
CH2CH2CH2CH2
CH2CH2CH2CH2CH2
CH2CH2OCH2CH2
CH2CH2N(CH3)CH2CH2
H
2-Methoxyethyl
2-(1-Pyrrolidinyl)ethyl
2-(1-Pyrrolidinyl)ethyl
H
Me
0
a Values are means of greater than three experiments; pIC50 = Àlog(IC50).
b Bioavailability (nd, not determined).
the cyclic constrained N-methyl piperazine analog (com-
pound 44), although the flexible N–H and N–Me pyrr-
olidinoethyl groups were well tolerated (compounds 46
and 47). Unfortunately, with the notable exception of
the 2-pyrrolidino- and 2-piperidino-1H-benzimidazole
derivatives (compounds 41 and 42 at 76% and 31%,
respectively), the unsubstituted analogs exhibited unfa-
vorable bioavailabilities (<5%).
2-methyl-1H-benzimidazoles. Second, there did not ap-
pear to be a substantial effect on potency from N-substi-
tution of the benzimidazoles, with the glaring exception
being the 4-methoxybenzyl derivative where the substi-
tution is proximal to the thienopyrimidinone core (series
II, compound 54). Third, and most importantly, this ser-
ies produced a number of compounds that showed
promising bioavailabilities necessary for progression,
most notably compound 50, which possesses a favorable
mix of potency and high oral bioavailability.
Thus, a series of 1-substituted-2-dialkylamino-1H-benz-
imidazoles was prepared to potentially elicit improved
bioavailabilities (Table 4). One curious aspect of this
exploration was how regioisomeric substitution on the
benzimidazole ring would affect both potency and bio-
availability. A few general conclusions could be made
regarding this series. First, as exemplified in compound
48, analogs with dialkylamino functionality at the 2-po-
sition typically had increased plasma exposure over the
Efforts to establish the utility of an MCH R1 antagonist
in an animal model of obesity led to the examination of
compound 50 in a semi-chronic study. The compound
exhibited good pharmacokinetic properties in mouse
(bioavailability15 >90%, t1/2 = 6 h) with good brain pen-
etration (brain:plasma ratio = 2.6). Importantly, com-
pound 50 was found to be selective (>100·) over a

A. J. Carpenter et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4994–5000
4999
Table 4. SAR and bioavailability of regioisomeric 2-amino-1H-benzimidazoles (compounds 48–58)
R1
N
N
N
O
N
O
N
R
R
S
S
N
N
N
R1
Cl
Cl
I
II
R1
pIC50
% Fb
a
Compound
Series
R
26
48
49
50
51
52
53
54
55
56
57
58
I
Me
4-Methoxyphenyl
4-Methoxyphenyl
Me
8.3
8.0
8.2
8.8
8.3
8.3
7.9
5.6
8.0
7.9
7.6
8.2
3
I
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NC4H8
NC4H8
16
nd
P10014b
30
21
I
II
I
Me
n-Pr
II
I
n-Pr
4-Methoxybenzyl
4-Methoxybenzyl
2-Hydroxyethyl
2-Hydroxyethyl
Me
nd
nd
II
I
59
55
II
I
nd
P10014b
II
Me
a Values are means of greater than three experiments; pIC50 = Àlog(IC50).
b Bioavailability (nd, not determined).
battery of G-protein coupled receptors, ion channels,
and enzymes. Its efficacy in inducing weight loss was
evaluated in high fat (58% kcal of fat, Research Diets
#D12331) diet-induced obese AKR/J mice.
In conclusion, a series of benzimidazole-containing thie-
nopyrimidinones was synthesized based upon a screen-
ing hit and assessed for their potency as antagonists of
MCH. SAR analysis showed that most compounds were
potent antagonists, with activities below 100 nM. There
also was a wide tolerance for a variety of sterically
demanding functional groups at ring-nitrogen substitu-
tion (positions 1 and 3) or at position 2 of the benzimid-
azole. Improvements in the bioavailability of these
antagonists were also made and one such analog, com-
pound 50, was progressed into an animal model of obes-
ity and produced weight loss over the 15-day treatment
period.
As shown in Figure 2, during a 15-day treatment, oral
administration of compound 50 at 0.3, 1, 3, and
10 mg/kg once daily caused a sustained dose-dependent
change in body weight of À1.6%, À2.1%, À5.1%, and
À10%, respectively, relative to vehicle controls.16
0
Vehicle (n=9)
References and notes
Compound 50 (0.3mg/kg, n=8)
-2
1. Burton, B. T.; Foster, W. R.; Hirsch, J.; Vanitallie, T. Int.
J. Obes. Relat. Metab. Disord. 1985, 9, 155.
Compound 50 (1mg/kg, n=8)
Compound 50 (3mg/kg, n=8)
2. For a recent review, see: Harrold, J.; Pinkney, J.; Williams,
G. Drug Discovery Today: Ther. Strateg. 2004, 1, 219.
3. (a) Presse, F.; Nahon, J.-L.; Fischer, W. H.; Vale, W. Mol.
