Design and synthesis of novel heterobiaryl amides as metabotropic glutamate receptor subtype 5 antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.12.083

A series of heterobiaryl amides was designed and synthesized as novel mGluR5 antagonists. The synthesis using palladium catalyzed Suzuki-Miyaura cross-coupling reactions provided an array of compounds with a range of in vitro activities. In particular, compound 9e, 4(3,5-difluorophenyl)-N-(6-methylpyridin-1-yl)picolinamide, exhibited nanomolar affinity at the mGluR5 and will serve as a template for future drug design.

Full text of DOI:10.1016/j.bmcl.2006.12.083

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2074–2079
Design and synthesis of novel heterobiaryl amides
as 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 8 November 2006; accepted 22 December 2006
Available online 4 January 2007
Abstract—A series of heterobiaryl amides was designed and synthesized as novel mGluR5 antagonists. The synthesis using
palladium catalyzed Suzuki–Miyaura cross-coupling reactions provided an array of compounds with a range of in vitro activities.
In particular, compound 9e, 4(3,5-difluorophenyl)-N-(6-methylpyridin-1-yl)picolinamide, exhibited nanomolar affinity at the
mGluR5 and will serve as a template for future drug design.
Ó 2007 Elsevier Ltd. All rights reserved.
Glutamate is a major excitatory neurotransmitter in the
central nervous system (CNS) that acts through ligand-
gated ionotropic glutamate receptors or through the
G-protein coupled (GPCR) metabotropic glutamate
receptors (mGluR).1 The mGluRs belong to group C
GPCRs, which contain a large N-terminal domain for
substrate binding, followed by seven transmembrane do-
mains. There are eight different subtypes of mGluRs;
mGluR5 belongs to the Group I subclass and is coupled
to the phosphoinositide/Ca2+ pathway.1–3 Overstimula-
tion of mGluR5s has been implicated in anxiety, depres-
sion, pain, mental retardation and drug dependence.4
MGluR5 has been shown to be involved in the reward-
ing effects of morphine, nicotine and ethanol.5 Further,
studies using either an mGluR5 antagonist or mGluR5
knockout mice showed reduced locomotor stimulant
effects induced by cocaine.6 Thus development of selec-
tive mGluR5 antagonists may provide a novel non-do-
paminergic strategy toward the discovery of drug
abuse medications and other neuropsychiatric disorders.
studies to improve the in vitro binding and functional
activity of these compounds at the mGluR5.
Based on site directed mutagenesis data and homology
modeling with the bovine rhodopsin crystal structure
as a template, the MPEP type ligands are predicted to
bind at the transmembrane domain.9 The binding site
consists of two hydrophobic regions with a limited toler-
ance for structural variation, which is further substanti-
ated with the SAR in the alkynes and amide based
compounds, as well as compounds from other structural
classes.10 Furthermore hydrophobic interactions seem to
be important, as the allosteric ligand binding site of
mGluR5 is lined with aromatic amino acid residues.9
A comparison of the molecular models of MPEP 1
and MTEP 2 with compounds 3 and 4 showed that
S
H3C
N
H3C
N
N
N
The non-competitive mGluR5 antagonists 1 and 2
(Fig. 1) have served as important tools to investigate
the role of mGluR5 in CNS pathophysiology and drug
abuse.7 We have recently reported a series of diaryl
amides, wherein 3 and 4 showed promising in vitro bind-
ing and functional activity at mGluR5.8 Herein we
describe further structure–activity relationship (SAR)
1
2
O
O
Cl
CN
H3C
N
H3C
N
N
H
H
3
4
*
Figure 1. Non-competitive antagonists of mGluR5: MPEP 1, MTEP
2, compounds 3 and 4.
Corresponding author. Tel.: +1 410 550 1455; e-mail: anewman@
intra.nida.nih.gov
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.12.083

