Discovery of imidazo[1,2-a]pyridines as potent MCH1R antagonists

Article abstract of DOI:10.1016/j.bmcl.2009.06.101

A series of imidazo[1,2-a]pyridine derivatives was identified and evaluated for MCH1R binding and antagonistic activity. Introduction of a methyl substituent at the 3-position of imidazo[1,2-a]pyridine provided compounds with a significant improvement in MCH1R affinity. Representative compounds in this series exhibited good potency and brain exposure in rats.

Full text of DOI:10.1016/j.bmcl.2009.06.101

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4589–4593
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of imidazo[1,2-a]pyridines as potent MCH1R antagonists
*
Hiroyuki Kishino , Minoru Moriya, Shunji Sakuraba, Toshihiro Sakamoto, Hidekazu Takahashi,
Takao Suzuki, Ryuichi Moriya, Masahiko Ito, Hisashi Iwaasa, Norihiro Takenaga, Akane Ishihara,
Akio Kanatani, Nagaaki Sato, Takehiro Fukami
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, 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 imidazo[1,2-a]pyridine derivatives was identified and evaluated for MCH1R binding and
antagonistic activity. Introduction of a methyl substituent at the 3-position of imidazo[1,2-a]pyridine
provided compounds with a significant improvement in MCH1R affinity. Representative compounds in
this series exhibited good potency and brain exposure in rats.
Received 20 May 2009
Revised 25 June 2009
Accepted 26 June 2009
Available online 4 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Melanin-concentrating hormone
MCH1R antagonists
Imidazo[1,2-a]pyridine
Obesity
Melanin-concentrating hormone (MCH) is a cyclic nonadeca-
peptide with a disulfide bond mainly expressed in the lateral hypo-
thalamus and zona incerta region of the brain. MCH is believed to
play an important role in the regulation of food intake and energy
homeostasis.1,2 Up-regulation of prepro-MCH mRNA is reported in
several obese animals.3–5 Chronic intracerebroventricular (icv)
infusion of MCH stimulates food intake, causing obesity with
hyperphagia.6,7 Targeted disruption of the prepro-MCH gene re-
duces food intake and increases metabolic rate, generating a lean
phenotype.8 In contrast, overexpression of the prepro-MCH gene
makes mice susceptible to insulin resistance and causes moderate
obesity.9 Recently, we showed that chronic administration of
MCH1R antagonists suppresses food intake and body weight gain
in diet-induced obesity (DIO) rats and mice.10,11 These data indi-
cate that MCH1R antagonists could be novel therapeutic agents
for the treatment of obesity.12,13
series of imidazo[1,2-a]pyridine derivatives and the discovery of
derivatives 8b and 8j, which are more brain permeable than com-
pound 1.
A general synthetic route for the preparation of imidazo[1,2-
a]pyridine derivatives is outlined in Scheme 1. The key intermediate
6 was prepared from commercially available 2-amino-5-nitropyri-
dine (5). Treatment of ketone 3 with bromine in methanol provided
a-bromoketone derivative 4 in moderate yields. Subsequent cycli-
zation of -bromoketone 4 with 2-amino-5-nitropyridine (5) under
a
thermal conditions afforded 2- or 2,3-disubstituted-6-nitroimi-
dazo[1,2-a]pyridines 6. In general, 2-substituted imidazo[1,2-a]pyr-
idine 6 (R1 = H) was produced in good yields, while 2,3-disubstituted
imidazo[1,2-a]pyridine 6 was obtained only in modest yields due to
sterical hindrance by the R1 group (R1 = Me, Et or cyclopropyl).
Reduction of the nitro group of 6 by hydrogenation over 10% palla-
dium on carbon afforded the corresponding aniline derivatives,
which were coupled with the desired biaryl carboxylic acid to pro-
vide the imidazo[1,2-a]pyridine-6-carboxamide derivatives 7a–h,
8a–r, 9, and 10. The diverse biaryl carboxylic acid partners were
In our previous Letter,14 we described the discovery of a series
of 2-aminobenzimidazole derivatives as potent MCH1R antago-
nists, as exemplified by compound 1 (IC50 of 2.7 nM, Fig. 1). After
oral administration of 10 mg/kg of compound 1 in rats, plasma
and brain levels after 2 h were 1.05 lM and 0.29 nmol/g, respec-
tively. To identify more brain permeable novel MCH antagonists,
we initiated a SAR study of the newly identified imidazo[1,2-a]pyr-
idine lead 2. Systematic modification of 2 resulted in the identifica-
tion of potent and brain permeable derivatives. In this Letter, we
describe the detailed structure–activity relationships (SAR) of a
F
F3C
N
N
H
H
H
N
N
N
N
N
O
O
N
N
2
1
* Corresponding author. Tel.: +81 29 877 2000; fax: +81 29 877 2029.
E-mail address: hiroyuki_kishino@merck.com (H. Kishino).
Figure 1.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.06.101

