A new series of pyridinyl-alkynes as antagonists of the metabotropic glutamate receptor 5 (mGluR5)

Article abstract of DOI:10.1016/j.bmcl.2006.06.079

Synthesis and some structure-activity relationships for a new series of propargyl ethers as mGluR5 antagonists are reported.

Full text of DOI:10.1016/j.bmcl.2006.06.079

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4792–4795
A new series of pyridinyl-alkynes as antagonists of the
metabotropic glutamate receptor 5 (mGluR5)
a,
a
a
a
*
Peter Bach, Karolina Nilsson, Andreas W a˚ llberg, Udo Bauer,
b
b
a
a
¨
Lance G. Hammerland, Alecia Peterson, Tor Svensson, Krister Osterlund,
a
a
c
David Karis, Maria Boije and David Wensbo
a
Department of Medicinal Chemistry, AstraZeneca R&D M o¨ lndal, Pepparedsleden 1, S-431 83 M o¨ lndal, Sweden
b
NPS Pharmaceuticals, 383 Colorow Drive, Salt Lake City, UT 84108, USA
Department of Medicinal Chemistry, Local Discovery CNS & Pain Control, AstraZeneca R&D S o¨ dert a¨ lje,
S-151 85 S o¨ dert a¨ lje, Sweden
c
Received 24 April 2006; revised 21 June 2006; accepted 24 June 2006
Available online 12 July 2006
Abstract—Synthesis and some structure–activity relationships for a new series of propargyl ethers as mGluR5 antagonists are
reported.
Ó 2006 Elsevier Ltd. All rights reserved.
The metabotropic glutamate receptors (mGluRs) are a
1
family of G-protein coupled receptors. Based on
S
N
O
N
N
sequence homology, the mGluRs have until now been
divided into eight subtypes, comprising 3 groups with
mGluR1 and mGluR5 forming group I. mGluR2 and
mGluR3 are forming group II, while group III includes
mGluR4, mGluR6, mGluR7, and mGluR8. The
sequence homology between the eight mGluRs is high,
O
O
N
F
3, MTEP
1
2, MPEP
Figure 1. HTS-hit 1 and known mGluR5-antagonists MPEP (2) and
MTEP (3).
40–50% between the groups, and more than 60% within
2
a group. For group I the homology is 61%.
selectivity over mGluR1 (IC50 P 10,000 nM, FLIPR).
Compound 1 belonged to a cluster of hits that are struc-
turally related to the two known non-competitive
The group I receptors work by stimulating phospholi-
pase C which raises the intracellular inositol phosphates
2
and Ca levels. Antagonism of mGluR5 has been
+
3
9
4
mGluR5-selective antagonists 2-methyl-6-(phenyl-ethy-
1
related to the treatment of disease states such as pain,
6
0
5
nyl) pyridine (MPEP, 2) and 3-[(2-methyl-1,3-thiazol-
1
depression, and anxiety. Another recently discovered
potential indication for mGluR5 antagonists is gastro-
1
4
potencies toward mGluR5 with IC50s of 2 nM and
-yl)ethynyl]pyridine (MTEP, 3) that showed high
7
esophageal reflux disease (GERD).
1
2
5
nM, respectively. Various analogues of MPEP and
1
3
MTEP have been reported. A series of close analogues
to 1 was synthesized by rather straightforward method-
ologies, as outlined in Scheme 1.
An HTS campaign on the AstraZeneca substance collec-
tion against the cloned human mGluR5 receptor pre-
8
sented the pyridinyl-alkyne 1 (Fig. 1) as a quite
potent ligand (racemate; IC50 = 300 nM, FLIPR) with
1
4
Thus, Sonogashira cross-coupling of 2-bromo-6-
methyl pyridine 4 with propargyl alcohol by route
1
5
a
with subsequent mesylation by route b gave 5.
Keywords: mGluR5 antagonists; Pyridinyl-alkynes; Propargyl ethers;
SAR.
The mesylate 5 was then reacted with a selection of
phenols in a parallel format by route c, forming a ser-
ies of ethers 6. Purification was done by reverse-phase
*
Corresponding author. Tel.: +46 31 70 64 795; fax: +46 31 63 798;
e-mail: Peter.Bach@astrazeneca.com
0
960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.06.079

