Discovery of tetralin ureas as potent melanin concentrating hormone 1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.12.080

Melanin concentrating hormone (MCH) plays an important role in the regulation of food intake and energy balance in mammals. MCH-1 receptor (MCH1R) deficient mice are lean and resistant to diet-induced obesity. As such, MCH1R antagonists are believed to ha

Full text of DOI:10.1016/j.bmcl.2006.12.080

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1718–1721
Discovery of tetralin ureas as potent melanin concentrating
hormone 1 receptor antagonists
Tao Guo,* Huizhong Gu, Doug W. Hobbs, Dennis E. Busler and Laura L. Rokosz
Pharmacopeia Drug Discovery, Inc., PO Box 5350, Princeton, NJ 08543-5350, USA
Received 21 November 2006; revised 14 December 2006; accepted 18 December 2006
Available online 24 December 2006
Abstract—Melanin concentrating hormone (MCH) plays an important role in the regulation of food intake and energy balance in
mammals. MCH-1 receptor (MCH1R) deficient mice are lean and resistant to diet-induced obesity. As such, MCH1R antagonists
are believed to have potential as possible treatments for obesity. The discovery of a novel class of tetralin ureas as potent MCH1R
antagonists is described herein.
Ó 2006 Elsevier Ltd. All rights reserved.
Melanin concentrating hormone (MCH) is a cyclic
19-amino-acid neuropeptide found in the brains of all
vertebrates which has been demonstrated to play an
important role in the regulation of food intake and ener-
gy homeostasis in mammals.1a Central administration of
MCH in mice stimulates food intake while fasting re-
sults in an increase in MCH expression.1b Transgenic
mice over-expressing MCH are susceptible to obesity
and insulin resistance,1c whereas MCH knockout mice
are hypophagic and leaner than wild-type mice but
otherwise healthy.1d MCH binds and activates two dis-
tinct receptors in the brain, MCH1R and MCH2R.2,3
MCH1R is present in all mammals, whereas MCH2R
is found in ferrets, dogs, rhesus monkeys, and humans
but not in rodents and lagomorphs. MCH1R knockout
mice are lean, hyperphagic but hyperactive and resistant
to diet-induced obesity, clearly establishing its critical
role in the regulation of food intake and energy homeo-
stasis.4 In contrast, the physiological function of
MCH2R has yet to be established.
chain between the biaryl and the urea moieties led to
the discovery of a series of biarylaniline ureas (2) which
demonstrated oral efficacy in reducing food intake and
body weight gain in rodent models of obesity.6c Howev-
er, the biarylaniline unit in 2 was found to give highly
positive results in the Ames test.6c Although compound
2 itself is not active in the Ames test, and no evidence
suggests that the biarylaniline unit is generated in vivo,
concerns about the highly mutagenic diarylaniline inter-
mediate have prompted the design and synthesis of
MCH1R antagonists devoid of biarylanilines. One
NC
NC
H
H
N
H
N
N
Cl
N
F3C
F
N
N
OH
O
O
F
1
2
MCH1R Ki = 0.98 nM
MCH1R Ki = 8.9 nM
A wide variety of small molecule MCH1R antagonists
has been reported as potential therapeutic agents for
the treatment of obesity and a number of these antago-
nists have demonstrated in vivo efficacy in rodent mod-
els of obesity.5 We recently disclosed the discovery of a
series of biaryl-diaminobutane ureas (1) as potent
MCH1R antagonists.6a,b Truncation of the carbon
CN
NC
N
N
H
H
N
N
N
N
Cl
N
F3C
F
N
O
O
F
Keywords: MCH; MCH1R antagonists; Obesity.
*
3
4
Corresponding author. Tel.: +1 609 452 3746; fax: +1 609 452
3699; e-mail: tguo@pcop.com
MCH1R Ki = 4.0 nM
MCH1R Ki = 2.7 nM
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.12.080

T. Guo et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1718–1721
1719
Table 1. MCH1R binding data
approach was to replace the biarylaniline unit of 2 with
non-mutagenic bicyclo[4.1.0]heptyl (3)6d or bicy-
clo[3.1.0]hexyl (4) scaffolds.6e,f,g Compounds 3 and 4
have demonstrated excellent oral efficacy in rodent mod-
els of obesity.6d,e–g Alternatively, we envisaged that the
biarylaniline unit could be replaced with a non-muta-
genic tetralin scaffold. We report in this paper the dis-
covery of a novel series of tetralin ureas as potent
MCH1R antagonists.
