Pyrimidine-based antagonists of h-MCH-R1 derived from ATC0175: In vitro profiling and in vivo evaluation

Article abstract of DOI:10.1016/j.bmcl.2009.09.003

A series of pyrimidine analogues derived from ATC0175 were potent antagonists of human MCH-R1 in vitro. Significantly improved receptor selectivity was achieved with several analogues from this series, but no improvement in brain partitioning was noted. One example from this series was shown to inhibit food intake and decrease body weight in a chronic study. However no clear correlation between the pharmacodynamic effect and the pharmacokinetic data with respect to brain concentration was discernible leading us to conclude that the observed effect was most likely not due to interaction with the MCH-R1.

Full text of DOI:10.1016/j.bmcl.2009.09.003

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6166–6171
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pyrimidine-based antagonists of h-MCH-R1 derived from ATC0175:
In vitro profiling and in vivo evaluation
a
a
a
a
a
Graeme Semple a, , Thuy-Anh Tran , Bryan Kramer , Debbie Hsu , Sangdon Han , Juyi Choi ,
Pureza Vallar a, Martin D. Casper a, Ning Zou a, Erin K. Hauser b, William Thomsen b, Kevin Whelan b,
Dipanjan Sengupta c, Michael Morgan d, Yoshinori Sekiguchi e, Kosuke Kanuma e, Shigeyuki Chaki e,
Andrew J. Grottick b
*
a Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA
b Discovery Biology, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA
c Pharmaceutical Development, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA
d DMPK, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA
e Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of pyrimidine analogues derived from ATC0175 were potent antagonists of human MCH-R1
in vitro. Significantly improved receptor selectivity was achieved with several analogues from this series,
but no improvement in brain partitioning was noted. One example from this series was shown to inhibit
food intake and decrease body weight in a chronic study. However no clear correlation between the phar-
macodynamic effect and the pharmacokinetic data with respect to brain concentration was discernible
leading us to conclude that the observed effect was most likely not due to interaction with the MCH-R1.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 8 August 2009
Revised 1 September 2009
Accepted 2 September 2009
Available online 6 September 2009
Keywords:
MCH-R1
ATC0175
Obesity
Food intake
GPCRs
PK-PD
CNS
Melanin concentrating hormone (MCH) is a cyclic 19 amino acid
neuropeptide first isolated from salmon pituitary.1 MCH gene
expression is restricted to the lateral hypothalamic area and zona
incerta, indicating a possible role in feeding or metabolism.2
MCH is over-expressed in a number of rodent genetic models of
obesity and diabetes (e.g., ob/ob; db/db, kkAY mice and fa/fa rats),
whereas prepro-MCH deficient mice are lean, hypophagic and dis-
play a slight increase in metabolic rate.3 Melanin concentrating
hormone receptor-1 (MCH-R1) knock-out mice have normal body
weight but are lean and hyperphagic.4 MCH exerts its effects via
two receptors in higher species (MCH-R1 and MCH-R2), which
share approximately 38% homology, whereas only a single receptor
with high sequence homology (96%) to the human MCH-R1 has
been identified in rodents.5 Chronic (14-day, ICV) administration
of a selective peptide MCH agonist to rats results in hyperphagia
and an increase in fat mass, whereas central administration of a
peptidic MCH-R1 antagonist reduces feeding and bodyweight gain
over 14 days.6 From these data it can be inferred that a centrally
acting MCH-R1 antagonist would reduce food intake and body-
weight and hence may be useful for the treatment of obesity. This
appeared to be confirmed with a non-peptide antagonist (SNAP-
7941, Fig. 1), which when dosed twice daily (20 mg/kg, IP) reduced
food intake and bodyweight in diet-induced obese (DIO) rats.7
Moreover, there have been multiple reports that selective MCH-
R1 antagonists decrease food intake and body weight in the rat
after oral administration,8 as well as a recent report of similar ef-
fects in the rhesus monkey.9
From our in-house collection of GPCR-biased ligands, we used
high throughput screening with either a GTPcS binding or FLIPR
assay10 to identify a series of alkyl-amino quinazolines which were
functional antagonists at human MCH-R1. Our initial screening hits
for the receptor had IC50 values in the 100–500 nM range but
lacked selectivity against a panel of other GPCRs, in particular
the NPY Y5 receptor, and had somewhat poor in vitro metabolic
stability. A rapid, parallel, ‘hit-to-lead’ type expansion of the SAR
of this series led us into a number of sub-series with potent and
selective MCH-R1 antagonist activity as well as significantly
improved metabolic stability.11,12 Lead optimization of two of the
resulting series, again using a modular parallel synthesis approach,
* Corresponding author.