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H. Kishino et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4589–4593
O
a
O
R1
Br
R1
R2
R2
4
3
b
c, d
Ar1
R1
R1
H
O2N
Ar2
O2N
N
N
N
R2
R2
N
NH2
O
N
N
1
7a-h:
8a-r :
9:
R = H
5
6
1
R = Me
1
R = Et
1
10:
R =
Scheme 1. Reagents and conditions: (a) bromine, MeOH, 0 °C; (b) 4, EtOH, reflux, 12–48 h, 10–90% (two steps); (c) H2, Pd–C, MeOH, rt, 2 h; (d) biarylcarboxylic acid, HATU,
DIEA, DMF, rt, 16 h, 37–79% (two steps).
F3C
H
b, c
b, g
a
N
N
N
N
CO2Et
O
N
NMe2
N
OH
OH
N
7f
11
14
d
e, f
N
N
N
O
N
N
N
OH
N
13
12
15
Scheme 2. Reagents and conditions: (a) LAH, THF, 0 °C, 81%; (b) MsCl, Et3N, THF, 0 °C, 90%; (c) Me2NH, MeOH, 23%; (d) excess MeMgBr, THF, 0 °C–rt, 50%; (e) SO3ÁPy, Et3N,
DMSO, rt, 73%; (f) MeMgBr, THF, 0 °C, 44%; (g) MeNH2, MeOH then AcCl, Et3N, THF, 25%.
prepared by Suzuki cross coupling reactions of the corresponding
aryl halides with the aryl boronic acids.
activity was estimated by the inhibitory effect of compounds on
intracellular calcium induced by MCH using FLIPR in CHO cells
expressing human MCH1R.15
Imidazo[1,2-a]pyridine derivatives containing hydrophilic
groups at the 2-position were prepared as outlined in Scheme 2.
Ester 7f was converted to the corresponding primary alcohol 11
by reduction with lithium aluminum hydride or, alternatively, to
the tert-alcohol 13 by alkylation with an excess amount of MeM-
gBr. Oxidation of the alcohol 11 to the corresponding aldehyde fol-
lowed by alkylation with MeMgBr afforded secondary alcohol 12.
Treatment of alcohol 11 with methanesulfonyl chloride followed
by substitution with dimethylamine afforded dimethylamine 14.
Alternatively, the alcohol 11 was mesylated, displaced by methyl-
amine, and acylated to afford amide 15. Introduction of substitu-
ents at the 3-position of imidazo[1,2-a]pyridine derivative 7d
was achieved by treatment with formaldehyde or acetic anhydride
to give 16 and 17, respectively. Reduction of ketone 17 with NaBH4
provided compound 18 (Scheme 3).
Initial modification around the substituents at the 2-position of
the imidazo[1,2-a]pyridine ring was performed using lead com-
pound 2 as a template (Table 1). A variety of small alkyl groups,
such as methyl, ethyl (data not shown), n-propyl, i-propyl, cyclo-
propyl, and tert-butyl were effective to increase potency (7a–e).
Incorporation of an electron-withdrawing ethoxylcarbonyl group
as in 7f led to a significant decrease in potency. Incorporation of
polar substituents containing hydroxyl (11–13), dimethylamino
(14), and acetoamide (15) groups resulted in increased binding
affinities compared to lead compound 2, however decreased po-
tency compared to 7a–e, suggesting that the receptor binding
pocket around the 2-position of the imidazo[1,2-a]pyridine ring
prefers lipophilic substituents.
Based on these binding data, further optimization of the substi-
tuent at the 3-position was conducted using 7d as a template (Ta-
ble 2). Incorporation of a methyl group to the 3-position of the
imidazo[1,2-a]pyridine ring resulted in a comparable potency to
Compounds were evaluated for their binding affinity to the
membranes of CHO cells expressing human MCH1R in a competi-
tion binding assay with [125I]-MCH as the radioligand. Antagonistic
OH
a
b
F3C
N
N
H
16
N
N
O
N
O
OH
c
N
N
7d
N
N
17
18
Scheme 3. Reagents and conditions: (a) 30% HCHO solution, AcONa, AcOH, 60 °C, 34%; (b) Ac2O, toluene, reflux, 27%; (c) NaBH4, MeOH, 0 °C, 50%.