X
6
7
Y
5
2
8
4
3
1
N
H
Cl
N
N
N
O
F
Compound
X
Y
h-MCH1R K a (nM)
i
Scheme 1 shows the general synthesis of tetralin ureas
7a–i. Heating a neat mixture of 2-tetralones 5, 1-(3-
aminopropyl)-4-methylpiperazine, and titanium iso-
propoxide at 80 °C for 3 h (to generate imine intermedi-
ates), followed by reduction with NaBH4 in MeOH at
0 °C to rt for 12 h, provided the secondary amine inter-
mediate 6. Treatment of 6 with 3-chloro-4-fluorophenyl
isocyanate and Hunig base in dichloromethane afforded
target compounds 7a–i.
7a
7b
7c
7d
7e
7f
H
H
H
H
H
380
180
340
190
92
Br
CN
OMe
H
OMe
SO2Me
H
1300
3000
3000
11
7g
7h
7i
H
SO2NHMe
SO2NMe2
NO2
H
H
7j
H
NH2
260
6.0
61
7k
7l
H
NHCOMe
NHCO-i-Pr
NHCONHEt
NHSO2Me
CN
The MCH1R binding data for tetralin ureas 7a–i are
shown in Table 1. These compounds all contain the 3-
chloro-4-fluoro-phenylurea on the left hand side and
the 1-(3-aminopropyl)-4-methylpiperazine on the right
hand side, both of which have been shown to be among
the optimal side chains for MCH1R activity.6a,b–g As
shown in Table 1, the unsubstituted tetralin compound
7a displayed modest potency (Ki value of 380 nM).
Mono-substitution at the tetralin C-6 position with
either electron withdrawing groups (7b: 6-Br, 7c: 6-
CN) or electron donating groups (7d: 6-methoxy) caused
little change in potency relative to the unsubstituted
compound 7a. However, mono-substitution at the tetra-
lin C-7 position resulted in pronounced potency chang-
es. As can be seen, C-7 substitution with a methoxy
group (7e) increased the potency by 4-fold relative to
7a, whereas C-7 substitutions with sulfonyl or sulfon-
amido groups (7f–h) decreased the potency by 3- to
7-fold relative to 7a. Most interestingly, introduction
of a C-7 nitro group (7i: Ki = 11 nM) enhanced the
potency by 35-fold relative to 7a.
H
7m
7n
7o
H
160
96
H
H
8.5
a Kis are mean values of two or more determinations with the standard
deviations no greater than 50% from the mean.7
The MCH1R binding data for 7j–o are also listed in Ta-
ble 1. Conversion of 7-nitro (7i) into 7-amino (7j) caused
a 25-fold decrease in potency. But interestingly, acetyla-
tion of the amino group brought the potency level into
the single digit nanomolar range (7k: Ki = 6.0 nM).
Replacement of the acetamido group (7k) with isopropi-
onamido (7l), ethylureido (7m) or methylsulfonamido
(7n) groups, all resulted in potency decreases of 10-fold
or more relative to 7k. However, the 7-cyano compound
7o displayed potent, single digit nanomolar activity
(Ki = 8.5 nM), similar to 7k.
Compounds 7k and 7o were further evaluated in rapid
rat AUC8 and mouse ex vivo binding9 studies (Table
2). The acetamido compound 7k displayed poor rapid
rat AUC (195 ng h/mL, 10 mg/kg, po) and poor brain
receptor ex vivo binding (23% I, 30 mg/kg, po, 6 h),
whereas 7o exhibited modest AUC (642 ng h/mL,
10 mg/kg, po) and significant ex vivo binding (84%,
30 mg/kg, po, 6 h), indicating that the cyano compound
To further explore C-7 substituents, conversion of the
nitro group 7i into amino (7j), amido (7k–l), ureido
(7m), sulfonamido (7n), and cyano (7o) groups was next
carried out. Thus, as shown in Scheme 2, hydrogenation
of 7i provided 7j, which, upon acylation, generated
7k–n. Diazotization of 7j followed by treatment with
NaCN/CuCN provided 7o.
