Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 3: Identification and biological activity of indanone containing mGlu2 receptor potentiators

Article abstract of DOI:10.1016/j.bmcl.2005.01.077

We have identified and synthesized a series of phenyl-tetrazolyl and 4-thiopyridyl indanones as allosteric potentiators of the metabotropic glutamate receptor 2. Structure activity relationship studies directed toward improving the potency and level of po

Full text of DOI:10.1016/j.bmcl.2005.01.077

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1565–1571
Allosteric potentiators of the metabotropic glutamate receptor
2 (mGlu2). Part 3: Identification and biological activity of
indanone containing mGlu2 receptor potentiators
Anthony B. Pinkerton,* Rowena V. Cube, John H. Hutchinson, Joyce K. James,
´
Michael F. Gardner, Blake A. Rowe, Herve Schaffhauser, Dana E. Rodriguez,
Una C. Campbell, Lorrie P. Daggett and Jean-Michel Vernier
Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA
Received 12 November 2004; revised 27 January 2005; accepted 31 January 2005
Abstract—We have identified and synthesized a series of phenyl-tetrazolyl and 4-thiopyridyl indanones as allosteric potentiators of
the metabotropic glutamate receptor 2. Structure activity relationship studies directed toward improving the potency and level of
potentiation, as well as PK properties, led to the discovery of 28 (EC50 = 186 nM), which displayed activity in a rodent model
for schizophrenia.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
site.12–14 Screening of the Merck sample collection for
allosteric modulators of the mGlu2 receptor identified
phenyl-tetrazolyl indanone 1 (EC50 = 600 nM, 86%
potentiation, with potentiation being defined as the re-
sponse obtained using the test compound up to 10 lM
plus an EC10 of glutamate normalized to the maximal
response obtained with glutamate alone)15 along with
Glutamate is the major excitatory neurotransmitter in
the CNS and plays an important role in many CNS
functions. Glutamate receptors are classified into two
main types, ionotropic (iGlu), which are glutamate med-
iated ion channels, and metabotropic (mGlu), which are
a class of G-protein coupled receptors.1,2 Currently,
mGlu receptors are divided into eight subtypes and three
main groups (I–III). Group II (mGlu2 and -3) mGlu
receptors are mainly concentrated presynaptically and
generally inhibit neurotransmission. Therefore, agents
targeting group II mGlu receptors may have utility in
a variety of CNS disorders3–5 including epilepsy, anxi-
ety, and schizophrenia.6 Recently, nonselective mGlu2/
3 receptor agonists7–9 have shown activity in numerous
animal models as well as human clinical trials.10,11 These
agonists are generally rigid glutamate analogs. However,
compounds selective for mGlu2 over mGlu3 have not
been discovered using this approach. Therefore, another
strategy for selectivity involves the discovery of alloste-
ric modulators that do not bind at the glutamate binding
phenyl-tetrazolyl acetophenone
2
(EC50 = 348 nM,
31% potentiation), which has been disclosed previ-
ously.16,17 Indanone 1 displayed no activity in the ab-
sence of glutamate as well as no activity at mGlu3 in
the presence or absence of glutamate, confirming it
was a selective mGlu2 receptor modulator. Concurrent
to our work on compound 2, we investigated similar ap-
proaches to improve the potency, brain penetration, and
biological activity of compound 1. This paper outlines
the discovery of a brain penetrant, nontetrazole contain-
ing mGlu2 receptor potentiator that shows activity in a
rodent model for schizophrenia after systemic dosing.
2. SAR studies
In order to improve the potency and PK properties of
compound 1, three areas were addressed: (1) the effect
of the linker between the indanone and the aryl tetra-
zole, (2) the effect of groups on the indanone, and (3)
the replacement of the tetrazole. All compounds
Keywords: GPCRs; Glutamate; mGlu receptors; Allosteric;
Schizophrenia.
*
Corresponding author. Tel.: +1 858 202 5379; fax: +1 858 202
5752; e-mail: anthony_pinkerton@merck.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.01.077

