Discovery of heterobicyclic templates for novel metabotropic glutamate receptor subtype 5 antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.03.066

Investigation of a series of heterobicyclic compounds with essential pharmacophoric features of the metabotropic glutamate receptor 5 (mGluR5) antagonists MPEP and MTEP provided novel structural templates with sub-micromolar affinities at the mGluR5.

Full text of DOI:10.1016/j.bmcl.2007.03.066

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2987–2991
Discovery of heterobicyclic templates for novel
metabotropic glutamate receptor subtype 5 antagonists
Santosh S. Kulkarni and Amy Hauck Newman*
Medicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, NIH,
DHHS, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA
Received 16 March 2007; accepted 21 March 2007
Available online 24 March 2007
Abstract—Investigation of a series of heterobicyclic compounds with essential pharmacophoric features of the metabotropic gluta-
mate receptor 5 (mGluR5) antagonists MPEP and MTEP provided novel structural templates with sub-micromolar affinities at the
mGluR5.
Published by Elsevier Ltd.
The metabotropic glutamate receptor 5 (mGluR5)
belongs to family C of the G-protein coupled receptors
(GPCR) and it mediates the actions of the excitatory
neurotransmitter, L-glutamate.1–3 Recently, preclinical
investigation into the role of mGluR5 in anxiety, depres-
sion, pain, mental retardation, and drug dependence has
suggested that the mGluR5 may be a novel target for
therapeutic intervention.4 In particular, studies using
either an mGluR5 antagonist or mGluR5 knockout
mice showed reduced locomotor stimulant effects
induced by cocaine.5 Moreover, mGluR5 appears to be
involved in the rewarding effects of morphine, nicotine,
and ethanol.6 Thus, development of selective mGluR5
antagonists may provide a novel strategy toward the
discovery of medications for various CNS disorders.
S
H3C
N
H3C
N
N
1
2
Figure 1. Non-competitive antagonists of mGluR5, MPEP 1 and
MTEP 2.
oped from our diaryl- and heterobiaryl amides.9 Herein,
we describe the discovery of novel heterobicyclic leads
and preliminary SAR studies on these compounds.
The allosteric ligand binding site of MPEP-like antago-
nists at mGluR5 has been predicted to be in the trans-
membrane region of the receptor.10 The binding site
consists of two hydrophobic regions, wherein the aro-
matic rings (a and b) of the compounds interact, with
a linker in between, to position these groups in proper
orientation. The pyridyl ‘N’ is essential for activity,
and there is a limited tolerance of substitutions on both
the aromatic rings. Bearing this in mind, we introduced
the pyridyl ring in a bicyclic ring system (heterobicyclic
compounds, Fig. 2), whereby the important pharmaco-
phoric groups were kept intact. Thus, a series of quino-
line, benzothiazole, and pyridothiazole analogues were
synthesized, as depicted in Schemes 1–4, and evaluated
for binding at mGluR5.
The alkyne based non-competitive mGluR5 antagonists
MPEP (1) and MTEP (2) have been used to investigate
the role of mGluR5 in CNS disorders.7 A series of com-
pounds with different structural templates incorporating
tetrazoles, phenyl ureas, thiopyrimidines, and arylmeth-
oxy pyridines have been reported recently as mGluR5
antagonists8 (Fig. 1).
To further explore the SAR at mGluR5 and to seek
compounds with novel structural templates, we have
designed a series of compounds based on the SAR devel-
Keywords: Metabotropic glutamate receptor 5; Non-competitive
antagonist; Suzuki–Miyaura coupling.
*
The 7-substituted quinolines were obtained as shown
in Scheme 1. The 7-chloro-2-methyl quinoline 4 was
Corresponding author. Tel.: +1 410 550 6568x114; fax: +1 410 550
6855; e-mail: anewman@intra.nida.nih.gov
0960-894X/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2007.03.066

2988
S. S. Kulkarni, A. H. Newman / Bioorg. Med. Chem. Lett. 17 (2007) 2987–2991
O2N
NO2 O2N
+
NH2 H3C
NO2
NH2
a
X
a
Y
+
O
H3C
N
NH2
H3C
N
NH2 H3C
N
N
b
H3C
N
Z
13
19
20
18
H3C
N
*
N
H
*
b
Heterobiyclic compounds
3
NH2
N
Figure 2. Design of heterobicyclic mGluR5 antagonsits.
