Lead optimization of 4-(dimethylamino)quinazolines, potent and selective antagonists for the melanin-concentrating hormone receptor 1

Article abstract of DOI:10.1016/j.bmcl.2005.05.121

The optimization of a series of 4-(dimethylamino)quinazoline antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. The combination of the elaboration of both the linker portion and the terminal phenyl ring provided N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino} cyclohexyl)-3,4-difluorobenzamide hydrochloride 28 (ATC0175), which showed excellent antagonist activity at the MCH-R1 (IC₅₀ = 3.4 nM) as well as good selectivity over the Y5 and the α_2A receptors.

Full text of DOI:10.1016/j.bmcl.2005.05.121

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3853–3856
Lead optimization of 4-(dimethylamino)quinazolines, potent
and selective antagonists for the melanin-concentrating
hormone receptor 1
Kosuke Kanuma,a Katsunori Omodera,a Mariko Nishiguchi,a Takeo Funakoshi,a
Shigeyuki Chaki,a Graeme Semple,b Thuy-Anh Tran,b Bryan Kramer,b Debbie Hsu,b
Martin Casper,b Bill Thomsenb and Yoshinori Sekiguchia,*
aMedicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan
bArena Pharmaceuticals Inc., 6166 Nancy Ridge Drive, San Diego, CA 92121, USA
Received 16 March 2005; revised 23 May 2005; accepted 30 May 2005
Available online 5 July 2005
Abstract—The optimization of a series of 4-(dimethylamino)quinazoline antagonists of the melanin-concentrating hormone receptor
1 (MCH-R1) is described. The combination of the elaboration of both the linker portion and the terminal phenyl ring provided
N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride 28 (ATC0175), which showed
excellent antagonist activity at the MCH-R1 (IC50 = 3.4 nM) as well as good selectivity over the Y5 and the a2A receptors.
Ó 2005 Elsevier Ltd. All rights reserved.
Melanin-concentrating hormone (MCH) is a cyclic 19
amino acid peptide expressed in the lateral hypothalam-
ic area (LHA) and the rostromedial zona incerta.1,2 The
intracerebroventricular (icv) injection of MCH in rats
results in increased food intake.3,4 In contrast, prepro-
MCH-knockout mice were found to be hypophagic
and have reduced body weight and increased leanness
relative to their wild type counterparts.5 T-226296, a
selective MCH-R1 antagonist, has been reported to
attenuate MCH-induced hyperphagia, suggesting impli-
cation of MCH-R1 in the actions of MCH on food in-
take.6 Thus, it can be inferred that a centrally acting
MCH-R1 antagonist may be effective in treating obesity.
In addition, MCH has been reported to induce an anx-
iogenic effect when injected into the medial preoptic area
in rats,7 while icv injection of MCH exhibited anxiolytic-
like effect in the elevated plus-maze test,8 suggesting that
MCH may also be implicated in the modulation of emo-
tional states. This hypothesis is supported by the recent
finding that SNAP-7941, a selective antagonist for the
MCH-R1, exhibits anxiolytic- and antidepressant-like
effects in rodent models.9
As previously reported, high throughput screening of
our in-house GPCR-directed library resulted in the iden-
tification of our lead compound, AR129330 (Table 1).10
In our initial modifications, we identified that both 4-
amino-substitution of the quinazoline and the terminal
phenyl group are crucial for MCH-R1 activity. Subse-
quent optimization of the spacer portion between the
quinazoline ring and the sulfonamide linker resulted in
the identification of compounds 1–3. Although these ini-
tial hits showed lower receptor selectivity, in particular,
for the a2A adrenergic receptor, we considered com-
pounds AR129330, 1, 2, and 3 to be of sufficient potency
and diversity, as well as having promise for improving
MCH-R1 potency and selectivity over the Y5 and a2A
receptors, to merit further optimization. We herein
describe our efforts to investigate structure–activity
relationships (SAR) at the MCH-R1 based on the 4-
(dimethylamino)quinazoline series and to improve selec-
tivity leading to the identification of ATC0175, a potent
and selective antagonist of MCH-R1.
Keywords: Melanin-concentrating hormone receptor 1 antagonists;
MCH-R1 antagonists; ATC0175.
Preparation of the quinazoline derivatives with the cis-
cyclohexane-1,4-diamine is summarized in Scheme 1.
The quinazoline core 6 was synthesized in two steps
*
Corresponding author. Tel.: +81 48 669 3064; fax: +81 48 652
7254; e-mail: yoshi.sekiguchi@po.rd.taisho.co.jp
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.05.121