X
X
X
Y
Y
Y
a,b
c
N
H
N
Cl
N
N
N
HN
N
O
O
F
5
6
7a-i
Scheme 1. Preparation of tetralin ureas 7a–i. Reagents and conditions (yields for 7a): (a) 1-(3-aminopropyl)-4-methylpiperazine, Ti(O-i-Pr)4, 80 °C,
3 h; (b) NaBH4, MeOH, 0 °C to rt, 12 h, 67% (two steps); (c) 3-chloro-4-fluorophenyl isocyanate, i-Pr2NEt, CH2Cl2, 48%.

1720
T. Guo et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1718–1721
H
O2N
H2N
R
N
(O)n
b
a
N
N
N
H
H
H
Cl
N
N
N
Cl
N
N
N
Cl
N
N
N
O
O
O
F
F
F
7k-n
7i
7j
c,d
NC
N
H
Cl
N
N
N
O
F
7o
Scheme 2. Preparation of tetralin ureas 7j–o. Reagents and conditions: (a) Raney Ni, H2 (50 psi), EtOH, rt, 2 h, 75%; (b) acylating agent, i-Pr2NEt,
CH2Cl2, rt, 16 h, 83–92%; (c) NaNO2, HCl (aq), 0 °C, 30 min; (d) Na2CO3, NaCN, CuCN, H2O, 50 °C, 30 min, 24% (two steps).
Flier, J. S.; Maratos-Flier, E. J. Clin. Invest. 2001, 107,
Table 2. Rapid rat PK and mouse ex vivo binding data
379; (d) Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, J.
a
Compound Rapid rat AUC0–6h
Mouse MCH1R ex vivo
S.; Maratos-Flier, E. Nature 1998, 396, 670.
(10 mg/kg, po, ng h/mL) bindingb (30 mg/kg,
po, 6 h, % I)
2. (a) Chamber, J.; Ames, R. S.; Bergsma, D.; Muir, A.;
Fitzgerald, L. R.; Hervieu, G.; Dytko, G. M.; Foley, J. J.;
Martin, J.; Liu, W. S.; Park, J., et al. Nature 1999, 400,
261; (b) Saito, Y.; Nothacker, H. P.; Wang, Z.; Lin, S. H.;
Leslie, F.; Civelli, O. Nature 1999, 400, 265.
3. (a) Hill, J.; Duckworth, M.; Murdock, P.; Rennie, G.;
Sabido-David, C.; Ames, R. S.; Szekeres, P.; Wilson, S.;
Bergsma, D. J.; Gloger, I. S.; Levy, D. S., et al. J. Biol.
Chem. 2001, 276, 20125; (b) Sailer, A. W.; Sano, H.; Zeng,
Z.; McDonald, T. P.; Pan, J.; Pong, S. S.; Feighner, S. D.;
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Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 7564.
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., et al. Proc.
Natl. Acad. Sci. U.S.A. 2002, 99, 3240.
5. For reviews of small molecule MCH1R antagonists, see:
(a) Rokosz, L. L.; Hobbs, D. W. Drug News Perspect.
2006, 19, 273; (b) Handlon, A. L.; Zhou, H. J. Med. Chem.
2006, 49, 4017; (c) Kowalski, T. J.; McBriar, M. D. Annu.
Rep. Med. Chem. 2005, 40, 119; (d) Dyke, H. J.; Ray, N.
C. Expert Opin. Ther. Patents 2005, 15, 1303.
6. (a) Guo, T.; Hunter, R. C.; Gu, H.; Rokosz, L. L.;
Stauffer, T. M.; Hobbs, D. W. Bioorg. Med. Chem. Lett.
2005, 15, 3691; (b) Guo, T.; Shao, Y.; Qian, G.; Rokosz,
L. L.; Stauffer, T. M.; Hunter, R. C.; Babu, S. D.; Gu, H.;
Hobbs, D. W. Bioorg. Med. Chem. Lett. 2005, 15, 3696; (c)
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. E. J. Med. Chem. 2005, 48, 4746; (d) Xu,
R.; Li, S.; Paruchova, J.; McBriar, M. D.; Guzik, H.;
Palani, A.; Clader, J. W.; Cox, K.; Greenlee, W. J.; Hawes,
B. E.; Kowalski, T. J.; O’Neill, K.; Spar, B.; Weig, B.;
Weston, D. J. Bioorg. Med. Chem. 2006, 14, 3285; (e)
7k
7o
195
642
23
84
a Data represent the pooled samples from two rats in cassette-accel-
erated rapid rat protocol as described in Ref. 8.
b Data are expressed as a percent inhibition of MCH–ADO binding
relative to vehicle control (mean values, n = 3).9
7o has superior in vivo properties as compared to the
acetamido compound 7k.
