Structure-activity relationships for the linker in a series of pyridinyl-alkynes that are antagonists of the metabotropic glutamate receptor 5 (mGluR5)

Article abstract of DOI:10.1016/j.bmcl.2006.06.078

Studies of structure-activity relationships for the linker in a new series of metabotropic glutamate receptor 5 antagonists are presented together with in vitro and in vivo pharmacokinetic data.

Full text of DOI:10.1016/j.bmcl.2006.06.078

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4788–4791
Structure–activity relationships for the linker in a series
of pyridinyl-alkynes that are antagonists of the
metabotropic glutamate receptor 5 (mGluR5)
Peter Bach,a,* Karolina Nilsson,a Tor Svensson,a Udo Bauer,a Lance G. Hammerland,b
b
a
a
a
¨
˚
Alecia Peterson, Andreas Wallberg, Krister Osterlund, David Karis,
Maria Boijea and David Wensboc
aDepartment of Medicinal Chemistry, AstraZeneca R&D Mo¨lndal, Pepparedsleden 1, S-431 83 Mo¨lndal, Sweden
bNPS Pharmaceuticals, 383 Colorow Drive, Salt Lake City, UT 84108, USA
cDepartment of Medicinal Chemistry, Local Discovery CNS and Pain Control, AstraZeneca R&D So¨derta¨lje,
S-151 85 So¨derta¨lje, Sweden
Received 25 April 2006; revised 21 June 2006; accepted 24 June 2006
Available online 11 July 2006
Abstract—Studies of structure–activity relationships for the linker in a new series of metabotropic glutamate receptor 5 antagonists
are presented together with in vitro and in vivo pharmacokinetic data.
Ó 2006 Elsevier Ltd. All rights reserved.
We recently disclosed1 that a number of compounds
having the common structure 1 (Fig. 1) showed good
to excellent affinity towards the cloned human metabo-
tropic glutamate receptor 5 (mGluR5).
N
O
R
1
Figure 1.
The aim of the present study was to examine the SAR
around the linker (L) with optional variation of the aryl
B ring under the restriction that the 6-methyl-pyridine
ring (A) and the triple bond are retained (Fig. 2). X
could be, for example, CH2, S, O, or NH (optionally
substituted), while R0 could be alkyl branches or part
of a bicycle with the B ring.
N
X
R
A
R'
L
B
Figure 2.
All compounds were screened in a FLIPR assay and
IC50 values of potent (IC50 < 10,000 nM) compounds
were determined as means of triplicate measurements.2
3. The mesylate 3 was then reacted with a number of
phenols, thiophenols, and anilines by route c to form a
series of compounds 4. Compound 31 was made like
compound 21 in 34% yield, 19 like 22 in 38% yield.
The synthesis of 20 is previously described.1 A different
route had to be employed in those cases where an appro-
priately branched alcohol for step a (e.g., R0 = i-Pr) was
not commercially available. Thus, 2 was reacted with
TMS-alkyne and the product 5 was desilylated with base
to give terminal alkyne 6. Reaction of 6 with an alde-
hyde gave 7 which after mesylation was reacted in situ
with thiophenols to give 8. Low yields for the f–g
To synthesize analogues with X being O, S, or NH and
R0 being H or small alkyl, the procedures described in
Scheme 1 were employed. Thus, Sonogashira cross-cou-
pling3 of 2-bromo-6-methyl-pyridine 2 with a propargy-
lic alcohol by route a4 with subsequent mesylation gave
Keywords: mGluR5 antagonists; Pyridinyl-alkynes; SAR; Gastro-eso-
phageal reflux disease (GERD).
*
Corresponding author. Tel.: +46 31 70 64 795; fax +46 31 63 798;
e-mail: Peter.Bach@astrazeneca.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.06.078