Endocrinol. 1990, 4, 632; (b) Qu, D.; Ludwig, D. S.;
Gammeltoft, S.; Piper, M.; Pelleymounter, M. A.; Cullen,
M. J.; Mathes, W. F.; Przypek, J.; Kanarek, R.; Maratos-
Flier, E. Nature 1996, 380, 243; (c) Skofitsch, G.; Jacobo-
witz, D. M.; Zamir, N. Brain Res. Bull. 1985, 15, 635; (d)
Rossi, M.; Choi, S. J.; O’Shea, D.; Miyoshi, T.; Ghatei, M.
A.; Bloom, S. R. Endocrinology 1997, 138, 351.
Compound 50 (10mg/kg, n=8)
-4
-6
-8
4. Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, J. S.;
Maratos-Flier, E. Nature 1998, 396, 670.
-10
-12
5. (a) 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.; MacIn-
tyre, D. E.; Van der Ploeg, L. H. T.; Qian, S. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 3240; (b) Chen, Y.; Hu, C.;
Hsu, C.-K.; Zhang, Q.; Bi, C.; Asnicar, M.; Hsiung, H.
M.; Fox, N.; Slieker, L. J.; Yang, D. D.; Heiman, M. L.;
Shi, Y. Endocrinology 2002, 143, 2469.
Figure 2. Effect of compound 50 at 0.3, 1, 3, and 10 mg/kg (orally, qd)
on body weight loss in high fat diet-induced obese AKR/J mice.
Weight loss is expressed as percentage weight change from pre-
treatment value for each treatment group (average pre-treatment body
weight value was 49.6 0.6 g, n = 41). Values are means SEM; n,
number of mice per group.

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A. J. Carpenter et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4994–5000
6. Several reviews have been written that detail the search for
as described in WO 2004/092181 A1 (corrected version),
pages 215–216. CHO cells expressing an elkgal4-luc+
reporter gene (host) were transfected with human MCH
R1. The ability of the antagonists to inhibit an EC80
response of MCH was assessed via a TopCount micro-
plate scintillation counter (Packard) and the specificity of
the MCH R1 response was determined by measuring the
ability of the antagonists to inhibit an EC80 thrombin
response in the host cells. All compounds were assayed
with n P 4.
MCH R1 antagonists as potential therapeutics for obesity.
Please see: (a) Dyke, H. J.; Ray, N. C. Expert Opin. Ther.
Pat. 2005, 15, 1303; (b) Kowalski, T. J.; McBriar, M. D.
Expert Opin. Investig. Drugs 2004, 13, 1113; (c) Browning,
A. Expert Opin. Ther. Pat. 2004, 14, 313; (d) Collins, C.
A.; Kym, P. R. Curr. Opin. Investig. Drugs 2003, 4, 386.
7. Witty, D. R.; Bateson, J.; Hervieu, G. J.; Al-Barazanji, K.;
Jeffrey, P.; Hamprecht, D.; Haynes, A.; Johnson, C. N.;
Muir, A. I.; O’Hanlon, P. J.; Stemp, G.; Stevens, A. J.;
Thewlis, K.; Winborn, K. Y. Bioorg. Med. Chem. Lett. in
press.
8. Hertzog, D. L.; Al-Barazanji, K. A.; Bigham, E. C.; Bishop,
Michael, 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, F. X.; Zhou, H. Bioorg. Med. Chem
Lett. in press.
9. For a general synthesis of pyrimidinones, see: (a) Gupton,
J. T.; Miller, J. F.; Bryant, R. D.; Maloney, P. R.; Foster,
B. S. Tetrahedron 1987, 43, 1747; (b) Unpublished results.
10. See Ref. 7 for full experimental details. The amino-1H-
benzimidazole derivatives used to prepare final com-
pounds 24–31, 34, and 35 (not detailed in Ref. 7), were
synthesized using Scheme 1.
11. For a review of the more general syntheses of benzimid-
azoles, see: Preston, P. N. Chem. Rev. 1974, 74, 279.
12. Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43,
1893.
14. (a) Bioavailabilities (% F) were determined in rats using an
i.v. (ꢀ3 mg/kg) and oral (ꢀ5–10 mg/kg) arm of dosing
(n = 1 each) and were used primarily as a screening filter.;
(b) A value greater than 100% is achieved due to
variability amongst the individual animals or due to
saturation of clearance mechanisms when comparing the
intravenous and oral dosings.
15. This oral bioavailability (% F) value was determined in
mice using an i.v. (1.6 mg/kg) and oral (5.2 mg/kg) arm of
dosing (n P 2 each).
16. The weight loss achieved with a related MCH R1
antagonist, GW 803430 (Fig. 1), was due entirely
to fat mass loss as determined by dual-energy X-
ray absorptiometry (DEXA) scanning. Al-Barazanji,
K.; Grizzle, M.; Britt, C.; Lancaster, M.; Daniels,
A.; Ignar, D.; Cooper, J.; Hertzog, D. Anti-
obesity effects of
a novel MCH R1 antagonist in
the diet-induced obese AKR/J mouse. Supplement
Program Abstracts, NAASO’s 2004 Annual Meet-
ing, Las Vegas, Nevada, November 14–18, 2004,
56-OR.
13. The compounds were evaluated in a functional assay for
MCH R1 activity utilizing luciferase activity as a readout