E-mail address: gsemple@arenapharm.com (G. Semple).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.003

G. Semple et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6166–6171
6167
O
O
N
O
N
N
S
N
N
OMe
Cl
H
F
II, GW3430
pIC50 = 9.3
I, T-226296
IC50 = 5.5 nM
F
F
F
F
N
N
O
H
N
MeO2C
MeO
N
N
N
N
H
H
O
N
N
N
H
O
HCl
H
O
IV, ATC0175
IC50 = 7.2 nM
III, SNAP-7941
pA2 = 9.24
Figure 1. Known h-MCH-R1 antagonists.
confirmed further important aspects of the SAR. The inclusion of
the dimethylamino substituent on the quinazoline portion of the
lead series was found to be critical for optimal h-MCH-R1 activity,
but a wide range of substituents were well tolerated at the other
extreme of the molecule enabling us to manipulate the CNS parti-
tioning properties of the series. This culminated in the identifica-
tion of our early lead compound, ATC0175 (Fig. 1).13 ATC0175
showed good oral bioavailability and moderate brain partitioning
in rats (brain/plasma ratio 0.5–0.7 after oral administration) and
was used as a pharmacological tool for proof of concept studies
in vivo. For example, when dosed perorally (b.i.d.), ATC0175
dose-dependently decreased food intake and body weight over a
four-day period in Sprague-Dawley rats fed on a high-fat diet.14
To further improve some of the properties of ATC0175 we fo-
cused in particular on trying to increase CNS partitioning so as to
decrease the efficacious dose in vivo after oral administration, as
well as improving the receptor selectivity profile. In an attempt
to address both of these issues simultaneously, we turned our
attention to analogues with lower molecular weight and reduced
polar surface area. Hence, we targeted compounds in which the
fused benzo ring of the quinazoline series was replaced by a
methyl group, resulting in the preparation of a series of substituted
pyrimidines 4 as shown in Scheme 1. Selective dimethylamination
of the dichloropyrimidine starting materials (e.g., R = 5-Me or 6-
Me) provided the 4-substituted intermediates 1a and 1b in good
yield (>95%) with only a trace of the undesired 2-substitution prod-
ucts observed. A second nucleophilic substitution under more forc-
ing conditions with a mono-protected diamine provided the
intermediates 2 which were converted to the desired final products
4 by removal of the protective group to provide 3, followed by acyl-
ation with the appropriate benzoyl chloride.
The resulting compounds were tested for antagonism of the cal-
cium response to MCH in cells stably transfected with a constitu-
tively activated (CART) version of the human MCH-R1 in a FLIPR
assay.15 The resulting data is shown in Table 1. As can be seen,
the pyrimidine analogue series followed a very similar SAR to that
previously observed in the quinazoline series. As with the earlier
series, activity was retained across a wide range of substitutions
around the right hand side aromatic ring, but 3- or 4-substitution
was favoured, as was substitution with halogen or methoxy
Cl
N
N
N
m
R'
(iii) or (iv)
(i)
(ii)
N
N
N
N
R
R
R
H
Cl
N
Cl
N
N
H
1a = 5-Me
1b = 6-Me
2a = 5-Me ; m = 0; R' = Boc
2b = 6-Me ; m = 0; R' = Boc
2c = 5-Me ; m = 1; R' = Cbz
2d = 6-Me ; m = 1; R' = Cbz
N
N
O
N
m
m
NH2
(v)
N
N
N
R1
R
H
R
N
N
N
H
H
3a = 5-Me ; m = 0
4
3b = 6-Me ; m = 0
3c = 5-Me ; m = 1
3d = 6-Me ; m = 1
´
Scheme 1. Preparation of pyrimidine analogues of ATC0175. Reagents and conditions: (i) NHMe2 (40% w/v in water), THF, 0 °C, (40–60% yield); (ii) R = Boc; cis-NH2–
i
t
´
´
cyclohexyl–CHmNHBoc, PrOH, DIEA, microwave, 175–185 °C or R = Cbz; cis-NH2–cyclohexyl–CHmNHCbz, BuOH, DIEA, microwave 175–185 °C (40–86% yield); (iii) R = Boc;
1
´
TFA, DCM, rt (70–80% yield); (iv) R = Cbz; H2, Pd/C, EtOH, rt, (70–80% yield); (v) R PhCOCl, DCM, Et3N, rt (20–60% yield).