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K. Kanuma et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3853–3856
Table 1. Quinazoline derivatives as MCH-R1 antagonists
Compound
IC50 (nM)a
Y5
MCH-R1
a2A
7.7
AR129330
160
140
83
2.7
120
880
1
2
3
130
57
250
8900
170
a Compounds were evaluated for their ability to compete with [125I](Phe13, Tyr19)MCH, [125I]PYY, or [3H]MK912 at a human CA-MCH-R1 stably
expressed in HEK293 cells or a human Y5 or a2A transiently expressed in COS-1 cells. Data represent the mean of 1–3 separate experiments
performed from five concentrations and in duplicate.
Scheme 1. Representative synthetic route of quinazolines. Reagents and conditions: (a) POCl3, N,N-dimethylaniline, reflux, 7 h, 86%; (b) aq 50%
Me2NH, THF, room temperature, 80 min, 94%; (c) tert-butyl (cis-4-aminocyclohexyl)carbamate, isopropanol, reflux, 24 days, 93%; (d) (i) 4 M HCl
in EtOAc, EtOAc, room temperature, 70 min, (ii) RSO2Cl, iso-Pr2NEt, CH2Cl2, 4 °C; (e) (i) 4 M HCl in EtOAc, EtOAc, room temperature, 70 min,
(ii) RCOCl, iso-Pr2NEt or Et3N, CH2Cl2, room temperature; (f) (i) 4 M HCl in EtOAc, EtOAc, room temperature, 70 min, (ii) RCHO,
NaBH(OAc)3, AcOH, CH2Cl2, room temperature.
from commercially available 1H,3H-quinazoline-2,4-
dione 4. The starting material was reacted with phos-
phorous oxychloride (POCl3) under reflux in the
presence of N,N-dimethylaniline to provide 2,4-dichlo-
ro-quinazoline 5. Selective substitution of the chlorine
at the 4-position with 50% aqueous dimethylamine gave
the corresponding 4-dimethylamino-2-chloro-quinazo-
line 6. Coupling of 6 with tert-butyl (cis-4-amin-
ocyclohexyl)carbamate was accomplished upon reflux
in isopropanol to afford coupling product 7. Deprotec-
tion of the Boc-group was achieved with hydrogen
chloride to provide the amine as a precursor for target
quinazoline derivatives 8a–c. The amine was coupled
with a sulfonyl chloride or an acid chloride to afford
the desired quinazoline sulfonamide 8a or quinazoline
carboxylic amide 8b, respectively. The quinazoline
amine 8c was obtained by reductive amination with
the appropriate aldehyde.
We first examined the importance of the linker between
the spacer portion and the terminal phenyl ring for
MCH-R1 potency and selectivity over the Y5 and a2A
receptors (Table 2). In a series of trans-1,4-cyclo-
hexylmethyldiamine compounds, replacement of the sul-
fonamide group with an amide 10 or an amine 11
showed a modest loss of affinity for the MCH-R1. The
N-methylated sulfonamide analogue 9, however resulted
in a more drastic decrease in affinity. Likewise, N-meth-
ylation of the amine 11 provided compound 12, which
was less active at both the MCH-R1 and the Y5 recep-
tors and revealed that the N–H, presumably active as
a hydrogen bond donor, was crucial for MCH-R1 activ-
ity. In the series of 4-aminomethyl-cis-cyclohexylamine
analogues 1, 13, and 14, the amide analogue 13 was
around 2-fold more potent at MCH-R1 than the corre-
sponding sulfonamide 1. Interestingly, the affinity for
the Y5 and the a2A receptors decreased markedly (IC50

