SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide

Article abstract of DOI:10.1016/j.bmcl.2004.04.017

The major excitatory neurotransmitter in the Central Nervous System is L-glutamic acid. As a result much attention has been given to the discovery of selective modulators of both the ionotropic glutamate receptors (iGluRs) and the metabotropic glutamate receptors (mGluRs). In this study we describe a novel class of subtype selective allosteric potentiators of the mGlu2 receptor. An active compound N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide, LY181837, was identified in the course of compound screening. The synthesis of two series of analogs examined the structural requirements of the diaryl region of this compound. This SAR study also resulted in compounds with an increase in potency of over 100-fold where the most potent compound reported has EC ₅₀=14nM.

Full text of DOI:10.1016/j.bmcl.2004.04.017

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3099–3102
SAR study of a subtype selective allosteric potentiator
of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-
N-(3-pyridinylmethyl)ethanesulfonamide
David A. Barda,* Zhao-Qing Wang, Thomas C. Britton, Steven S. Henry,
G. Erik Jagdmann, Darrell S. Coleman, Michael P. Johnson, Sherri L. Andis
and Darryle D. Schoepp
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN 46285, USA
Received 30 October 2003; revised 7 April 2004; accepted 10 April 2004
Abstract—The major excitatory neurotransmitter in the Central Nervous System is L-glutamic acid. As a result much attention has
been given to the discovery of selective modulators of both the ionotropic glutamate receptors (iGluRs) and the metabotropic
glutamate receptors (mGluRs). In this study we describe a novel class of subtype selective allosteric potentiators of the mGlu2
receptor. An active compound N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide, LY181837, was identified in the
course of compound screening. The synthesis of two series of analogs examined the structural requirements of the diaryl region of
this compound. This SAR study also resulted in compounds with an increase in potency of over 100-fold where the most potent
compound reported has EC50 ¼ 14 nM.
Ó 2004 Elsevier Ltd. All rights reserved.
L
-Glutamic acid is the primary excitatory neurotrans-
lular glutamate binding domain and displace other
glutamate-site ligands, which include the group II-
selective antagonist LY341495 (3) (Fig. 1).3 These
compounds have shown efficacy in a number of behav-
ioral models, for example behavioral models of anxiety.2
While these compounds are selective for group II
mGluRs, agonists selective for mGlu2 have not been
identified. As a result, the physiological role and thera-
peutic potential of selective modulation of individual
mitter in the brain. Glutamate acts via two main classes
of receptors known as ionotropic, a series of ligand
gated ion channels (iGluRs), and metabotropic
(mGluRs).1 The eight known subtypes of mGluRs be-
long to the type III superfamily of G-protein coupled
receptors by virtue of their structural homology to other
members of this class including the calcium sensing
receptors, GABAB receptors, and phermone receptors.
The subtypes can be further classified into three groups
as a result of their sequence homology and function. The
group II mGluRs, which consist of the mGlu2 and
mGlu3 subtypes, have been shown to be negatively
coupled to adenylate cyclase via activation of Gai-
protein.
O
HO2C
HO2C
H
CO2H
NH2
H
CO2H
NH2
2, LY379268
1, LY354740
Efforts from these laboratories and others toward
effecting the direct modulation of group II metabotropic
glutamate receptors has resulted in a number of group II
selective agonists.1;2 These direct acting agonists (e.g.
LY354740, 1 and LY379268, 2)2 bind to the extracel-
O
O
N
O S O
N
HO2C
Me
4, LY181837
mGlu2 EC50 = 1.5 µM
H2N
CO2H
3, LY341495
Keywords: Glutamate; Allosteric potentiators; mGlu2 Receptor.
* Corresponding author. Tel.: +1-3174332382; fax: +1-3176516509;
e-mail: barda@lilly.com
Figure 1. Metabotropic glutamate receptor compounds.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.017