6168
G. Semple et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6166–6171
Table 1
methyl substituted analogue 4q retained activity, but offered no
SAR of pyrimidinyl analogues of ATC0175
improvement in potency over either the 5- or 6-monomethyl ser-
ies. Substitution on the pyrimidine ring in the 5- or 6-position with
larger alkyl or dimethyl amino groups was not well tolerated.
The SAR for the series containing a methylene spacer (4, m = 1)
was somewhat different. In this case, with either 5- or 6-methyl
substituted pyrimidines, the 3,4-difluorophenyl amide was not
optimal. Instead we found that 3,5-substitution on the terminal
aromatic ring was favoured, as was the incorporation of larger sub-
stituents such as chloro or trifluoromethyl. Another striking differ-
ence was the clear preference for the 5-substituted methyl
pyrimidine in this elongated series that was not seen in the m = 0
series. With these differences in mind, we re-checked the previ-
ously observed absolute requirement for a dimethylamino substi-
tuent in the 4-position of the pyrimidine. However, even modest
changes to this position resulted in significant loss of activity at
h-MCH-R1 (Table 2), with only the methylethyl-amino group toler-
ated to any extent, thus confirming our previous observations.
With the change in scaffold from the dimethylamino quinazo-
line to dimethylamino pyrimidine, we observed a significant
improvement in receptor selectivity for a number of analogues.
ATC0175 had shown moderate to significant affinity for a range
of monamine receptors and compounds with h-MCH-R1 activity
were routinely tested against several of these receptors (Table 3).
In general, it can be seen that the reduction in size led to an overall
improvement in the compound profiles in vitro. From these data
we identified compound 4x as the analogue with the most promis-
ing selectivity profile. Of particular concern with ATC0175 was
binding affinity for the serotonin 5-HT2B and 5-HT1A receptors.
The former is present in the heart and its activation has been impli-
cated in cardiac complications such as valvulopathy.16 Binding to
this receptor was reduced as a result of the scaffold switch, with
all examples showing moderately lower affinity for 5-HT2B than
ATC0175, with 4x being the most selective. To further alleviate
the cardiovascular concerns, both ATC0175 and 4x were shown
to be inverse agonists of the 5-HT2B receptor in an IP3 functional
assay. ATC0175 also showed high affinity for the 5-HT1A receptor.
Although this receptor was not screened routinely, compound 4x
proved to be significantly more selective than ATC0175 for h-
MCH-R1 over h5-HT1A (ATC0175: IC50 h5-HT1A = 16.9 nM13b; 4x:
N
O
m
N
R
N
R1
H
N
N
H
Compound
R
m
R1
IC50 h-MCH-R1a (nM)
ATC0175
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
Fused phenyl
6-Me
6-Me
6-Me
6-Me
6-Me
6-Me
6-Me
6-Me
6-Me
5-Me
5-Me
5-Me
5-Me
5-Me
H
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
3,4-F2
3-CH3
4-Cl
13.513b
9.6
16
6.5
25
230
7.6
2.5
4.8
8
3-Cl
4-F
4-OCF3
3-OCH3
3,4-F2
3,4-Cl2
3,5-(CF3)2
3-CH3
4-CH3
4-F
2.9
13
6
10
2
4-Cl
3,4-F2
3,4-F2
3,4-F2
3,4-F2
3,4-F2
3,4-F2
3,4-F2
3-CF3
3,5-(CF3)2
3,5-Cl2
3,5-(CF3)2
3,5-Cl2
n.e.
100
2.3
58
210
120
26
5-Et
5,6-Me2
6-NMe2
6-Me
5-Me
5-Me
6-Me
6-Me
5-Me
5-Me
4s
4t
4u
4v
4w
4x
4y
81
64
5
4
n.e. = no effect at any concentration up to 10 lM.
a
Values are means of at least three determinations for all compounds with IC50
<10 nM and at least two determinations for all other compounds. Log S.D. <0.35 in
all cases where n P 3.
substituents. In the case where the methyl substitution on the
pyrimidine ring was in the 5- or the 6-position, and where there
was no spacer between the cyclohexyl ring and the amide linker
(i.e., 4, m = 0) the optimal aryl group was again 3,4-difluoro and
essentially equal potency to ATC0175 was achieved with a signifi-
cant reduction in molecular weight. At least one methyl substitu-
ent on the pyrimidine ring was required however, as 4o showed
no h-MCH-R1 antagonism in the FLIPR assay. In contrast, the di-
IC50 h5-HT1A = 4.8 lM).