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A. B. Pinkerton et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1565–1571
O
OH
Cl
O
Cl
H
N
O
O
O
N
O
N
N
N
1
2
N
HN
N
HN
described herein were synthesized and tested as race-
mates unless otherwise noted. Likewise, all compounds
described herein showed no activity at mGlu3 or other
mGlu receptors.
indicating that there appears to be an aliphatic binding
area. Potency also decreased with a phenyl group (18).
Interestingly when two larger groups, for example, a
butyl group and a cyclopentyl group (19) are present,
activity is 5-fold less indicating a limit to the steric bulk
that can be accommodated at the binding site.
We began with modification of the linker, as indanone 1
displayed poor PK parameters (vide infra) and we felt
that the amide linkage was potentially responsible for
this. Therefore, initial efforts focused on removing the
amide. As shown in Table 1, complete removal of the
amide moiety to give biphenyl compound 3 led to a total
loss of potency. We surmised that there needed to be
some minimal distance between the indanone and the
tetrazole for potency. We then prepared a series of alkyl
tetrazoles (4–6) to address this question. Indeed, the 3
carbon linker 4 displayed poor potency but the 4 and 5
carbon linker gave moderately potent compounds 5
and 6, the former with an EC50 of 589 nM. Reincorpo-
rating the aryl group further increased the potency, as
long as the tetrazole was in the meta- or para-position.
As shown, ortho-substituted 7 was not active, whereas
both the meta- (8) and para- (9) substituted compounds
displayed significantly improved potency compared to
the original amide lead, with the latter being slightly pre-
ferred. Interestingly, construction of an all carbon linked
compound (10), the immediate analog of 9, led to a 5–6-
fold decrease in activity. Because of this we focused only
on compounds with at least one oxygen atom in the lin-
ker. The final compounds examined (11–13) showed that
extending the linker by 2 (11), 3 (12), or 4 (13) more
atoms gave compounds of similar activity to 9, indicat-
ing that there was some flexibility in the SAR concerning
longer linker lengths. However, subsequent SAR utilized
the simple benzylic linkage due to the observation that
no obvious potency boost was obtained with the longer
linkers and we desired to keep molecular weight down.
We also investigated the stereochemical requirements
for mGlu2 receptor potentiation in this series. Com-
pound 9 was also resolved and only the (ꢀ) isomer
was found to be active ((ꢀ) isomer EC50 = 122 nM,
90% potentiation; (+) isomer EC50 > 10 lM).
Due to issues associated with poor brain penetration for
the tetrazole containing compounds, we investigated
replacements for the tetrazole group as illustrated in
Table 3. Simple methylation of the tetrazole led to a
complete loss of activity (20). A sulfonamide derivative
was also not potent (21). A number of other groups con-
taining an acidic proton gave moderate levels of potency
and potentiation. For example, a simple carboxylic acid
(22), an imide (23) and an acyl sulfonamide (24) showed
activity close to the tetrazole. Due to our previous suc-
cess in a related series of compounds18 replacing the tet-
razole with a thiopyridine moiety, we investigated
incorporating this group. Gratifyingly, this strategy
gave a compound (25) that was close in potency to the
original lead.
To further optimize the potency of compound 25, we
reinvestigated the indanone as well as ketone substitu-
tion. Similar to our results with the tetrazole containing
compounds, both smaller aliphatic (bis-methyl) and lar-
ger aliphatic (n-butyl/cyclopentyl) on the indanone gave
less potent compounds. A phenyl group also gave
diminished potency and potentiation (data not shown).
Much larger improvements were seen with the incorpo-
ration of monosubstituted indanones 26–28 wherein the
methyl group of 25 was not present. One of the most
promising compounds in this series was 28, displaying
both good potency (186 nM) and extremely high levels
of potentiation (169%), implying that this compound
gave a much stronger response than even the maximal
glutamate response at the mGlu2 receptor. The implica-
tions of this high level of potentiation are not under-
stood at this time, although it should be noted that
this compound also does not display activity in the ab-
sence of glutamate. Due to its potency, this compound
was profiled further (vide infra). We also investigated
several dimethyl substituted indanones in the place of di-
chloro indanones and found compounds with good, but
slightly lessened potency. For example, 29 showed 3-fold
less potency than 26 and 30 was slightly less potent than
28. Both 29 and 30 also had lower levels of potentiation.
It should be noted that compounds such as 30, which
had only a 48% level of potentiation, as well as other
compounds with lower levels of potentiation, displayed
no antagonist activity at the mGlu2 receptor, rather
only partial agonist like behavior.
With the result of compound 9 in hand, we next focused
on modification of the group a to the ketone on the
indanone. As shown in Table 2, a range of substituents
are tolerated. Removal of the methyl group in 9 gave a
monosubstituted compound (14) that displayed a 2-fold
increase in potency (to 122 nM), which represents one of
the most potent compound in this series. Other groups
in place of the cyclopentyl also displayed potency, with
isopropyl (15) and propyl (16) being appropriate surro-
gates. When only smaller alkyl groups are present, for
example, two methyl groups (17), potency is diminished,