P. Bach et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4788–4791
4789
d
e
a+b
N
N
Br
N
O
56%
97%
N
O
S
Si
6
3
O
2
R'
5
f
c
R'=H, Me
17%
h
N
N
X
OH
R'
R
4
R'
N
7
X=O, S, NH
X=S, R=o-Cl
R'=Et, i-Pr
g
35
X=S; R=R'=H
63%
i
O
S
N
N
S
Cl
R'
24
8
Scheme 1. Reagents and conditions: (a) HC„CCH(R0)OH, (PPh3)2PdCl2, CuI, NEt3, 60 °C, 3.5–4 h (R0 = H: 56%; R0 = Me: 67%); (b) MsCl, NEt3,
DCM, ꢀ20 °C, 1 h (R0 = H or R0 = Me: quant.); (c) compound 21: R = o-Cl, R0 = H, X = S: Ar-SH, NEt3, DCM, rt, 24 h (44%); compound 22:
R = R0 = H, X = NH: ArNH2, NEt3, rt, 1.5 h (40%); compound 23: R = R0 = H, X = S: Ar-SH, NEt3, THF, rt, 1 h (39%); compound 25:
R = R0 = H, X = N–Me: ArNHMe, K2CO3, DMF, 70 °C, 3 days (38%); compound 29: R = o-Cl, R0 = Me, X = NH: ArNH2, LiN(SiCH3)2, THF,
0 °C, 20 min, then rt, 20 h (14%); compound 30: R = o-Cl, R0 = Me, X = O: ArOH, NaH, THF, 0 °C, 20 min, then rt, 24 h (46%); (d)
HC„C(Si(CH3)3), (PPh3)2PdCl2, CuI, NEt3, 60 °C, 2 h then rt, 16 h; (e) K2CO3, DCM/MeOH, rt, 2 h; (f) compound 33: R = o-Cl, R0 = i-Pr, X = S:
LiN(Si(CH3)3)2, 2-methylpropanal, THF, ꢀ78 °C to rt, elute through SCX column, concentrate and continue in (g) MsCl, NEt3, DCM, rt, 3 h,
concentrate, then add Ar-SH, NEt3, DCM, rt, 16 h (4%); (h) Br(CH2)3Ph, (n-Bu)4NF2SiPh3, 60 °C, 24 h; (i) R = R0 = H, X = S: m-CPBA, 1.4 equiv,
DCM, ꢀ50 to 0 °C over 1.5 h.
sequence was ascribed to instability of the mesylate. The
chain-elongated product 35 was obtained from 5, how-
ever in low yield, by using a fluorosilicate.5 Sulfoxide
24 was made by simple oxidation.
acid chloride or an isocyanate to give amide 27 and urea
28, respectively.
Development of structure–activity relationships for the
linker was done with compounds having 6-methyl-pyri-
dine as the A ring and with phenyl or m-chlorophenyl as
the B ring (see Table 1). A clear trend in the SAR of the
linker was the increase in affinity in the series
N < O < S < C (18–21 and 29–31). Compounds from
each of these series were tested against mGluR1, which
has the highest sequence homology to mGluR5 among
the mGluRs, and found to be inactive. Further, com-
pounds 18 and 34 were tested against the mGluRs 3,
4, and 8 and found to be inactive. Interestingly, com-
pound 20 when lacking the Cl-substituent showed no
activity in our assay towards mGluR5;1 nothing similar
was observed for the analogous compounds with N, S,
or C in the linker (compare pairs 19/22, 21/23, and
18/34). In the N-series, N-methylation dramatically de-
creased potency (25) while amides and ureas were either
of low or no potency (26–28). Branching with a methyl
at the a-C somewhat reduced potency (29–31); however,
compounds 29–31 were racemates. By further branching
with ethyl or iso-propyl (32 and 33) the potency clearly
decreased. Branching at the b-C with a methyl group
was allowed (36). Further chain elongation or incorpo-
Alkyne 12 to be used for Sonogashira coupling was not
commercially available and was synthesized from the
corresponding aldehyde 11 by the Corey–Fuchs meth-
od6 followed by elimination and hydro-dehalogenation
(Scheme 2).7 Branched compound 36 (Table 1) was
made by the same method, starting with 3-phenyl-butyr-
aldehyde. Aldehyde 11 was obtained by coupling of the
iodobenzene 9 with allyl alcohol 10.8 Compound 34 was
made by Sonogashira coupling from commercial start-
ing materials in 69% yield, according to procedure d in
Scheme 2.
The 2,2-dibromoalkene 15 (Scheme 3) was prepared by
the Corey–Fuchs method from aldehyde 14 and subse-
quently converted into terminal lithium alkyne that
was reacted in situ with phenyl isocyanate to give amide
26. Alternatively, 15 was converted into the 1-bromo al-
kyne16 which was used for a Suzuki coupling to obtain
the heterocyclic 37. To obtain chain-elongated amides
and ureas, the mesylate 3 was reacted with ammonia
to give amine 17 which could be easily reacted with an
OH
d
Cl
I
a
Cl
Cl
c
b
O
+
59%
N
34%
87%
96%
Cl
crude
9
10
11
12
13
Scheme 2. Reagents and conditions: (a) Pd(OAc)2, (n-Bu)4NCl, NaHCO3, DMF, rt, 16 h, then 50 °C, 16 h; (b) CBr4, PPh3, Zn, DCM, rt, 14 h;
(c) LiN(Si(CH3)3)2, 1.5 equiv, THF, ꢀ78 °C, 0.5 h, then n-BuLi, 2.5 equiv, ꢀ78 °C, 1 h, then rt, 1 h, then quench with H2O; (d) 2, (PPh3)2PdCl2,
CuI, NEt3, 60 °C, 12 h.