Compound 4x proved efficacious in our 4-day screening model
of food intake (dosed at 30 mg/kg PO qd). As a result of this positive
effect, 4x was tested in a chronic feeding study in diet-induced
Table 2
SAR of amino variants on 5-Me-pyrimidine core
R1
R2
N
N
N
O
m
N
Ar
H
N
H
Compound
R1
R2
m
Ar
IC50 h-MCH-R1a (nM)
4n
Me
Me
Me
Et
iPr
Me
Me
H
Me
Et
H
H
H
Me
H
H
0
0
0
0
0
1
1
1
1
1
3,4-F2-Ph
3,4-F2-Ph
3,4-F2-Ph
3,4-F2-Ph
2
46
4ab
4ac
4ad
4ae
4x
4af
4ag
4ah
4ai
n.e.
n.e.
n.e.
5
200
600
n.e.
n.e.
3,4-F2-Ph
3,5-(CF3)2-Ph
3,5-(CF3)2-Ph
3,5-(CF3)2-Ph
3,5-(CF3)2-Ph
3,5-(CF3)2-Ph
Et
H
Cyclo-(CH2)4
n.e. = no effect at any concentration up to 10
l
M.
Values are means of at least three determinations for all compounds with IC50 <10 nM and at least two determinations for all other compounds. Log S.D. <0.35 in all cases
where n P 3.
a

G. Semple et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6166–6171
6169
Table 3
Receptor selectivity data for selected compounds
a
b
d
Compound
IC50
(
l
M) h-5-HT2B (n, log S.D.)
IC50
(
l
M) h-a2A (n, log S.D.)
IC50
0.3
(
l
M) h-a1Ac(n, log S.D.)
IC50 (lM) h-Y1 (n, log S.D.)
*
ATC0175
0.15 (3, 0.07)
0.17 (5, 0.20)
0.13 (5, 0.22)
>10 (5, n.m.)
0.031 (4, 0.17)
0.12 (6, 0.14)
0.3 (5, 0.11)
0.3 (3, 0.15)
0.32 (3, 0.12)
3.1 (3, 0.31)
0.104
0.15 (2, n.m.)
0.8 (3, 0.15)
0.39 (4, 0.42)
1.21 (4, 0.35)
1.6 (3, 0.21)
0.17 (4, 0.09)
0.81 (4, 0.12)
0.76 (3, 0.03)
0.92 (3, 0.41)
>10 (3, n.m.)
4b
4h
4i
4j
4k
4l
4m
4t
4x
0.73 (4, 0.32)
0.13 (3, 0.42)
0.20 (4, 0.09)
0.58 (4, 0.17)
1.77 (3, 0.32)
0.47 (4, 0.12)
1.59 (3, 0.45)
0.21 (6, 0.29)
0.31 (4, 0.39)
3.0 (4, 0.45)
>10 (2, n.m.)
1.32 (5, 0.22)
2.79 (5, 0.35)
>10 (7, n.m.)
7.5 (4, 0.95)
>10 (4, n.m.)
3.6 (5, 0.88)
3.2 (4, 0.5)
[3H]-rauwolsine binding; *Literature data; IC50 = 9.66 1.58 nM in [125I]-LSD binding.13b
a
b
c
[3H]-MK-912 binding.
[3H]-Prazosin binding.
[3H]-pyrilamine binding.
d
obese (DIO) female Wistar rats.19 Once-daily oral doses (1, 5, 10
and 15 mg/kg/day) were selected and sibutramine (6 mg/kg/day
PO) was included in this study as a positive control.
