Synthesis and SAR of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones as MCH-1 antagonists for the treatment of obesity

Article abstract of DOI:10.1016/j.bmcl.2010.09.037

A new series of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones possessing MCH-1 receptor antagonism is presented. Suzuki coupling of boronic acids with key triflate 6 allowed rapid generation of a range of analogs. The SAR of the MCH-1 receptor was explored with a variety of aryl and heterocyclic moieties. Selected compounds were studied in a five-day diet induced obese mouse model to evaluate their potential use as weight loss agents.

Full text of DOI:10.1016/j.bmcl.2010.09.037

Bioorganic & Medicinal Chemistry Letters 20 (2010) 7020–7023
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones
as MCH-1 antagonists for the treatment of obesity
Mark Hadden a, , Dustin M. Deering a, Alan J. Henderson a, Matthew D. Surman a, Michele Luche a,
⇑
Yuri Khmelnitsky a, Steven Vickers b, Jean Viggers b, Sharon Cheetham b, Peter R. Guzzo a
a AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
b RenaSci Consultancy Ltd, Biocity, Nottingham, NG1 1GF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones possessing MCH-1 receptor antagonism is pre-
sented. Suzuki coupling of boronic acids with key triflate 6 allowed rapid generation of a range of analogs.
The SAR of the MCH-1 receptor was explored with a variety of aryl and heterocyclic moieties. Selected
compounds were studied in a five-day diet induced obese mouse model to evaluate their potential use
as weight loss agents.
Received 10 August 2010
Revised 7 September 2010
Accepted 8 September 2010
Available online 21 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
MCH
Obesity
Suzuki
Indazole
Antagonist
Weight loss
SAR
Melanin concentrating hormone is a 19 amino acid cyclic neu-
ropeptide that is expressed in the central nervous system of verte-
brates.1 In mammals, the MCH-1 receptor is highly expressed in
the hypothalamus and exerts effects on food intake and body
weight regulation.2 Intracerebroventricular injection of MCH in-
creases food intake in rodents and MCH mRNA levels are elevated
in fasted animals that are normal weight or obese.3
body weight in rodent models of obesity.7 Two representative
examples are shown in Figure 1 (compounds 1 and 2).8,9
Compound 3 was identified in a previously explored 5-(pyridi-
non-1-yl)indazole series and in a five-day diet induced obese (DIO)
mouse feeding study showed 2.8% weight loss (60 mg/kg, po,
qd).10,11 Given the high affinity of compound 3 for the MCH-1
receptor (Ki = 2.6 nM), the modest weight loss was attributed, at
Knock-out studies, in which the gene encoding MCH was de-
leted, led to mice with reduced body weight and fat mass com-
pared to wild type.4 Weight loss was higher than expected from
the observed reduction in food intake and an increase in oxygen
consumption pointed to an elevated metabolic rate as a contribut-
ing factor. Transgenic mice lacking the MCH-1 receptor are resis-
tant to diet induced obesity compared to wild type.5 Despite
being hyperphagic when maintained on normal chow, the animals
demonstrated a lean phenotype and normal fat mass with in-
creased metabolism and hyperactivity offsetting the increased
food intake. This has lead to the development of MCH-1 antago-
nists as one class of centrally acting targets being explored for
the treatment of obesity.6 Indeed, a variety of small molecule
MCH-1 receptor antagonists have been shown to effectively reduce
NC
O
O
OCH3
O
N
N
N
NH
F
S
N
Cl
N
N
H3C
CF3
1
2
(GW803430)
MCH-1 Ki = 2.8 nM
MCH-1 Ki = 1.2 nM
(Literature9 Ki = 2.7 nM)
(Literature8 IC50 = 0.5 nM)
N
N
N
N
O
N
N
O
N
N
O
Ar
3
4
MCH-1 Ki = 2.6 nM
⇑
Corresponding author. Tel.: +1 518 512 2835; fax: +1 518 512 2079.
E-mail address: mark.hadden@amriglobal.com (M. Hadden).
Figure 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.037