c
O
N
H
H3C
N
H3C
N
N
H
22
23
21
a
d
e
R1
X
Y
P
H3C
N
Cl
H3C
N
4
6
N
Y
X
b
H3C
N
N
H3C
N
24
5a, X= N(CH3)2, Y= H
5b, X=Y=OCH3
c
Scheme 4. Synthesis of compounds 22–24. Reagents and conditions:
(a) Concd HNO3, Concd H2SO4; (b) i—benzoyl chloride, toluene,
dioxane, reflux, 24 h, 35%; ii—10% Pd/C, methanol, H2, 60 psi, rt,
ꢀ98%; (c) NaOAc, gl. HOAc, 90%; (d) NaH, aryl/alkyl halides, DMF,
ꢀ40%; (e) i—benzaldehyde, 4A molecular sieves, methanol;
ii—NaBH3CN, rt, 1 h; iii—NaOAc, gl. HOAc, overall 86%.
O
CH3
CH3
CH3
H3C
N
B
H3C
N
N
R
O
8
7
H3C
Scheme 1. Synthesis of compounds 6–8. Reagents and conditions: (a)
aryl boronic acid, Pd(OAc)2, 5a–b, K3PO4, toluene, ethanol, 100 °C,
overnight, 55–95%; (b) bis(pinacolato)diboron, KOAc, 5b, Pd(OAc)2,
100 °C, 60 h, 95%; (c) Ar-Br, PdCl2(dppf), 2 M Na2CO3, dioxane,
100 °C, 40–88%; Ar-Cl, Pd(OAc)2, 5b, K3PO4, dioxane, H2O, 100 °C,
overnight, 43–86%.
treated with various substituted aryl boronic acids
under Suzuki–Miyaura conditions using the biphenyl
phosphine ligands 5a–b to give a set of substituted
quinolines 6.11 In further exploration of the SAR,
boronic ester 7 was synthesized using the biphenyl
phosphine catalyst and coupled with either heteroaryl
bromides or chlorides.
S
N
S
N
a
c
H3C
H3C
Br
R2
9
10
b
Similarly, benzothiazole compounds (10–12) were syn-
thesized (Scheme 2) by Suzuki coupling on compound
9. Additionally the boronic ester (11) was synthesized
under standard Miyaura borylation conditions and then
subjected to Suzuki coupling with various heteroaryl
bromides or chlorides.12
S
N
S
N
H3C
H3C
O
CH3
CH3
B
N
R
O
12
11
CH3
H3C
In addition, the pyridothiazole and imidazopyridine
compounds were synthesized as shown in Schemes 3
and 4. wherein, 6-methyl 2-amino pyridine 13 was
brominated with excess N-bromo succinimide (NBS).
The benzamide (15) was then prepared with relative
ease, which underwent cyclization in the presence
of Lawesson’s reagent to afford bromopyridothiazole
16.13 The compound 16 was then treated with vari-
ous reagents to give a small set of substituted pyrido-
thiazoles (17).
Scheme 2. Synthesis of compounds 10–12. Reagents and conditions:
(a) aryl boronic acid, Pd(PPh3)4, 2 M aq Na2CO3, toluene, ethanol,
reflux 5 h, 65–70%; (b) bis(pinacolato)diboron, KOAc, PdCl2(dppf),
DMF, 105 °C, 3 h, 95%; (c) Ar-Br, PdCl2(dppf), 2 M Na2CO3,
dioxane, 100 °C, 65%; Ar-Cl, Pd(OAc)2, 5b, K3PO4, dioxane, H2O,
100 °C, overnight, 40%.
Br
Br
Br
Br
O
b
a
H3C
N
NH2
H3C
N
NH2
H3C
N
N
H
13
The imidazopyridines were obtained by nitrating the 6-
methyl-2-amino pyridine 13 to obtain a mixture of reg-
ioisomeric nitropyridines (18–20), which were purified
with extreme care by steam distillation.14 The 3-nitro
compound 19 was treated with benzoyl chloride to
obtain the benzamide, which was cyclized into imidazo-
pyridine 22, after reduction of the nitro group.15 The
substituted imidazopyridines were synthesized by
treating compound 22 with various alkyl or arylalkyl
bromides in the presence of NaH. Compound 24 was
obtained by treating the benzamide 21 with benzalde-
hyde under reductive amination conditions, followed
by cyclization.16
14
15
R3
Br
H3C
S
S
N
c
d
N
H3C
N
N
17
16
Scheme 3. Synthesis of compounds 15–17. Reagents and conditions:
(a) NBS, DMF, rt, 1 h, 95%; (b) benzoyl chloride, pyridine, reflux,
80%; (c) Lawesson’s reagent, HMPA, 140 °C, 1 h, ꢀ95%; (d) i—
Anhydrous NaOAc, 10% Pd/C, methanol, 60 psi, 45 h; or ii—sodium
methoxide, Cu(I)Br, DMF, 120 °C, 30 min; or iii—aryl boronic acid,
Pd(PPh3)4, 2 M aq Na2CO3, toluene, ethanol, reflux, 5 h, 50–90%.