ria diet (Fig. 2), with daily intake returning to control levels within
8 days of dosing. This resulted in a decreased body weight relative
to the control group. However, after 14 days the animals began to
regain weight and their growth rate after this point essentially par-
alleled that of the control group. In contrast, the 10 and 15 mg/kg
As previously demonstrated,20 sibutramine caused a profound
but transient effect on total energy intake on this modified cafete-
1500
1200
900
1500
1200
900
600
300
0
600
300
WITHDRAWAL: 15mg/kg
0
BL
1
2
3
4
5
6
7
BL
1
2
3
4
5
6
DAYS
WEEKS
460
440
420
400
380
360
340
320
300
*
*
*
WITHDRAWAL: 15mg/kg
-6 -4 -2
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
DAYS
Figure 2. The dose–response effect of once daily oral doses of compound 4x (1 mg/kg, d; 5 mg/kg, N; 10 mg/kg, j; 15 mg/kg, ꢀ) on food intake and body weight in DIO
female Wistar rats compared to sibutramine (6 mg/kg, h) and vehicle (water, s).

6170
G. Semple et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6166–6171
doses of 4x produced a strikingly opposing pattern of effect, with
maximal decreases in food intake becoming apparent after only 2
and 3 days, respectively, although statistical separation from vehi-
cle was achieved on day 2 at both doses, and continued throughout
the dosing period. This pattern of food intake change resulted in
progressive weight loss. After 14 days of dosing, the highest dose
group was deemed to have lost too much weight too rapidly
(>15% relative to control) and was allowed to recover. Food intake
gradually returned to normal and the body weight decline was re-
versed. A similar effect was observed in the 10 mg/kg dose group
where after 28 days of dosing a 17% decrease in body weight rela-
tive to the vehicle group was observed. A subgroup of these ani-
mals was allowed to recover after this period and in this case we
observed a modest but statistically significant rebound in daily en-
ergy and water intake, resulting in a recovery of body weights to
control values over the ensuing 2 two weeks. The third dose group
of 5 mg/kg failed to achieve statistical significance in terms of
decreasing food intake, although a trend was observed resulting,
by day 28, in a statistically significant decrease in body weight rel-
ative to the vehicle group (À5.4%). The 1 mg/kg dose had no effect
on any of the measured parameters.
The clear difference in the pattern of food intake and body
weight changes between rats treated with sibutramine, which is
known to act centrally, and those treated with 4x, was immedi-
ately suggestive that the effect of the latter may not be centrally
mediated. Indeed the pattern of effect on food intake and body
weight much more closely resembled that observed with exen-
din-4, which is known to act by inhibiting gastric emptying. In-
deed, when we examined the pharmacokinetic data for 4x and
related compounds, it was clear that the scaffold change we had
engineered did not enhance the brain partitioning properties in
rat for this series over ATC0175. For compound 4x for example,
the brain to plasma ratio remained significantly below unity at
all time points tested (Table 4), and below concentrations previ-
ously believed to be required for in vivo efficacy of MCH-R1 antag-
onists. McBriar et al. demonstrated a requirement for 70% receptor
occupancy at a 6 h time point with chronic efficacy on food intake
and body weight in rats with MCH-R1 antagonists.17 In addition,
with another series of MCH-R1 antagonists, very high concentra-
an off-target effect. In 14-day toxicity studies, no significant effects
(other than a decrease in food intake) were observed at doses up to
100 mg/kg/day. Although a non-specific toxicity effect can not be
completely ruled out, we have since further investigated other pos-
sible mechanisms of action and these experiments will be de-
scribed in due course.
In this present investigation we have again demonstrated the
importance of correlating the pharmacokinetic and pharmacody-
namic effects on food intake in rodents to try and confirm that
the observed effects are specific to the molecular target thought
to be responsible.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.09.003.
References and notes
1. Kawauchi, H.; Kawazoe, I.; Tsubokawa, M.; Kishida, M.; Baker, B. I. Nature 1983,
305, 321.
2. Bittencourt, J. C.; Presse, F.; Arias, C.; Peto, C.; Vaughan, J.; Nahon, J. L.; Vale, W.;
Sawchenko, P. E. J. Comp. Neurol. 1992, 319, 218.
3. Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, J. S.; Maratos-Flier, E. Nature 1998,
396, 670.
4. (a) 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; (b) 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. Saito, Y.; Nothacker, H. P.; Wang, Z.; Lin, S. H.; Leslie, F.; Civelli, O. Nature 1999,
400, 265.
6. Shearman, L. P.; Camacho, R. E.; Stribling, D. S.; Zhou, D.; Bednarek, M. A.;
Hreniuk, H. L.; Feighner, S. D.; Tan, C. P.; Howard, A. H.; Van der Ploeg, L. H. T.;
MacIntyre, D. E.; Hickey, G. J.; Strack, A. M. Eur. J. Pharmacol. 2003, 475, 37.