K. Kanuma et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3853–3856
Table 2. In vitro data of quinazolines with linker modifications
3855
Compound
Structure
Conformation
m
n
A
R
IC50 (nM)a
Y5
MCH-R1
a2A
AR129330
9
I
trans
trans
trans
trans
trans
cis
1
1
SO2
SO2
CO
H
160
5800
1500
960
5600
140
79
2.7
460
7.7
34
I
1
1
Me
H
10
11
12
1
I
1
1
470
560
9.9
31
I
1
1
CH2
CH2
SO2
CO
H
I
1
1
Me
H
>1000
120
44
I
0
1
130
570
360
57
13
14
2
I
cis
cis
0
1
H
1800
2400
880
I
0
1
CH2
SO2
CO
H
4.9
I
cis
cis
0
0
H
83
15
16
3
I
0
0
H
160
35
>1000
>1000
8900
NEb
>1000
390
170
170
NE
520
I
cis
—
0
0
CH2
SO2
CO
H
II
II
II
—
—
—
—
—
—
—
—
—
250
1200
320
17
18
—
—
CH2
a Compounds were evaluated for their ability to compete with [125I](Phe13, Tyr19)MCH, [125I]PYY, or [3H]MK912 at a human CA-MCH-R1 stably
expressed in HEK293 cells or a human Y5 or a2A transiently expressed in COS-1 cells. Data represent the mean of 1–3 separate experiments
performed from five concentrations and in duplicate.
b Not evaluated.
for Y5 = 1800 nM). Replacement of the sulfonamide
with a simple amine provided compound 14, which
was highly potent at the MCH-R1 (IC50 = 4.9 nM)
and much less active at the Y5 receptor than our lead
compound. This combination of effects provided selec-
tivity for the MCH-R1 over the Y5 and a2A receptors
of 490-fold and 75-fold, respectively. In a similar series
of cis-1,4-cyclohexane-diamine derivatives, the conver-
sion of the sulfonamide 2 to the corresponding amide
15 led to a 2-fold decrease in affinity for the MCH-R1.
In contrast, the amine analogue 16 exhibited a 2-fold
higher affinity. Within the piperidine derivative series,
the conversion from the sulfonamide 3 to an amide 17
resulted in a significantly reduced affinity for the
MCH-R1. However, the amine analogue 18 provided
comparable potency to the sulfonamide 3, showing that
the SAR trends were different between this and the two
cis-1,4-cyclohexane series 1 and 2. Based on the data, we
concluded that cis-1,4-cyclohexanes 1 and 2 provided
the most interesting spacer groups for further study,
providing as they did, improved activity for the MCH-
R1 and a significant degree of selectivity over the Y5
and the a2A receptors. During the course of our investi-
gations, we had been routinely monitoring the in vitro
metabolic profile of selected active compounds. It be-
came clear that sulfonamide derivatives in general had
a tendency to be less metabolically stable than the amide
and the amine derivatives in rat and human liver micro-
some preparations.
appropriate combination of MCH-R1 activity and meta-
bolic stability in vitro. As a final elaboration, we synthe-
sized approximately 2500 compounds using the plate
formatted synthesis method.11 After the survey of the
compounds, we found that 4-[(dimethylamino-quinazo-
lin-2-ylamino)-cis-cyclohexyl]-benzamide
derivatives
provided an extensive series of compounds with high
affinity for the MCH-R1 and excellent selectivity over
the a2A receptor, a selection of which is shown in Table 3.
A direct comparison of the 2-fluoro substituted 19, 3-flu-
oro substituted 20, and 4-fluoro substituted 21 analogues
revealed that 19 had significantly reduced affinity relative
to the other two. In addition, the profiles of the more ac-
tive 20 and 21 were very similar with respect to selectivity
over the a2A receptor. Other meta-halogenated analogues
22 (3-chloro) and 23 (3-bromo) exhibited a 2-fold higher
affinity than 20 for both the MCH-R1 and the a2A recep-
tors and therefore did not provide improvement in selec-
tivity for the a2A receptor. The 3-methyl substituted
compound 24 displayed essentially the comparable affin-
ity as the halogenated analogues with a slight improve-
ment in selectivity. Electron-withdrawing groups such
as 3-trifluoromethyl substituted 25, 3-cyano substituted
26, and 3-nitro substituted 27 were also tolerated for the
activity for the MCH-R1, indicating broad tolerability
for substitution in this position. However, for 25 the selec-
tivity over the a2A receptor was significantly lower. 3,4-
Difluoro substituted 28 (ATC0175) showed not only
highly potent affinity at the MCH-R1 (IC50 = 3.4 nM)
but also 76-fold selectivity for the MCH-R1 over the
a2A receptor. In addition, the selectivity over the Y5
receptor was increased to a factor of 800. ATC0175 inhib-
Hence, we decided to further focus our efforts on the two
cis-1,4-cyclohexanes 1 and 2 as suitable spacers, and
amides and amines as acceptable linkers, providing an