S. S. Kulkarni, A. H. Newman / Bioorg. Med. Chem. Lett. 17 (2007) 2987–2991
2989
Table 2. Representative structures and mGluR5 binding affinities of
substituted benzothiazoles
The compounds were evaluated for biological activity in
a rat brain membrane preparation using [3H]MPEP as
the radioligand to measure binding affinity at mGluR5.
Data for all novel compounds described herein were
obtained through the NIMH PDSP program using
methods cited17 in Tables 1–3 and compared with
reference compound 1 and a diarylamide analogue 3a.9a
S
H3C
R2
N
Compound
R2
mGluR5 binding
affinity Ki SEM (lM)
10a
NAa
Substitution of a phenyl ring at the 7 position of quino-
line (compound 6a) showed 50% radioligand displace-
ment at a concentration of 10 lM at mGluR5; a
substantial decrease in affinity as compared to MPEP.
Moreover, substitution with the bioisosteric thiophene
10b
10c
10d
10e
12a
12b
NAa
F
Cl
43.39 3.29b
43.05 2.47b
2.10 0.58
17%c
Table 1. Structures and mGluR5 binding affinities of substituted
quinolines
OCH3
CN
H3C
N
R1
mGluR5 binding
Compound
R1
affinity Ki SEM (lM)
N
N
N
CH3
6a
50%
29%c
S
6b
6c
8a
8b
8c
8d
<1%a
0.11 0.02
28%a
>60
N
OCH3
CN
12c
39%c
N
a Not active at 100 lM.
N
N
b IC50 (lM) using methods described in Ref. 9a.
c Percent inhibition at 10 lM.
N
N
(6b) completely eliminated activity. Substitution on the
7-phenyl ring however improved activity for some ana-
logues, for example, 6c with a 3-CN group showed a
Ki = 110 nM in the mGluR5 binding assay. A similar
improvement in affinity was observed in the diarylamide
series, wherein the 3-CN compound (3a) showed
improved activity over the unsubstituted lead
compound.9a In a related series of compounds, substitu-
tion with pyridine and pyrimidine rings as a part of aryl
ring ‘b’ improved the mGluR5 affinity.9b Thus, a small
set of substituted pyridines/pyrimidines (8a–h) at the
7-position of the quinoline ring were prepared. Neverthe-
less, none of these compounds showed any improvement
in mGluR5 activity, thereby illustrating a limited
tolerance of substitution with inconsistent SAR across
different templates.
>20
N
N
9%a
CH3
N
N
OCH3
8e
8f
1.55 0.17
5.43 0.83
N
N
OCH3
CH 3
OC H3
N
8g
8h
N
N
2.09 0.40
>1%a
Substitution on the appended phenyl ring (compounds
10b–e) provided benzothiazoles with moderate affinity
(Table 2). The 3-CN compound 10e showed the highest
affinity for mGluR5 in this set. Substitution with either
pyridyl or pyrimidinyl rings (12a–c) did not improve
mGluR5 binding affinity, as observed previously in the
quinoline series.
CH 3
N
F
1
3ac
MPEP
—
0.02 0.001
0.33 0.02b
a Percent inhibition at 10 lM.
b IC50 (lM) using methods described in Ref. 9a.
Further investigation into other related heterocyclic ring
systems that could be modified was undertaken. In this
c 3-cyano-N-(6-methylpyridin-2-yl)benzamide from Ref. 9a.