4790
P. Bach et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4788–4791
Table 1. Variations of the linker (L) and aryl group B
A
N
L
B
R
Compound
L-B
IC50 (nM)
5
SEM
1.1
Cl
18
H
N
Cl
Cl
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
174
100a
43
6
O
S
0.6
5.2
Cl
H
N
223
17
S
589
195
O
S
>10,000
6728
>10,000
2614
>10,000
709
—
N
1391
—
193
—
28
3
H
N
O
H
N
Cl
O
O
H
N
H
N
Cl
H
N
Cl
(rac)
O
S
S
S
Cl
(rac)
281
Cl
118
7
(rac)
Cl
(rac)
862
18
25
Cl
(rac)
461
78
6.6
258
142
59
10.8
(rac)
306
40
S
The alkyne is connected to the 6-methyl-pyridine.
a Value from Ref. 1, included for comparison.

P. Bach et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4788–4791
4791
a
known mGluR5-selective antagonists 2-methyl-6-(phen-
yl-ethynyl) pyridine (MPEP) in dog (N = 3) at dose
8.7 lmol/kg (iv) reduced the TLESRs with 59%
(SEM = 11).9
b
Br
Br
O
H
N
N
N
39%
8%
N
26
14
O
15
c
In conclusion, structure–activity relationships around
the linker in a series of pyridinyl-alkynes as mGluR5
antagonists have been presented together with dem-
onstration of in vivo effect of one selected
compound.
d
N
N
33%
(2 steps)
Br
37
S
16
e
N
NH2
N
Acknowledgment
99%
O
O
O
S
17
3
f
Assistance from the 96296 parallel purification group at
R&D,
g
82%
91%
AstraZeneca
acknowledged.
Mo¨lndal,
is
gratefully
H
H
N
H
N
N
N
Cl
N
Cl
27
28
O
O
References and notes
Scheme 3. Reagents and conditions: (a) CBr4, PPh3, 0 °C, 0.5 h; (b)
LiN(Si(CH3)3)2, THF, ꢀ78 °C, 10 min, then add BuLi, ꢀ78 °C, 1.5 h,
then add PhNCO, ꢀ78 °C, 2 h, then ꢀ10 °C, 1.5 h; (c) LiN(Si(CH3)3)2,
1.1 equiv, THF, ꢀ78 °C, 1 h; continue in (d) 1-benzothien-2-ylboronic
acid, Pd(PPh3)4, Na2CO3, rt, 3 days, then 110 °C, 3 h; (e) excess NH3
(conc, aq), rt, 5 min; (f) m-Cl-Ph–COCl, NEt3, DCM, 16 h, rt; (g)
m-Cl-Ph–NCO, DCM, 2 h, rt.
˚
1. Bach, P.; Nilsson, K.; Wallberg, A.; Bauer, U.; Hammer-
land, L. G.; Peterson, A.; Svensson, T.; Osterlund, K.;
¨
Karis, D; Boije, M.; Wensbo, D. ‘A New Series of
Pyridinyl-alkynes as Antagonists of the Metabotropic
Glutamate
Receptor
5
(mGluR5)’,
doi:10.1016/
j.bmcl.2006.06.079.
2. Effect of the compounds on glutamate induced [Ca2+] in a
cell line expressing human mGluR5d using a fluorescence
imaging plate reader (FLIPR). For details, see: Bach, P.;
ration of a bicycle resulted in some loss of potency
(35 and 37).
˚
Bauer, U.; Nilsson, K.; Wallberg, A. PTC application
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TLESRs with 31% (SEM = 13).2 As a comparison, the
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