7. 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.
8. (a) 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; (b) 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; (c) McBriar, M. D.; Guzik, H.; Xu, R.; Paruchova, J.; Li, S.; Palani,
A.; Clader, J. W.; Greenlee, W. J.; Hawes, B. E.; Kowalski, T. J.; O’Neill, K.; Spar, B.;
Weig, B. J. Med. Chem. 2005, 48, 2274; (d) Palani, A.; Shapiro, S.; McBriar, M. D.;
Clader, J. W.; Greenlee, W. J.; Spar, B.; Kowalski, T. J.; Farley, C.; Cook, J.; van
Heek, M.; Weig, B.; O’Neill, K.; Graziano, M.; Hawes, B. J. Med. Chem. 2005, 48,
4746; (e) Kym, P. R.; Iyengar, R.; Souers, A. J.; Lynch, J. K.; Judd, A. S.; Gao, J.;
Freeman, J.; Mulhern, M.; Zhao, G.; Vasudevan, A.; Wodka, D.; Blackburn, C.;
Brown, J.; Che, J. L.; Cullis, C.; Lai, S. J.; LaMarche, M.; Marsilje, T.; Roses, J.; Sells,
T.; Geddes, B.; Govek, E.; Patane, M.; Fry, D.; Dayton, B. D.; Brodjian, S.; Falls, D.;
Brune, M.; Bush, E.; Shapiro, R.; Knourek-Segel, V.; Fey, T.; McDowell, C.;
Reinhart, G. A.; Preusser, L. C.; Marsh, K.; Hernandez, L.; Sham, H. L.; Collins, C.
A. J. Med. Chem. 2005, 48, 5888; (f) 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.
9. Thomas, L.; Reichl, R.; Mueller, S. G.; Stenkamp, D.; Schindler, M. A novel MCH-
1R antagonist reduces body weight in Rhesus monkeys. NAASO meeting, 2005,
P2-224.
10. Tran, T.-A; Beeley, N. R. A.; Thomsen, W.; Lin, I.; Sekiguchi, Y. Discovery of
MCH-R1 antagonists from GPCR-directed libraries. 228th ACS National
Meeting, Philadelphia, PA, USA, August 22–26, 2004, MEDI-051.
11. Kanuma, K.; Omodera, K.; Nishiguchi, M.; Funakoshi, T.; Chaki, S.; Semple, G.;
Tran, T.-A.; Kramer, B.; Hsu, D.; Casper, M.; Thomsen, W.; Beeley, N. R. A.;
Sekiguchi, Y. Bioorg. Med. Chem. Lett. 2005, 15, 2565.
12. Kanuma, K.; Omodera, K.; Nishiguchi, M.; Funakoshi, T.; Chaki, S.; Semple, G.;
Tran, T.-A.; Kramer, B.; Hsu, D.; Casper, M.; Thomsen, W.; Sekiguchi, Y. Bioorg.
Med. Chem. Lett. 2005, 15, 3853.
tions were required (>10 lg/mg in brain i.e., 1000-fold higher than
in this study) to show a significant chronic effect on food intake
and body weight following once daily oral dosing in rats.18 Hence,
for compound 4x and related analogues we concluded, based on
the low levels of brain concentrations observed, that the effect
on feeding is most likely not mediated by the central MCH-R1.
In summary, we have demonstrated that the in vitro potency of
ATC0175 at the h-MCH-R1 may be preserved by removing the
fused ring of the quinazoline and replacing it with a methyl substi-
tuent, resulting in a series of pyrimidine analogues. Several exam-
ples from this series had greatly improved receptor selectivity
profiles compared to ATC0175. However, although compounds
from this series decreased food intake in vivo, this modification
did not provide compounds with good brain partitioning. Given
that central exposure appears to be a requirement for MCH-R1
antagonist-induced decreases in food intake, we believe that the
profound and dose-dependent decrease in energy intake and body
weight in a 28-day DIO rat model observed for 4x was most likely
Table 4
13. a Semple, G.; Kramer, B.; Hsu, D.; Casper, M.; Strah-Pleynet, S.; Thomsen, W.;
Lin, I. -L.; Beeley, N.; Bjenning, C.; Whelan, K.; Tran, T.-A.; Sekiguchi, Y.;
Kanuma, K.; Omodera, K.; Nishiguchi, M.; Funakoshi T.; Chaki, S. Identification
and biological activity of a new series of antagonists of hMCH-R1 228th ACS
National Meeting, Philadelphia, PA, USA, August 22–26, 2004, MEDI-7.;
Brain and plasma concentrations of 4x compared to ATC0175 following a per oral
dose of 10 mg/kg to fed male Sprague-Dawley rats
PLASMA (ng/mL)
4 h
BRAIN (ng/g)
4 h
2 h
50
109
2 h
ATC0175: An Orally Active Melanin-Concentrating Hormone Receptor
1
Antagonist for the Potential Treatment of Depression and Anxiety: (b) Chaki,
S.; Yamaguchi, J.; Yamada, H.; Thomsen, W.; Tran, T.; Semple, G.; Sekiguchi, Y.