2990
S. S. Kulkarni, A. H. Newman / Bioorg. Med. Chem. Lett. 17 (2007) 2987–2991
Table 3. Representative structures and mGluR5 binding affinities of pyridothiazole or imidazopyridine compounds
R3
X
Y
H3C
N
Compound
R3
X
Y
mGluR5 binding affinity Ki SEM (lM)
16
Br
H
OCH3
S
N
1%a
17a
17b
17c
17d
17e
17f
17g
22
S
N
16%a
<1%a
33.48 2.24b
3%a
S
N
Ph
40F–Ph
30Cl–Ph
30CN–Ph
2-Thioph-
S
N
S
N
S
N
1%a
13%a
>10
S
N
S
N
NH
H
H
H
H
H
N
>10
23a
23b
23c
24
N
NCH2Ph
NCH2-c-C3H5
NCH3
>10
N
<1%a
<1%a
>10
N
NCH2Ph
N
a Percent inhibition at 10 lM.
b IC50 (lM) using methods described in Ref. 9a.
pursuit, compounds with a pyridothiazole or imidazo-
pyridine scaffold were synthesized. However, none of
this series (16–24) gave improved mGluR5 activity. In
the pyridothiazole series, substitution with additional
aromatic rings (17c–g) to potentially improve the activ-
ity by gaining additional hydrophobic interactions did
not yield any tractable SAR. Similarly exploration of
binding sites in the linker region (23a–c and 24) on the
imidazopyridine template showed no improvement in
activity.
Thus, modifications to seek novel structural templates
yielded some substituted quinolines and benzothiaz-
oles with moderate mGluR5 binding affinities. How-
ever, there was a limited tolerance of substitution
with little discernable SAR in these series of com-
pounds. Similarly, no SAR could be obtained from
a large set of compounds recently reported by Zhao
et al. as positive allosteric modulators at mGluR5.18
The discovery of only a few active compounds from
exhaustive efforts in structural modifications depicts
the inherent difficulty in optimizing the activity at this
receptor. In the present study, as observed previously,
substitution with a cyano group at the 30 position of
the appended phenyl ring provided some improve-
ments in mGluR5 activity. A superimposition of these
templates on the MPEP 1 and compound 3a ana-
logues shows good overlap of the pharmacophoric
features (see Fig. 3). Although there are few minor
differences in the overlap, it is difficult to account
for the dramatic changes in activity across different
templates.
Figure 3. Superimposition of MPEP 1, compounds 3, 6a (green), 10a
(blue), and 17a (red).
Acknowledgments
SSK was supported by a NIH-visiting fellowship. We
thank Dr. Mu-Fa Zou for critically reading this manu-
script. We acknowledge Ms. Barbara Nightingale for
technical assistance, Dr. Bryan Roth, Director of the
National Institute on Mental Health-Psychoactive Drug
Screening Program (PDSP), for his support and Ms.
Estela Lopez for help with the PDSP database. This
work was supported by the NIDA-IRP, NIH.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2007.03.066.
In summary, we identified two structural templates with
moderate mGluR5 antagonist activity. Most structural
modification did not yield compounds with any
improvement in mGluR5 affinity. In the functional
assay measuring the hydrolysis of phosphoinositide at
mGluR5 in CHO cells, compound 6c showed antagonist
activity (IC50 = 0.26 0.05 lM)19 hence this template
may provide a new lead for further SAR investigation.
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16. All compounds were purified by flash chromatography
and characterized by spectroscopic and microanalytical
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din-2-yl)quinoline, 8c, mp 276–278 °C; 1H NMR
(400 MHz, CDCl3)
d 2.78 (s, 3H), 7.22–7.24 (t,
J = 4.8 Hz, 1H), 7.31–7.33 (d, J = 8.8 Hz, 1H), 7.87–7.89
(d, J = 8.4 Hz, 1H), 8.07–8.09 (d, J = 8.4 Hz, 1H), 8.53–
8.56 (dd, J = 2, 8.4 Hz, 1H), 8.86–8.87 (d, J = 4.8 Hz, 2H),
9.18 (s, 1H); 13C NMR (101 MHz, CDCl3) d 25.66, 119.60,
123.09, 125.12, 127.96, 128.11, 129.33, 136.08, 138.87,
148.24, 157.60, 159.79, 164.70; IR (Neat, cmꢁ1) 3401.1,
1606.4, 1566.4, 1554.6, 1420.2, 1406.9; GC-MS (EI) m/z
221 (M+); Anal. (C14H11N3ÆHBrÆH2O) C, H, N. The
experimental and spectral data for all other compounds
are reported in the Supporting information.
17. Binding affinities were determined by the National Insti-
tute on Mental Health-Psychoactive Drug Screening
Program as described in http://pdsp.med.unc.edu/
indexR.html.
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