3856
K. Kanuma et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3853–3856
Table 3. In vitro data of quinazolines with R substituion modifications
Compound
R
IC50 (nM)
Selectivity a2A/MCH
MCH-RIa
a2A
Y5b
b
15
19
4-Br-2-OCF3
2-F
3-F
160
170
9.5
9.4
4.5
5.9
4.6
15
390
NEc
130
150
76
>1000
NE
NE
NE
NE
NE
NE
NE
NE
NE
2700
NE
NE
NE
2.4
—
20
21
14
16
4-F
3-Cl
22
23
17
11
3-Br
3-Me
63
24
25
110
60
24
3-CF3
3-CN
4.0
15
26
27
10
150
97
3-NO2
3,4-di F
3,4-di Cl
2,3,4-tri F
3,5-di OMe
6.8
3.4
5.0
38
14
76
28 (ATC0175)
260
47
29
30
31
9.4
5.3
36
200
71
2.0
a Compounds were evaluated for their ability to inhibit transient intracellular calcium-mobilization evoked by MCH agonist in HEK293 cells stably
expressing CA-MCH-R1 receptor. Data represent the mean of 1-3 separate experiments performed from five concentrations and in duplicate.
b Compounds were evaluated for their ability to compete with [125I]PYY or [3H]MK912 at a human Y5 or a2A transiently expressed in COS-1 cells.
Data represent the mean of 1–3 separate experiments performed from five concentrations and in duplicate.
c Not evaluated.
ited [125I](Phe13, Tyr19)MCH binding to recombinant hu-
2. Kolakowski, L. F., Jr.; Jung, B. P.; Nguyen, T.; Johnson,
man MCH-R1 with an IC50 value of 7.23 0.59 nM.12
M. P.; Lynch, K. R.; Cheng, R.; Heng, H. H. Q.; George,
S. R.; OÕDowd, B. F. FEBS Lett. 1996, 398, 253.
3. Qu, D.; Ludwig, D. S.; Grammeltoft, S.; Piper, M.;
Pelleymounter, M. A.; Cullen, M. J.; Mathes, W. F.;
Przypek, J.; Kanarek, R.; Maratos-Flier, E. Nature 1996,
380, 243.
4. Rossi, M.; Choi, S. J.; OÕShea, D.; Miyoshi, T.; Ghatei, M.
The activity for the MCH-R1 of 3,4-dichloro substituted
29 was essentially equal to that of ATC0175, but the selec-
tivity over the a2A receptor of 29 was reduced significant-
ly. 2,3,4-Trifluoro substituted 30 displayed lower affinity
for the MCH-R1. All of the compounds that had substit-
uents incorporated in the 2-position (15, 19, and 30)
showed only modest affinity for the MCH-R1 in compar-
ison to the other analogues, suggesting that the binding
site of the MCH-R1 is very sensitive to steric properties
of substitution at the 2-position. 3,5-Dimethoxy substi-
tuted 31 demonstrated the most potent antagonist activity
(IC50 = 2.0 nM) in this series, but the selectivity over the
A.; Bloom, S. R. Endocrinology 1997, 138, 351.
5. Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, J. S.;
Maratos-Flier, E. Nature 1998, 396, 670.
6. 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.
7. Gonzalez, M. I.; Vaziri, S.; Wilson, C. A. Peptides 1996,
17, 171.
a2A receptor of 31 was lower than that of ATC0175.
8. Monzon, M. E.; De Barioglio, S. R. Physiol. Behav. 1999,
67, 813.
Through a systematic optimization of the spacer, linker,
and right-hand side aromatic ring portion of our lead ser-
ies, we succeeded in identifying a new class of potent and
selective non-peptide antagonists for the MCH-R1, based
around a core 4-(dimethylamino)quinazoline-cis-1,4-cy-
clohexane amide or amine structure. ATC0175 (28), in
particular, displayed potent antagonist activity for the
MCH-R1 (IC50 = 3.4 nM). Importantly, the selectivity
of ATC0175 for the MCH-R1 over the Y5 and the a2A
receptors represented a significant improvement over that
of initial trans-1,4-cyclohexane sulfonamide derivative.
9. Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marzabadi,
M. R.; Deleon, J.; Heurich, R.; Lichtblau, H.; Shaposh-
nik, Z.; Daniewska, I.; Blackburn, T. P.; Branchek, T. A.;
Gerald, C.; Vaysse, P. J.; Forray, C. Nat. Med. 2002, 8,
825.
10. Kanuma, K.; Omodera, K.; Nishiguchi, M.; Funakoshi,
T.; Chaki, S.; Semple, G.; Tran, T. A.; Kramer, B.; Hsu,
D.; Casper, M.; Thomsen, B.; Beeley, N.; Sekiguchi, Y.
Bioorg. Med. Chem. Lett. 2005, 15, 2565.
11. Sekiguchi, Y.; Kanuma, K.; Omodera, K.; Tran, T. A.;
Kramer, B. A.; Beeley N. R. A. International Patent WO
28641, 2003.
12. Chaki, S.; Funakoshi, T.; Hirota-Okuno, S.; Nishiguchi,
M.; Shimazaki, T.; Iijima, M.; Grottick, A. J.; Kanuma,
K.; Omodera, K.; Sekiguchi, Y.; Okuyama, S.; Tran, T.
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References and notes
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Vale, W. Endocrinology 1989, 125, 1660.