3100
D. A. Barda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3099–3102
receptor subtypes in this class is essentially unknown.
Binding allosteric to the glutamate binding site allows
for the possibility of more differentiated binding sites
for the different subtypes and as a result, the potential
for subtype selectivity. Positive allosteric modulators
or potentiators of related receptor systems have
been recently described.4 Previous communications
describe the discovery of a series of mGlu2 selective
potentiators5 and aspects of their in vitro and in vivo
activities.5;6
CO2Me
CO2Me
a,b
c
N
H2N
SO2Et
N
5a
6a
R
N
7a, R = CH2OH
8a, R = CHO
d
SO2Et
N
A functional assay was designed to identify subtype
selective modulators of mGluRs. The assay which links
receptor activation to a fluorescent response via a G-
protein mediated intracellular calcium release, has been
previously described in detail.5 Lilly compound files
were screened against this assay in a high-throughput
format. This effort led to the identification of LY181837,
4, a selective potentiator at mGlu2 having an EC50 of
1.5 lM.5;7 The EC50 in this case, and as it is used to
characterize and compare the allosteric potentiators
presented herein, is the concentration of the potentiator
required to achieve 50% of the maximal glutamate re-
sponse in the functional assay in the presence of a sub-
maximal glutamate concentration of 1 lM.
OH
e
f
8a
N
SO2Et
N
9a
O
R
g
N
N
SO2Et
SO2Et
N
N
10a
11a, R = CH2
12a, R = H, CH3
h
R
In this report we describe studies to develop the struc-
ture–activity relationship surrounding 4 and its activity
at mGlu2. These results provide an understanding of the
structural requirements surrounding the diaryl ether
region of 4. One question we set out to answer was
whether we could replace the diaryl ether linkage with
other groups. We prepared both the meta and para
isomers to determine, which regioisomeric substitution
pattern was preferred on the central aniline. In a second
series we also examined the possibility of aryl alkyl
ethers in that region.
h or i
9a
N
SO2Et
13a, R =H
14a, R =F
N
OPh
j
7a
N
SO2Et
N
15a
Scheme 1. Reagents and conditions: (a) 3-pyridine carboxaldehyde,
MeOH, NaBH4, (b) EtSO2Cl, pyridine, (c) DIBAL, THF, (d) DMSO,
Cl2(CO)2, NEt3, (e) PhMgCl, THF, (f) MnO2, CH2Cl2, (g)
CH2@PPh3, (h) TFA, Et3SiH, (i) DAST, CH2Cl2, (j) DEAD, Ph3P,
PhOH, THF.
A series of 4-substituted anilines was prepared as shown
in Scheme 1.8 Methyl 4-aminobenzoate underwent
reductive amination with 3-pyridine carboxaldehyde.
The product of this reaction was subjected to ethane-
sulfonyl chloride and pyridine to give 6a. DIBAL
reduction of 6a to the alcohol followed by Swern oxi-
dation resulted in aldehyde 8a. This intermediate was
treated with PhMgCl in THF to give 9a. The benzylic
alcohol 9a gave rise to 10a, 11a, and 12a through a
sequence of oxidation (MnO2), olefination (CH2@PPh3),
and reduction (TFA/triethylsilane). As a route to two
other derivatives, 9a could be converted to 13a or 14a by
treatment with TFA/triethysilane or DAST, respec-
tively. Starting from intermediate 7a, we were also able
to obtain the benzyl, phenyl ether, 15a using Mitsunobu
conditions.
A complementary set of compounds was prepared
starting from methyl 3-aminobenzoate.8 Similar chem-
istry as shown in Scheme 1 was used to prepare 9b–15b.
The 3-substituted aniline series was more potent in every
case. Analogs 10b, 11b, and 13b were several times more
potent than 10a, 11a, and 13a. Examples 9b, 12b, and
15b were 10–20 times more active than their counter-
parts, 9a, 12a, and 15a. And in the most dramatic case,
14b was more than 150 times more potent than 14a. The
most potent compound in this series 12b with and EC50
value of 72 nM was about 20 times more potent that 4
itself. The general trend was that substitution 1,3 to the
aniline nitrogen on the central ring gave more potent
potentiation of mGlu2 than the corresponding 1,4
regioisomers.
EC50 determinations on these compounds indicated that
the ether linkage could be replaced in some cases with a
carbon or with a substituted carbon without a signifi-
cant loss in activity (10a–13a) (Table 1). In a couple of
cases substitution on the benzylic position was not well
tolerated (9a and 14a). In the case of 15a, lengthening
the linker by the insertion of a methylene into the chain
was also tolerated.
Another series of active compounds was identified by
modifying the diaryl ether in 4 to give aryl alkyl ethers.8
These studies focused on the 3-substituted aniline iso-