A. B. Pinkerton et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1565–1571
Table 1. Binding affinities for linker-modified indanones
1567
Cl
O
Cl
Group
Compd
Group
hmGlu2
GTPcS binding EC50 (nM)a
% Potentiationb
H
N
O
1
3
600
86
—
O
N
N
N
HN
NAc
N
N
N
N
HN
N
O
4
5
6
5000
589
30
63
91
N
NH
O
O
N
N
NH
N
N
N
N
NH
O
761
NAc
371
223
—
79
85
N
N
7
8
9
o
N
HN
m
p
N
N
10
11
12
13
1160
276
270
225
30
75
89
97
N
HN
O
O
O
O
N
N
HN
N
N
N
O
N
N
HN
O
N
N
HN
a Value represents mean of two or more experiments.
b Result expressed as a percentage of the maximum glutamate response at 1 mM.
c NA denotes not active <10 lM concentration.
3. PK properties and biological activity
bilities of 65% and 14%, respectively. However, these
compounds had very low brain penetration (<1%). As
has been observed before,18 the thiopyridine replace-
ment improved the brain penetration. For example,
compound 28 has a brain/plasma ratio of 108%.
Although the absolute brain levels were low, we felt that
this compound would be suitable for in vivo evaluation
due to this increased brain penetration. The model we
A number of indanones were investigated for their rat
pharmacokinetics (Table 5). As stated above, initial lead
1 showed extremely poor rat PK, presumably due to the
amide linkage. However, tetrazole containing com-
pounds 9 and 12 showed greatly improved PK with
clearances of 35 and 19 mL/min/kg as well as bioavaila-

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A. B. Pinkerton et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1565–1571
Table 2. Modifications to ketone substitution
Table 3. Tetrazole replacements
Cl
Cl
Cl
O
O
Cl
R
R'
O
O
N
R"
HN
N
Compd R0
hmGlu2
N
GTPcS binding % Potentiationb
Compd
R
R0
hmGlu2
EC50 (nM)a
GTPcS
binding
% Potentiationb
N
N
NH
EC50 (nM)a
9
223
85
N
N
9
–CH3
–H
223
85
80
N
NCH3
20
NAc
—
N
–SO2NH(CH3)
14
122
21
22
NAc
892
—
CH3
CH3
–CO2H
76
15
16
–H
–H
195
282
80
57
O
O
O
23
442
54
N
H
CH3
CH3
O
S
O
17
18
–CH3
–CH3
–CH3
–Ph
782
629
35
58
24
25
515
562
105
114
N
H
CH3
N
19
–nC4H9
1090
24
S
a Value represents mean of two or more experiments.
b Result expressed as a percentage of the maximum glutamate response
at 1 mM.
a Value represents mean of two or more experiments.
b Result expressed as a percentage of the maximum glutamate response
at 1 mM.
c NA denotes not active <10 lM concentration.
phrenia.19 In this assay compound 28 was found to be
efficacious after a systemic dose (ip) at 40 mpk (Fig. 1).
chose to investigate was the blockade of ketamine in-
duced hyperactivity, which is a rodent model for schizo-
Table 4. Activity of thiopyridines
R
O
R
N
R'
R"
S
O
Compd
R
R0
R0
hmGlu2
GTPcS binding EC50 (nM)a
% Potentiationb
114
25
26
–Cl
–Cl
–CH3
–H
562
165
100
CH3
CH3
27
28
29
30
–Cl
–H
–H
–H
–H
839
186
596
291
106
169
70
–Cl
CH3
–CH3
–CH3
48
CH3
a Value represents mean of two or more experiments.
b Result expressed as a percentage of the maximum glutamate response at 1 mM.