S. S. Kulkarni, A. H. Newman / Bioorg. Med. Chem. Lett. 17 (2007) 2074–2079
2075
O
a
H3C
N
N
H
H3C
N
NH2
Het
6 a-i
5
Scheme 1. Reagents and conditions: (a) acid chlorides, pyridine/TEA,
CHCl3, rt, 1–2 h, 30–70%.
pound 12. The synthesis of boronic ester 11 from the
chloroarene (6h) provides another example of the versa-
tility of the biphenyl ligand 10 in the palladium cata-
lyzed cross-coupling reactions.12
Figure 2. Comparison of MPEP 1 (i) and compound 4 (ii) in low
energy conformations.
for the diarylamides, the aryl ring ‘b’ is out of plane
(ꢀ65°) from the aryl ring ‘a’ (Fig. 2).
Using an analogous approach, compounds with substi-
tution at the 40 position of the aryl ring ‘b’ were synthe-
sized as shown in Scheme 3. The 5-bromo picolinic acid
14, was obtained from compound 13 after refluxing with
10 N HCl. The standard amide synthesis yielded com-
pound 15, which was used for Suzuki coupling reactions
to give compounds 16a–d. Additionally, bipyridyl amide
18 was synthesized from the boronic ester 17 using the
standard Miyuara borylation conditions followed by
the Suzuki coupling reaction.13,14
Thus it was hypothesized that perhaps a restricted bind-
ing site in the mGluR5 hinders optimal interactions of
compounds 3 and 4 and if the aryl ring ‘b’ is made copla-
nar with the aryl ring ‘a’ the activity of compounds
might be improved. Hence, we introduced a hydrogen
bond acceptor atom at the 50 position of the aryl ring
‘b’ which would force this ring to be coplanar with the
aryl ring ‘a’ due to an intramolecular hydrogen bond
with the amide N–H (Fig. 3). The importance of an
intramolecular hydrogen bond to attain higher binding
affinity at mGluR5 has been reported recently.11 Herein,
we report the synthesis and pharmacological evaluation
of a series of heterobiaryl amides that used this strategy.
All novel compounds were evaluated for binding at
mGluR5 in a rat brain membrane preparation using
[3H]MPEP as the radioligand.8,10b Representative com-
pounds and binding data are shown in Table 1 and
are compared to previously, reported diarylamides in
which substitution with Cl (3) and CN (4) at the 30 posi-
tion of the aryl ring ‘b’ provided the most active com-
pounds in that series.8
The series of compounds was synthesized as shown in
Schemes 1–3, wherein 2-amino 6-methyl pyridine 5
was reacted with a set of acid chlorides containing a
hydrogen bond acceptor atom at the 50 position (Scheme 1)
to provide compounds of type 6.
Incorporating a H-bond acceptor atom in the aryl ring
‘b’ in 6b as compared to 6a suggested that intramolecu-
lar H-bonding improved mGluR5 binding affinity by
>3-fold. The imidazole ‘N’ in compound 6b could form
a H-bond with the amide N–H whereas such a H-bond
is not possible for compound 6a. The formation of an
intermolecular H-bond was confirmed by a downfield
shift in the chemical shift of amide N–H proton to d
9.74 ppm in compound 6b from d 8.22 ppm for com-
pound 6a. However substitution with additional aro-
matic rings on the aryl ring ‘b’ (6c–g) substantially
reduced binding affinity at mGluR5. The loss in activity
of compound 6h was surprising considering the activity
of compound 3 as both have a chloro substitution at the
30 position of the aryl ring ‘b’. However there was sub-
stantial improvement in activity for compound 6i as
compared to 6j. Based on this SAR, it may be possible
to improve the activity by substitution with a H-bond
acceptor at the 50 position and additional hydrophobic
interactions by aromatic substitution at the 30 and 40
positions of the aryl ring ‘b’.
Compounds 9a–h and 12 were synthesized as shown in
Scheme 2. The chloro (6h) and bromo (8) substituted
picolinamides were obtained as shown in Schemes 1
and 2. These compounds were then further elaborated
into compounds 9a–h by either Suzuki coupling reac-
tions on compound 8 or by cross-coupling reactions
using the biphenyl phosphine ligand, 2-dic-
yclohexylphosphino-20,60-dimethoxybiphenyl 10, on
the chloro picolinamide (6h). Significantly lower yields
of compound 8 led to the employment of the much more
economical chloro picolinamide (6h) for the synthesis of
a set of related compounds. The reaction using the
biphenyl ligand 10, proved to be more efficient and
yielded compounds 9b–h in good yields (ꢀ70%). To sub-
stitute with heteroaryl rings, compound 6h was reacted
with bis(pinacolato)diboron, Pd(OAc)2 and the biphenyl
ligand 10 to obtain compound 11 in ꢀ90% yield, which
was treated with 2-bromo pyrimidine to obtain com-
Thus a second series of compounds was designed to fur-
ther explore SAR using this hypothesis and retaining the
dipyridyl amide template (Tables 2 and 3).
O
O
R1
a
N
1'
a
N
R2
R3
H3C
N
H
H3C
N
H
b
b
5'
N
The compounds 9a and 9b showed comparable affinities
to compound 6i. Substitution with a group at the 300
position of the appended phenyl ring (9c) reduced
n
Figure 3. Design of heterobiaryl amides.