D. A. Barda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3099–3102
Table 1. EC50 values for mGluR2 potentiation of selected compounds
3101
R1
R2
N
S
O
O
Me
R2
N
Compound
R1
mGluR2 Potentiator EC50 (nM)
4
9a
OPh
CH(OH)Ph
C(O)Ph
H
H
H
H
H
H
H
H
1500
>30,000
4200
780
10a
11a
12a
13a
14a
15a
9b
C(@CH2)Ph
CH(CH3)Ph
1400
1600
>30,000
2100
2500
1100
200
CH2Ph
CH(F)Ph
CH2OPh
H
H
H
H
H
H
H
CH(OH)Ph
C(O)Ph
10b
11b
12b
13b
14b
15b
C(@CH2)Ph
CH(CH3)Ph
CH2Ph
72
310
CH(F)Ph
CH2OPh
180
160
As would have been expected from our results in the
carbon-linker series, the 1,3 phenyl ether, 18a, was
about 4-fold more potent than the 1,4 regioisomer, 4
(Table 2). In two cases both the ethane-sulfonamide and
the 2,2,2-trifluoroethanesulfonamide were prepared.
The differences in activity between the two different
sulfonamides ranged from little difference in the case of
the benzyl ether (compare 18b with 18c) to a 11-fold
difference favoring the 2,2,2-trifluoroethyl sulfonamide
in the case of the trifluoromethoxy ethers (compare 18d
with 18e). Due to the tendency for the trifluoroethyl
sulfonamides to be more potent, we prepared those
sulfonamides throughout the remainder of this series.
The ethers prepared showed a few key trends. Small
alkyl groups like Me resulted in a significant loss in
activity (18f). Fluorinated alkyl ethers trifluoromethyl
and 2,2,2-trifluoroethyl showed good potency (18d and
18g). Interestingly, a- and b-branched alkyl ethers such
as isopropyl, isobutyl, 2-butyl, 2-pentyl, 3-pentyl, and 2-
methyl pentyl were found to be especially potent
potentiators (18g–m). The cyclic alkyl ethers 18n–p also
showed a similarly high level of activity. The glycolate
ester ethers 18q–s provided another illustration of the
correlation between more branching and greater
potency. Synthesis of the alkyl aryl ethers resulted in the
branched alkyl ethers, e.g. 18l (EC50 ¼ 16 nM), the most
potent mGlu2 potentiators reported to date.
a
N
H
OR1
H2N
OR1
N
16
17
b
N
O S O
OR1
N
R2
18
a,b
N
OH
H2N
OH
O S O
N
19
R2
20
c
18
Scheme 2. Reagents and conditions: (a) 3-pyridine carboxaldehyde,
NaBH4, (b) R2CH2SO2Cl pyridine, (c) NaH, R1Br.
mers since they were found to be more potent in the
previously described carbon-linker series. The chemistry
of this series (Scheme 2) consisted of two short routes.
First, reductive amination of commercially available
ether anilines 16 with pyridine 3-carboxaldehyde fol-
lowed by sulfonylation with either ethanesulfonyl chlo-
ride or 2,2,2-trifluoroethanesulfonyl chloride provided
access to compounds 18a, and 18d–h. A second route
involved reductive amination of 3-aminophenol with
3-pyridine carboxaldehyde followed again by sulfonyl-
ation to give phenol 20. This intermediate was alkylated
with alkyl bromides to give the corresponding ethers
18b, c, and 18i–t.
These compounds were also tested for their ability to act
as agonists in the absence of glutamate. In most cases,
including the most potent potentiators described, e.g.
18k or 18l, the compounds showed less than 5% of the
maximal glutamate response at 50 lM concentrations of
compound. In select cases (12b, 14b, and 15b) we ob-
served partial agonist-like behavior but only at much
higher concentrations than what was required for
potentiator activity. In the most potent case, 14b gen-
erated 50% of the maximal glutamate response at
2.5 lM but gave only a 73% maximal response at 50 lM.