H. Kishino et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4589–4593
4591
Table 1
Table 3
SAR of substituents at the 2-position of imidazo[1,2-a]pyridine derivatives
SAR of a variety of biaryl analogs
Ar1
F3C
R1
H
N
Ar2
N
H
O
N
N
N
R2
O
Compound Ar1–Ar2
R1 MCH1R binding MCH1R FLIPR clog Pb
N
a
a
IC50 (nM)
IC50 (nM)
R2
MCH1R binding IC50 (nM)
a
Compound
2
H
300
5.4
4.6
11
7g
H
8.2
nd
5.0
5.4
F3C
7a
7b
7c
iPr
Me
nPr
N
8b
Me 3.5
1000
7d
7e
7f
5.6
7h
H
140
nd
26
3.6
4.1
N
7.1
8c
Me 3.3
Me 2.2
Me 5.4
CO2Et
>1000
130
Cl
11
OH
8d
100
90
4.9
4.0
N
12
13
14
15
30
17
83
35
F
OH
8e
N
OH
N
Me
8f
Me 4.8
Me 6.0
Me 48
Me 4.0
Me 4.4
85
4.5
4.3
2.6
5.5
4.1
O
N
N
a
Values are means of 2 experiments. Compounds competed with [125I]-MCH for
MeO
binding at the human MCH1 receptor.
8g
122
94
N
the unsubstituted derivative 7d. Increasing the size of alkyl substit-
uents as in the 3-ethyl and 3-cyclopropyl derivatives (9 and 10) led
to a decrease in potency. Substitution with polar groups as in 16,
17, and 18 also led to a decrease in potency.
We next turned our attention to the left-hand side biaryl moiety
of the molecule as shown in Table 3. Incorporation of a 5-trifluoro-
methyl-2-pyridyl group provided compound 7g with a comparable
binding affinity to the phenyl analogue 7d (IC50 values of 8.2 and
5.6 nM for 7g and 7d, respectively). Removing the trifluoromethyl
group as in 7h resulted in a 17-fold decrease in potency. In con-
MeO2S
8h
N
F3C
8i
109
20
N
F
Table 2
8j
N
SAR of substituents at the 3-position of imidazo[1,2-a]pyridine derivatives
F3C
R1
H
N
F3C
F
N
N
8k
8l
Me 160
Me 2.0
nd
59
3.9
4.4
N
O
N
a
Compound
R1
MCH1R binding IC50 (nM)
8a
9
Me
Et
4.8
26
N
10
16
17
18
a
260
11
OH
OH
F
8m
Me 4.0
94
4.6
O
320
330
N
Values are means of 2 experiments. Compounds competed with [125I]-MCH for
binding at the human MCH1 receptor.
(continued on next page)

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H. Kishino et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4589–4593
Table 4
Table 3 (continued)
Brain penetrability of imidazo[1,2-a]pyridine compounds 8b and 8ja
Compound Ar1–Ar2
R1 MCH1R binding MCH1R FLIPR clog Pb
a
a
IC50 (nM)
IC50 (nM)
Compound
Plasma (
lM)
Brain (nmol/g)
8b
8j
1.4
5.0
1.6
2.5
F
8n
Me 6.8
29
3.7
a
N
Values are means of 3 experiments. The plasma and brain concentrations were
measured 2 h following oral administration of 10 mg/kg of compounds in SD rat.
N
F
functional activities, high brain and plasma concentrations were
observed 2 h after oral dosing (2.5 nmol/g and 5.0 lM for brain
and plasma levels, respectively). The brain level of 8j was eightfold
higher than that of 1.
In conclusion, we have discovered imidazo[1,2-a]pyridine ana-
logs as potent MCH1R antagonists. Detailed SAR studies around
the imidazo[1,2-a]pyridine series revealed that incorporation of a
methyl substituent at the 3-position of the imidazo[1,2-a]pyridine
ring significantly improves binding and functional activity. Fur-
thermore, appreciable brain exposure was achieved in rats after
oral administration of imidazo[1,2-a]pyridine derivative 8j.
N
N
8o
Me 2.5
Me 102
Me 61
Me 44
70
4.2
2.5
3.3
3.2
F
N
8p
164
217
121
N
N
F
8q
N
N
References and notes
F
N
8r
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lM, respectively.
In the case of 8j, which had a good combination of binding and

H. Kishino et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4589–4593
4593
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