2076
S. S. Kulkarni, A. H. Newman / Bioorg. Med. Chem. Lett. 17 (2007) 2074–2079
O
O
O
X
X
HO
H3C
N
N
H
a
b
H3C
N
N
H
R
N
N
N
6h X=Cl,
9a-h
7a X=Cl,
7b X=Br
8
X=Br
c
H3CO
OCH3
O
O
B
O
N
P
O
H3C
N
N
H
H3C
N
N
H
N
d
N
N
12
10
11
Scheme 2. Synthesis of compounds 9–12. Reagents and conditions: (a) i—SOCl2, DCM, cat. DMF, reflux, 2 h; ii—2-amino-6-methyl pyridine 5,
pyridine, DCM, rt, 2 h, 71% (6h), 20% (8); (b) ArB(OH)2, Pd(OAc)2, 10, K3PO4, toluene, EtOH, 120 °C, overnight, 55–88%; (c) 6h,
bis(pinacolato)diboron, KOAc, Pd(OAc)2, 10, dioxane, 100 °C, 60 h, ꢀ90%; (d) 2-bromopyrimidine, PdCl2(dppf), 2 M aq Na2CO3, dioxane, 100 °C,
6 h, 55%.
O
O
R1
H3C
N
N
H
H3C
N
N
H
c
b
R
N
N
N
Br
Br
15
Het
16a-d
13 R1 = CN
d
a
14 R1 = COOH
O
O
e
H3C
N
N
H3C
N
N
H
H
N
N
O
B
N
O
18
17
Scheme 3. Synthesis of compound 16–18. Reagents and conditions: (a) 10 N HCl, reflux, 24 h, 85%; (b) i—SOCl2, DCM, cat. DMF, reflux, 3 h; ii—
2-amino-6-methyl pyridine 5, pyridine, rt, 2 h, 20%; (c) 16a, b, d: ArB(OH)2, Pd(PPh3)4, 2 M aq Na2CO3, toluene/DME, EtOH, reflux, overnight,
80%, 16c 2-OCH3–Ph–B(OH)2, Pd(OAc)2, 10, K3PO4, toluene, EtOH, reflux, 1 h, 90%; (d) bis(pinacolato)diboron, KOAc, PdCl2(dppf), DMF,
105 °C, 3 h, 65%; (e) 2-bromo pyridine, PdCl2(dppf), 2 M aq Na2CO3, IPA, DMF, 105 °C, 3 h, 45%.
mGluR5 affinity, however, substitution at the 200 posi-
tion provided compound, 9d with favorable activity.
Substitution with the 300, 500-difluoro phenyl group pro-
vided the most potent compound, 9e, in this series with
an affinity of 43 nM. Substitution with a bulky 1-naph-
thyl group (9f) maintained moderate affinity, whereas a
close homologue, the 2-naphthyl compound 9g, was
inactive, suggesting a restricted binding site in this re-
gion of the receptor. Substitution with heteroaryl rings
(9h and 12) reduced binding affinity suggesting perhaps
hydrophobic interactions are more important in this re-
gion of the receptor.
Substitution at the 40 position (Table 3) provided com-
pounds with mixed results as compounds 16a and 16b
were substantially less active. However substitution with
a methoxy group at the 200 position provided compound
16c with moderate affinity. Substitution with the 2-pyr-
idyl group 18 improved the affinity, however substitu-
tion with another heteroaromatic ring, thiophene (16d)
reduced mGluR5 binding affinity. These data further
emphasize the sensitivity of the mGluR5 binding site
to substitutions on the dipyridyl amide template.
Several of the active compounds were evaluated in a
functional assay measuring phosphoinositide hydrolysis
at mGluR5 in CHO cells (Table 4).15 All compounds
showed an antagonist profile like the alkyne based com-
pounds 1 and 2 with favorable lipophilic character for
CNS penetration and activity, as calculated by ClogP.
In order to visualize the tolerated and restricted substi-
tutions on the aryl ring ‘b’ in the present series of com-
pounds, a comparison of the van der waals volume
(vdw) of active and inactive compounds was carried
out (Fig. 4). Inactive compounds 9c and 9g have bulky
substituents that perhaps overlap in the non-tolerated
space (depicted as blue contour), thus reducing their
potency.
As observed previously, the diaryl amides showed loss in
potency in the functional assay as compared to their
binding affinities at mGluR5.8 In the present series of