In summary, a novel class of tetralin ureas has been dis-
covered as potent MCH1R antagonists. Compound 7o
has demonstrated excellent in vitro activity, modest oral
bioavailability, and good ex vivo MCH1R receptor
binding, making it suitable for further in vivo studies.
Acknowledgments
We are grateful to Dr. Brian E. Hawes and Dr. Daniel J.
Weston of Schering-Plough Research Institute for
obtaining the rapid rat AUC and the mouse ex vivo
binding data for compounds 7k and 7o.
References and notes
1. (a) Hervieu, G. J. Expert. Opin. Ther. Targets 2006, 10,
211; (b) Rossi, M.; Choi, S. J.; O’Shea, D.; Miyoshi, T.;
Ghatei, M. A.; Bloom, S. R. Endocrinology 1997, 138, 351;
(c) Ludwig, D. S.; Tritos, N. A.; Mastaitis, J. W.;
Kulkarni, R.; Kokkotou, E.; Elmquist, J.; Lowell, B.;

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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; (f) McBriar, M. D.; Guzik, H.;
Shapiro, S.; Paruchova, J.; Xu, R.; Palani, A.; Clader, J.
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J.; O’Neill, K.; Spar, B.; Weig, B.; Weston, D. J.; Farley,
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competition binding model for IC50 determination using
the program GraphPad Prism (GraphPad Software, Inc.,
San Diego, CA). Ki values were calculated using the
Cheng–Prusoff equation with a Kd of 1 nM. All Kis
represent the average of two or more determinations. The
standard deviations were not greater than 50% from the
mean.
8. Korfmacher, W. A.; Cox, K. A.; Ng, K. J.; Veals, J.;
Hsien, Y.; Wainhaus, S.; Broske, L.; Prelusky, D.;
Nomeir, A.; White, R. E. Rapid Commun. Mass Spectrom.
2001, 15, 335.
9. Mouse MCH1R ex vivo binding assay: Animals were
administered compound (30 mg/kg) via oral gavage. At
subsequent time points, brains were harvested and
frozen. Brain sections from the caudate were placed
on slides and allowed to bind to radiolabeled MCH–
ADO ([125I]-S36057, NEN)10 for 30 min. The sections
were then rinsed with binding buffer and dried. The
amount of radiolabeled MCH–ADO that remained
bound to the brain section following washing was
specific to MCH binding sites. Addition of nonlabeled
MCH to the binding reaction completely abolished
radiolabeled MCH–ADO binding to the brain section.
Radioactivity bound to the section was quantified using
a Storm 860 phosphorimager. Hawes, B. E.; Green, B.;
O’Neill, K.; Fried, S.; Graziano, M. P. Endocrinology
2000, 141, 4524.
7. MCH1R Ki determination: Membranes prepared from
CHO cells that express human MCH1R (0.05 mg/mL
final) were incubated with wheatgerm–agglutinin (WGA)
coated SPA beads (1 mg/mL final, Amersham Biosciences,
Piscataway, NJ) in assay buffer (25 mM HEPES, 10 mM
NaCl, 10 mM MgCl2, 5 mM MnCl2, and 0.1% BSA, pH
7.4) for 5 min on ice and subsequently washed two times in
assay buffer. Test compound (20 lL) prepared in 7.5%
DMSO, 7.5% DMSO (vehicle) or MCH (1.0 lM final –
used to quantify the non-specific signal) was mixed with
45 lL assay buffer in 96-well assay plates (Corning #3604).
20 lL of the bead/membrane mixture was added to the
compounds followed by 10 lL of [125I]-MCH (0.125 nM
final, Perkin Elmer, Boston, MA). The assay plates were
shaken for 5 min on a plate shaker and then incubated for
2 h. Binding of [125I]-MCH to the bead/membrane mixture
was detected using a Microbeta TriluxTM scintillation
counter (Perkin-Elmer). The data were fit to a one-site
10. Audinot, V.; Lahaye, C.; Suply, T.; Beauverger, P.;
Rodriguez, M.; Galizzi, J. P.; Fauchere, J. L.; Boutin, J.
A. Br. J. Pharmacol. 2001, 133, 371.