CNS Drug Rev. 2005, 11, 341.
4x
ATC0175
63
101
9
55
10
70

G. Semple et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6166–6171
6171
14. Bjenning, C.; Thomsen, W.; Whelan, K.; Creehan, K.; Gonzalez, L.; Al-Shamma,
H.; Tran, T.; Semple, G.; Funakoshi, T.; Nishiguchi, M.; Shimazaki, T.; Kanuma,
K.; Sekiguchi, Y.; Chaki. S. Novel and potent non-peptide antagonists of
Melanin-concentrating hormone receptor-1: ATC0065 and ATC0175 reduce
appetite and bodyweight in high-fat diet-fed male rats. Society for
Neuroscience Meeting, San Diego CA, Oct 22–27, 2004, Abstr. 629.8.
Xu, R.; Palani, A.; Clader, J. W.; Cox, K.; Greenlee, W. J.; Hawes, B. E.; Kowalski,
T. J.; O’Neill, K.; Spar, B. D.; Weig, B.; Weston, D. J.; Farley, C.; Cook, J. J. Med.
Chem. 2006, 49, 2294.
18. Potent, Selective, and Orally Efficacious Antagonists of Melanin-Concentrating
Hormone Receptor 1: Tavares, F. X.; Al-Barazanji, K. A.; Bigham, E. C.; Bishop,
M. J.; Britt, C. S.; Carlton, D. L.; Feldman, P. L.; Goetz, A. S.; Grizzle, M. K.; Guo, Y.
C.; Handlon, A. L.; Hertzog, D. L.; Ignar, D. M.; Lang, D. G.; Ott, R. J.; Peat, A. J.;
Zhou, H.-Q. J. Med. Chem. 2006, 49, 7095.
19. The study (RenaSci Consultancy Ltd, BioCity Nottingham, Pennyfoot Street,
Nottingham, UK) investigated the effect of chronic administration of 4x (and
withdrawal) on body weight and food and water intake in female Wistar rats
made obese by exposure to a simplified cafeteria diet (high-fat chow, chocolate
and peanut granules) for 12 weeks, that is, dietary-induced obesity (DIO).
Following the induction of obesity, rats were given deionised water orally for a
7 day baseline period and then dosed orally once daily with vehicle, one of four
doses of 4x (1, 5, 10 and 15 mg/kg) or sibutramine (6 mg/kg PO) for up to
28 days.
15.
A functional high throughput screening assay using a fluorescence based
(FLIPR) assay in 384-well format was used. MCH induced
a robust,
concentration-dependent elevation of Ca2+ in HEK293 cells stably transfected
with a constitutively activated (CARTTM) form of human MCH-R1 with an EC50
of 3.7 nM. Active compounds were identified by their ability to inhibit this
Gaq-dependent response, in a concentration-dependent manner.
16. Evidence for possible involvement of 5-HT2B receptors in the cardiac
valvulopathy associated with fenfluramine and other serotonergic
medications Rothman, R. B.; Baumann, M. H.; Savage, J. E.; Rauser, L.;
McBride, A.; Hufeisen, S. J.; Roth, B. L. Circulation 2000, 102, 2836.
17. Discovery of Orally Efficacious Melanin-Concentrating Hormone Receptor-1
Antagonists as Antiobesity Agents. Synthesis, SAR, and Biological Evaluation of
Bicyclo[3.1.0]hexyl Ureas McBriar, M. D.; Guzik, H.; Shapiro, S.; Paruchova, J.;
20. Stock, M. J. Int. J. Obesity 1997, 21, S25.