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D. A. Barda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3099–3102
Table 2. EC50 values for mGluR2 potentiation of compounds 18a–t
Annu. Rep. Med. Chem. 1997, 32, 1; (b) Schoepp, D. D.;
Jane, D. E.; Monn, J. A. Neuropharmacology 1999, 38,
1431.
OR1
2. (a) Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright, R. A.;
Salhoff, C. R.; Johnson, B. G.; Howe, T.; Alt, C. A.;
Rhodes, G. A.; Robey, R. L.; Griffey, K. R.; Tizzano, J. P.;
Kallman, M. J.; Helton, D. R.; Schoepp, D. D. J. Med.
Chem. 1997, 40, 528; (b) Monn, J. A.; Valli, M. J.; Massey,
S. M.; Hansen, M. M.; Kress, T. K.; Wepsiec, J. P.;
Harkness, A. R.; Grutsch, J. L.; Wright, R. A.; Johnson, B.
G.; Andis, S. L.; Kingston, A. E.; Tomlinson, R.; Lewis, R.;
Griffey, K. R.; Tizzano, J. P.; Schoepp, D. D. J. Med.
Chem. 1999, 42, 1027; (c) Schoepp, D. D.; Wright, R. A.;
Levine, L. R.; Gaydos, B.; Potter, W. Z. Stress 2003, 6, 189.
3. Kingston, A. E.; Ornstein, P. L.; Wright, R. A.; Johnson, B.
G.; Mayne, N. G.; Burnett, J. P.; Belagaje, R.; Wu, S.;
Schoepp, D. D. Neuropharmacology 1998, 37, 1.
4. (a) Knoflach, F.; Mutel, V.; Jolidon, S.; Kew, J. N. C.;
Malherbe, P.; Vieira, E.; Wichmann, J.; Kemp, J. A. Proc.
Natl. Acad. Sci. U.S.A. 2001, 98, 13402; (b) Urwyler, S.;
Mosbacher, M.; Lingenhoel, K.; Heid, J.; Froestl, W.;
Bettler, B.; Kaupmann, K. Mol. Pharm. 2001, 60, 963; (c)
Gasparini, F.; Kuhn, R.; Pin, J.-P. Curr. Opin. Pharmacol.
2002, 2, 43.
5. (a) Johnson, M. P.; Baez, M.; Jagdmann, G. E., Jr.; Britton,
T. C.; Large, T. H.; Callagaro, D. O.; Tizzano, J. P.; Monn,
J. A.; Schoepp, D. D. J. Med. Chem. 2003, 46, 3189; (b)
Britton, T.; Barda, D.; Hornback, W.; Jagdmann, G. E.;
Henry, S.; Fichtner, M.; Wang, Z.-Q.; Coleman, D.;
Chenoweth, D.; Vaught, G.; Fivush, A.; Dressman, B.;
White, R.; Milot, G.; Herr, R. J.; Burry, L.; Johnson, M.
P.; Large, T.; Monn, J.; Schoepp, D. Neuropharmacology
2002, 43, 279.
N
S
O
O
N
R2
Compound
R1
R2
mGluR2
Potentiator
EC50 (nM)
18a
18b
18c
18d
18e
18f
18g
18h
18i
Ph
Bn
CH3
360
620
440
140
1600
2100
100
32
CF3
CH3
CF3
CH3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Bn
CF3
CF3
CH3
CH2CF3
CH(CH3)2
CH2CH(CH3)2
27
18
18j
CH(CH3)CH2CH3
CH(CH3)CH2CH2CH3
CH(CH2CH3)2
18k
18l
14
16
18m
18n
18o
18p
18q
18r
18s
CH2CH(CH3)CH2CH3
CH(CH2)3
CH(CH2)4
17
36
24
29
CH(CH2)5
CH2CO2CH2CH3
CH(CH3)CO2CH2CH3
C(CH3)2CO2CH2CH3
640
230
88
Limited pharmacokinetic data is available on the com-
pounds in these series, although they tended to show
relatively low plasma exposure, after oral dosing. For
example after 14b and 18d were administered at 20 mg/
kg p.o. in rats, only low concentrations of compound
were detected in plasma (Cmax ¼ 61 and 100 ng/mL,
respectively).
6. (a) Johnson, K.; Dieckman, D.; Britton, T.; Johnson, M.;
Jagdmann, E.; Monn, J.; Barda, D.; Henry, S.; Chenoweth,
D.; Coleman, D.; Schoepp, D. Neuropharmacology 2002,
43, 291; (b) Johnson, M.; Baez, M.; Britton, T.; Jagdmann,
G. E., Jr.; Johnson, K.; Johnson, B.; Hornback, W.; Large,
T.; Nisenbaum, E.; Tizzano, J.; Monn, J.; Schoepp, D.
Neuropharmacology 2002, 43, 291; (c) Schaffhauser, H.;
Rowe, B. A.; Morales, S.; Chavez-Noriega, L. E.; Yin, R.;
Jachec, C.; Rao, S. P.; Bain, G.; Pinkerton, A. B.; Vernier,
J.-M.; Bristow, L. J.; Varney, M. A.; Daggett, L. P. Mol.
Pharmacol. 2003, 64, 798; (d) Lorrain, D. S.; Schaffhauser,
H.; Campbell, U. C.; Baccei, C. S.; Correa, L. D.; Rowe, B.;
Rodriguez, D. E.; Anderson, J. J.; Varney, M. A.; Pinker-
ton, A. B.; Vernier, J.-M.; Bristow, L. J. Neuropsychophar-
macology 2003, 28, 1622.
7. As an example of the subtype selectivity of these com-
pounds, LY181837 showed no potentiation at the mGlu
subtypes tested: 1, 3, 4, 5, and 8, up to 12.5 lM. mGluR
subtype selectivity was also monitored for representative
compounds from this series. In none of these cases did we
find activity at any of the other mGlu receptor subtypes at
concentrations up to 12.5 lM.
These studies provided us with an understanding of the
structural requirements for mGlu2 activity in this series
and ultimately with highly potent selective mGlu2
potentiators for further in vitro and in vivo studies.
Acknowledgements
We thank Dr. Karl Dahnke and George E. Novak for
their help with the synthesis of intermediates.
References and notes
8. Each final product and synthetic intermediate described
was fully characterized. All spectral data were consistent
with the assigned structures.
1. For recent reviews on the pharmacology of Metabotropic
Glutamate Receptors see: (a) Monn, J. A.; Schoepp, D. D.