M. Hadden et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7020–7023
7021
N
N
N
N
O
N
N
O
N
O
N
N
a
b
N
N
N
O
HO
TfO
3
5
6
N
N
O
N
c
N
Ar
4
Scheme 1. Reagents and conditions: (a) NH4OCHO, Pd/C, MeOH, 70 °C, 30 min, 86%; (b) PhNTf2, LiHMDS, THF, 50–75%; (c) arylboronic acid, PdCl2(dppf), K2CO3, DMSO, 90 °C,
16 h, 15–44%.
least in part, to suboptimal PK and CNS penetration (brain to plasma
ratio of 0.7 at 6 h in DIO mice). Therefore, a strategy was employed to
remove potential metabolic positions to improve PK and to reduce
the number of rotatable bonds to improve CNS exposure. Removal
ofthemethyleneoxylinkerbetweenthephenylandpyridinonerings
was seen as a way to remove a benzylic site of potential metabolism
and to remove two rotatable bonds. The increased rigidity of the
biaryl pyridinone ring system of compound 4 was expected to re-
duce metabolic clearance, improve brain penetration and hence im-
prove in vivo efficacy. The biaryl system was also expected to be
amenable to rapid analog development.
The benzyl group of 3 (synthesis described previously)11 was
removed by hydrogenolysis with ammonium formate and
palladium on carbon to give 4-hydroxypyridinone 5 (Scheme 1).
Conversion of the hydroxyl group to triflate 6, followed by palla-
dium-catalyzed coupling with various boronic acids provided a li-
brary of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones 4 in 15–44%
yield.
Table 1
SAR of 4-arylpyridin-2(1H)one
N
N
N
O
N
R
3, 4
Compound
R
MCH-1 bindinga,b Ki (nM)
Compound
R
MCH-1 bindinga,b Ki (nM)
O
3
2.6
4k
2.8
H3CO
Cl
Cl
4a
4b
>1000
539
4l
19
OCH3
4m
3.9
CH3
F3CO
H3CO
CH3
4c
>1000
4n
99
F
CH3
4d
4e
4f
24
4o
4p
4q
4r
16
62
11
25
H3C
F3C
Cl
F
275
15
F
F
Cl
F3C
4g
5.0
S
4h
23
4s
13
N
F3CO
Cl
CH3
4i
4j
3.4
5.8
4t
26
N
Cl
CH3
4u
272
N
F3C
Cl
Cl
a
Displacement of [3H]compound 1 from MCH-1 expressed in CHO-K1 cells (Kd = 1.42 0.08 nM and Bmax = 13.3 0.7 pmol/mg protein; mean SEM n = 4).
Values are means of at least two determinations where each determination is within 40% of the mean value shown.
b

7022
M. Hadden et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7020–7023
Reducing the number of rotatable bonds through the removal of
In addition to substituted phenyl compounds, bicyclic aromatic
derivatives were also well tolerated. For example, naphthyl, benzo-
thiophenyl, and indolyl analogs 4q–t showed only modest losses in
MCH-1 affinity compared to the most potent phenyl derivatives.
Pyridine 4u showed almost a 20-fold decrease in binding com-
pared with the corresponding chloro analog 4f.
Compounds 4g and 4i were chosen for further analysis, includ-
ing in vivo efficacy studies (Table 2). The compounds showed good
aqueous solubility and at least 400-fold separation between MCH-
1 affinity and cytochrome P450 inhibition (six isoforms tested).
Compounds 4g and 4i also were examined in a five-day diet in-
duced obese (DIO) mouse model of weight loss (Fig. 2). The animals
were given the test compounds for five days after a three-day base-
line period and body weights were recorded daily. Importantly,
both 4g and 4i showed improved efficacy (5.7% and 3.9% weight
loss, respectively at 30 mg/kg qd) compared with compound 3
(2.8% weight loss at 60 mg/kg qd) at half the dose. Both compounds
also compared favorably with known MCH-1 antagonists 1 and 2 in
terms of CYP inhibition, aqueous solubility, metabolic stability and
in vivo efficacy.
the methyleneoxy linker in compound 3 to give compound 4a re-
sulted in a dramatic loss in MCH-1 binding (Table 1). ortho Meth-
ylation of the phenyl ring restored some activity (compound 4b).
However, the benefit of the methyl group was lost when moved
to the meta-position (compound 4c). The para methyl analog 4d
improved the MCH-1 affinity to within approximately 7.5-fold of
the benzyloxy derivative 3. Binding affinity was reduced by more
than 10-fold when the smaller p-fluoro substituent was used (com-
pound 4e). However, larger electron withdrawing groups in the
para position (compounds 4f and 4g) improved MCH-1 affinity
with p-trifluoromethyl analog 4g showing comparable binding
affinity to benzyloxy derivative 3. In many cases, o,p-disubstituted
analogs provided additional enhancement in MCH-1 binding. For
example, 2,4-dichlorophenyl derivative 4i showed nearly 4.5-fold
improvement in affinity compared to 4-chloro analog 4f. Addition-
ally, 2-methyl-4-trifluoromethoxyphenyl derivative 4m demon-
strated a greater than 5.5-fold enhancement in affinity, compared
to 4-trifluoromethoxyphenyl derivative 4h. The addition of a fluo-
rine in the 2-position generally caused a drop-off in binding (4n–
p).
Table 2
Additional in vitro data and in vivo efficacy
Compound
R
MCH-1 binding
Ki (nM)
CYP 2C19a
CYP 3A4a
Half life (min)
RLMc
Aqueous solubilitye
(lM)
Five-day DIO mouse
feeding study
IC50
(
lM)
IC50
(lM)
HLMb
120
MLMd
187
5.7% weight loss
(30 mpk, po, qd)
p <0.001
4g
5.0
27
2.0
102
93
F3C
3.9% weight loss
(30 mpk, po, qd)
4i
1
3.4
2.8
40
1.7
1.6
121
603
66
136
574
100
10
Cl
Cl
p <0.01
N/A
9.3
196
3.6%, 6.4%f weight loss
(10 mpk, po, qd)
p <0.05, p <0.001
5.1% weight loss
(30 mpk, po, qd)
p <0.001
2
N/A
1.2
6.1
<0.05
77
109
574
54
a
b
c
d
e
f
Six isoforms tested. Other isoforms not reported have IC50’s greater than 10 mM.
Human liver microsomes.
Rat liver microsomes.
Mouse liver microsomes.
Aqueous solubility in PBS at pH 7.4.
Two separate studies at the same dose.
41.0
40.5
40.0
39.5
39.0
38.5
**
**
***
**
**
***
***
Vehicle
38.0
Compound 4i 30 mg/kg po qd -3.9%
***
***
37.5
37.0
Compound 4g 30 mg/kg po qd -5.7%
Day-2
Day-1
Day 0
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Figure 2. Effect of MCH-1 receptor antagonists 4g and 4i on the body weight of male DIO C57BL/6 J mice. Data are adjusted means (n = 8–10) SEMs are calculated from the
*
**
residuals of the statistical model. Data analyzed by ANCOVA with body weight on day 1 as covariate followed by Dunnett’s test for adjusted data; p <0.05, p <0.01,
***
p <0.001. Figures in legend refer to % difference from control on day 6 (i.e., after five-days dosing).