P. Bach et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4792–4795
4793
a+b
N
Br
N
O
O
O
S
5
4
c
d
e
HO
R
+
Br
N
O
6
R
Scheme 1. Reagents and conditions: (a) HC „ CCH
c) ArOH, K CO
NaH, THF, rt, 18 h (R = p-OMe: 12%); (d) K
2
OH, (PPh
3
)
2
PdCl
2
, CuI, NEt
3
, 60 °C, 3.5–4 h (56%); (b) MsCl, NEt
3
, DCM, À20 °C, 1 h (98%);
(
2
3
, acetone, 60 °C, 5 h (R = p-Cl: 40%) or ArOH, K
CO
2
CO , acetone, 60 °C, 20 h, then DMF, 60 °C, 20 h (R = p-Me: 28%) or ArOH,
3
2
3
, acetone, 60 °C, 17 h (R = H: 78%); (e) (PPh
3
)
2
PdCl
2
, CuI, NEt
3
, 60 °C, 2 h (R = H: 66%).
chromatography with focus on high purity of the
screening compounds rather than on high yields.
Thus, yields for step c varied from 11% to 85% with
yields 25–45% being typical. For scale-up it proved
Table 1. SAR around aryl Ar
1
Ar1
O
O
16
useful first to form a propargyl ether by route d , fol-
lowed by Sonogashira coupling by route e to give the
final ether products 6. Route e was also employed for
reactions with other halogenoheterocycles than 4 in
order to study structure–activity relationships (SAR)
around the binding site of the pyridine ring.
Compound
Ar
1
IC50 (nM)
1540
SEM
559
7
N
8
9
397
7926
78
3593
—
N
N
Development of SAR was made around the two aromatic
ring systems, Ar and Ar (Fig. 2). Synthesized com-
pounds were tested in a FLIPR assay. IC50 values
for active (IC50 < 10,000 nM) compounds were deter-
mined as means of three measurements. MPEP and
MTEP measured in this assay showed activities of
1
2
1
7
10
11
12
13
14
15
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
N
N
22 nM (SEM = 1.9) and 77 nM (SEM = 6.4),
respectively.
—
Initially, variation of the aryl Ar was investigated. A
1
series (compounds 7–12, Table 1) of methyl/methoxy
pyridines illustrated the very tight SAR around the
Ar1 ring. 6-Methylation gave a fourfold increase in
potency, while the 3-, 4-, and 5-monomethyl compounds
were inactive. Likewise, an attempt to introduce alterna-
tive heterocycles (13–15) gave inactive compounds.
Compounds 7 and 8 were also tested in a mGluR1 assay
and found to be inactive (IC50 > 10,000 nM). Having
identified the 6-methyl-pyridinyl group as optimal for
Ar , a SAR investigation was made for the aryl Ar (Ta-
—
O
N
N
—
S
N
—
N
1
2
N
—
ble 2). With the Ar2 ring being phenyl no potency
IC50 > 10,000 nM) was observed (16). A slight increase
(
in potency was observed for compounds having simple
substituents in the o-position (17). Remarkably, potency
was significantly increased by having simple substituents
in the m- and/or p-position (18–25) most pronounced for
lipophilic groups (compare 18–20 with 8 and 22–23)
with basically no dependency on the electron donating/
withdrawing ability of the substituents (compare 8 and
22). Further branching was allowed in the p-position
(21). Compounds with heterocycles (26–29) as the Ar2
group showed at best medium potencies. In vitro meta-
bolic stability of the most potent compound 24 in rat
liver microsomes showed a CLint = 278 lL/min/mg.
Ar1
O
For Ar there are some similarities to the SAR for
1
Ar2
1
3c
MPEP. For example in the series 8–12, the best com-
pound is 8 where the methyl group is in the 6-position like
Figure 2.

4794
P. Bach et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4792–4795
Table 2. SAR around aryl Ar
2
Acknowledgment
Assistance from the 96296 parallel purification group at
AstraZeneca R&D, M o¨ lndal, is gratefully acknow-
ledged.
N
O
Ar2
IC50 (nM)
Compound
Ar
2
SEM
—
16
17
18
19
20
21
22
23
24
25
26
27
28
29
>10,000
>3000
101
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in MPEP. Having methoxy instead of methyl in the 6-po-
sition lowered the activity 80-fold in the case of MPEP
and gave an inactive compound (12) in our series. Com-
pound 9 had low activity in analogy to the corresponding
5-methyl MPEP-isomer being inactive. However, com-
pounds 10 and 11 showed no activity, while the corre-
sponding 4- (respectively 3-) methyl MPEP-isomers still
had good activity. For Ar the SAR is not obviously relat-
ed to that for MPEP.
2
+
1
2. MPEP and MTEP screened by Ca flux assay using
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1
3. See for example: (a) Chua, P. C.; Nagasawa, J. Y.;
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2
In summary, a new series of pyridinyl-alkynes was
revealed to include potent antagonists of the cloned
human metabotropic glutamate receptor 5.

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