S. S. Kulkarni, A. H. Newman / Bioorg. Med. Chem. Lett. 17 (2007) 2074–2079
2077
Table 1. Representative structures and in vitro activities of com-
pounds 6
Table 2. Representative structures and in vitro activities of com-
pounds with substitution at the 30 position of the aryl ring ‘b’
O
O
R2
H3C
N
N
H
R1
H3C
N
N
H
N
Compound
R1
mGluR5 binding affinity
Ki SEM (lM)
Compound
R2
mGluR5 binding affinity
Ki SEM (lM)
Cl
3
1.73 0.10a
0.33 0.02a
>10
9a
9b
9c
0.32 0.09
0.50 0.10
13%a
CN
F
CN
4
OCH3
H3C
N
6a
6b
6c
6d
6e
6f
6g
6h
6i
9d
9e
9f
91%a
OCH3
F
H3C
N
3.07 0.96
N
0.043 0.01
0.25 0.05
F
H3C
8%b
N
H
N
<1%b
9g
32%a
S
N
9h
<1%a
11%b
S
12
2.48 1.15
0.021 0.001
N
40%b
O
N
MPEP, 1
—
a Percent inhibition at 10 lM.
S
<1%b
heterobiaryl amides, there was a similar loss in function-
al potency. This could be due to differences in the assay
conditions. Also such differences in the activity have
been observed in various other chemical classes of
mGluR5 allosteric modulators.16,17 Conversely, such
differences could also suggest different interactions at
the protein level and these binding differences will be
further explored with future SAR studies.
Cl
28%b
N
0.44 0.13
N
In summary, a series of heterobiaryl amides were synthe-
sized using palladium catalyzed cross-coupling reac-
tions. Novel mGluR5 antagonists with comparable or
improved binding affinities over previously described 3
and 4 were discovered. Further SAR for the mGluR5
were deduced based on these and previously reported
ligands. In addition, during the course of this work
6j
62.76 1.74a
a IC50 (lM) from Ref. 8.
b Percent inhibition at 10 lM.

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S. S. Kulkarni, A. H. Newman / Bioorg. Med. Chem. Lett. 17 (2007) 2074–2079
Table 3. Representative structures and in vitro activities of com-
pounds with 40 substitution in the aryl ring ‘b’
Bonnefous et al. reported the identification of a series of
pyridyl amides and described similar SAR wherein the
importance of intramolecular hydrogen bonding be-
tween two aromatic rings to improve the binding affinity
at mGluR5 was described.11 The SAR of these com-
pounds will be utilized for the future design of potent
and selective mGluR5 antagonists.
O
H3C
N
N
H
N
R3
Compound
16a
R3
mGluR5 binding affinity
Ki SEM (lM)
Acknowledgments
2.80 0.90
7.4%a
SSK was supported by a NIH-visiting fellowship, all
binding and functional data were provided by the
National Institute on Mental Health-Psychoactive Drug
Screening Program (PDSP) with special thanks to Dr.
Bryan Roth for his support. Also, the authors wish to
acknowledge Ms. Estela Lopez for her help with the
PDSP database. This work is supported by the NIDA-
IRP, NIH.
CN
16b
OCH3
16c
16d
18
0.56 0.08
Supplementary data
S
N
40%
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2006.12.083.
0.10 0.03
References and notes
a Percent inhibition at 10 lM.
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Figure 4. Comparison of vdw volumes for 30 substituted compounds
(Sybyl 7.2.3, Tripos Inc.).
Table 4. Functional activity at mGluR5
Compound
Functional activity IC50 SEM (lM)
ClogPa
3
66% at 10 lM
5.33 1.20
7.30 0.74
0.16 0.03
12.40 1.01
0.04 0.01b
0.46 0.11b
3.26
2.08
2.99
3.84
2.35
3.78
2.13
4
9a
9e
18
MPEP, 1
MTEP, 2
a Calculated by Sybyl 7.2.3 from Tripos Inc.
b From Ref. 10b.

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14. All compounds were purified by flash chromatography
and characterized by spectroscopic and microanalytical
techniques. The final products were crystallized as the HBr
salts for biological evaluation. The spectral data supported
the assigned structures, for example, 4-(3,5-difluorophe-
nyl)-N-(6-methylpyridin-2-yl)picolinamide hydrobromide,
9e yield 0.11 g, 55%, mp 260–264 °C; 1H NMR (400 MHz,
CDCl3) d .53 (s, 3H), 6.91–6.96 (m, 1H), 6.95–6.97 (d,
J = 7.6 Hz, 1H), 7.22–7.28 (m, 2H), 7.64–7.66 (dd, J = 2.0,
3.2 Hz, 1H), 7.66–7.69 (t, J = 7.2 Hz, 1H), 8.23–8.25 (d,
J = 8.4 Hz, 1H), 8.47–8.48 (dd, J = 0.8, 1.2 Hz, 1H), 8.70–
8.72 (d, J = 5.2 Hz, 1H), 10.49 (br s, 1H); 13C NMR
(101 MHz, CDCl3) d 24.19, 104.62, 104.87, 105.13, 110.13,
110.19, 110.31, 110.38, 110.82, 119.53, 120.14, 124.14,
138.62, 140.66, 147.77, 149.01, 150.35, 150.42, 157.28,
162.17, 162.25, 162.38, 164.73, 164.86; IR (Neat, cmꢁ1
)
3435.7, 1694.7, 1598.4, 1532.9, 1457.2; GC-MS (EI) m/z
325 (M+); Anal. (C18H13F2N3OÆHBrÆ1.5H2O) C, H, N.
The experimental and spectral data for all other com-
pounds are reported in the Supplementary information.
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