M. Hadden et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7020–7023
7023
5. (a) Marsh, D. J.; Weingarth, D. T.; Novi, D. E.; Chen, D. Y.; Trumbauer, M. J.;
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; (b) Bjursell, M.; Gerdin, A. K.; Ploj, K.;
Svensson, L.; Svensson, L.; Ocarsson, J.; Snaith, M.; Tornell, J.; Bohlooly, Y.
Diabetes 2006, 55, 725.
6. Sargent, B. J.; Moore, N. A. Br. J. Clin. Pharmacol. 2009, 68, 852.
7. McBriar, M. D. Curr. Opin. Drug Discov. Devel. 2006, 9, 496.
8. Hertzog, D. L.; Al-Barazanji, K. A.; Bigham, E. C.; Bishop, M. 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. 2006, 16, 4723.
9. McBriar, M. D.; Guzik, H.; Shapiro, S.; Paruchova, J.; Xu, R.; Palani, A.; Clader, J.
W.; Cox, K.; Greenlee, W. J.; Hawes, B. E.; Kowalski, T. J.; O’Neil, K.; Spar, B. D.;
Weig, B.; Weston, D. J.; Farley, C.; Cook, J. J. Med. Chem. 2006, 49, 2294.
10. Sargent, B.; Guzzo, P.; Surman, M.; Freeman, E.; Grabowski, J. F.; Jiang, M.;
Jiang, G.; Hadden, M.; Luche, M.; Michels, P.; Khmelnitsky, Y.; Lindsay, J.;
Mozhaeva, L.; Zaremba, J.; RenaSci: Viggers, J.; Vickers, S.; Goddard, S.;
Cheetham, S.; Comparative pharmacology of AMR-MCH-1 and AMR-MCH-2,
MCH-1 receptor antagonists for the treatment of obesity poster presented at
the British Pharmacological Society Meeting, Dec 16–18, 2008; Brighton, UK.
11. Surman, M. D.; Freeman, E. F.; Grabowski, J. F.; Guzzo, P. R.; Hadden, M.;
Henderson, A. J.; Jiang, G.; Jiang, X.; Luche, M.; Khmelnitsky, Y.; Vickers, S.;
Viggers, J.; Cheetham, S. Bioorg. Med. Chem. Lett. 2010, 20, 7015.
In conclusion,
a variety of 4-aryl-1-(indazol-5-yl)pyridin-
2(1H)ones were synthesized and tested for MCH-1 activity. Substi-
tutions on the aryl ring were found to be required for good MCH-1
binding. In particular, certain para-substituents and ortho, para-
substituent combinations were able to impart high MCH-1 affinity.
Bicyclic aryl ring systems also were found to provide good binding.
Selected compounds were studied in DIO mice and were found to
produce statistically significant weight loss after five days support-
ing the potential use of these compounds as weight loss agents.
Further progress toward the development of MCH antagonists with
improved drug like properties will be reported in the subsequent
manuscript.12
Reference and notes
1. Baker, B. I. Int. Rev. Cytol. 1991, 126, 1.
2. (a) Kohler, C.; Haglund, L.; Swanson, S. W. J. Comp. Neurol. 1984, 223, 501; (b)
Vaugham, H.; Fischer, W. H.; Hoeger, C.; Rivier, J.; Vale, W. Endocrinology 1989,
125, 1660.
3. Qu, D.; Ludwing, 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.
12. Henderson, A. J.; Deering, D. M.; Grabowski, J. F.; Guzzo, P. R.; Hadden, M.;
Jiang, X.; Khmelnitsky, Y.; Luche, M.; Surman, M. D.; Cheetham, S.; Vickers, S.;
Viggers, J. Bioorg. Med. Chem. Lett. 2010, 20, 7024.
4. Shimada, M.; Tritso, N. A.; Lowell, B. B.; Flier, M. S.; Maratos-Flier, E. Nature
1998, 396, 670.