A. B. Pinkerton et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1565–1571
Table 5. Selected rat pharmacokinetic parameters
1569
4. Chemistry
Compd Cla (mL/min/kg) % F a Brain/plasmab Brain levelb
(nM)
The compounds described in Tables 1 and 2 were syn-
thesized as outlined in Schemes 1–3.20 Starting from
dichloroanisole, this compound was converted to the
appropriate indanone (31) following the literature pro-
cedure in five steps in overall good yield.21 The appro-
priately substituted indanone 31 was then alkylated to
give a cyano precursor 32, which was converted to the
desired tetrazole using a tin catalyzed reaction with trim-
ethylsilyl azide. In this manner, compounds 7–9 and 14–
19 were prepared. Compounds 4–6 and 11–13 were pre-
pared in a similar fashion using the appropriate alkyl
bromide/nitrile following the same steps.
1
>100
35
19
NDc
0
65
NDc
<0.01
<0.01
1.08
—
—
9
12
28
21
NDc
—
240
a Dosed 2 mpk iv and 10 mpk po.
b Dosed 20 mpk ip, levels at 2 h.
c Not determined.
10000
7500
5000
Compound 3 was prepared as shown in Scheme 2. Inda-
none 33 was first converted into the corresponding tri-
flate using triflic anhydride. It was then subjected to a
palladium catalyzed cross-coupling with 4-cyanobro-
monezene to give the desired nitrile precursor, which
was transformed into tetrazole 3 as described previously.
Likewise, compound 10 was accessed via a cross-cou-
pling strategy, this time a Sonagashira coupling of the
same triflate with 4-cyanoethynylbenzene. The nitrile
34 was first converted to the tetrazole, then the triple
bond was fully reduced using palladium on carbon to
give 10 (Scheme 3).
*
2500
0
*
40
Veh
Veh
0
20
28 (mpk, ip)
+ Ketamine
Figure 1. Modulation of ketamine hyperactivity in rats by mGlu2
potentiator 28. Subjects were dosed with 28 (ip) or vehicle (ip) 30 min
before receiving sc injections of ketamine (25 mg/kg). Activity data
(total distance traveled) are presented as the group mean ( S.E.M)
recorded for the total duration of the 120 min test period. Data were
analyzed by a one-way ANOVA followed by DunnettÕs t-tests.
*p < 0.05 compared to vehicle/ketamine-treated rats.
The compounds in Table 3 were prepared as outlined in
Scheme 4. Indanone 33, prepared as described above,
was alkylated with methyl-4-(bromomethyl)benzoate in
good yield. The ester was then hydrolyzed to give acid
Cl
Cl
O
Cl
HO
b
Cl
a
R
R'
H3CO
31
Cl
O
Cl
O
Cl
Cl
R
R
c
R'
O
R'
O
N
7-9, 14-19
HN
32
NC
N
N
Scheme 1. Reagents and conditions: (a) five steps, see Ref. 21; (b) a-bromo-p-tolunitrile, K2CO3, acetone, 45 °C; (c) TMS–N3, Bu2SnO, toluene,
reflux.
Cl
O
Cl
Cl
O
Cl
a,b,c
N
HO
N
3
N
33
HN
Scheme 2. Reagents and conditions: (a) PhNTf2, Cs2CO3, CH3CN/DMF 9/1, 88%; (b) 4-cyanophenylboronoic acid, Na2CO3, Pd(PPh3)4, DME/H2O
2.5/1, 45 °C, 17%; (c) TMS–N3, Bu2SnO, toluene, reflux, 60%.

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A. B. Pinkerton et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1565–1571
Cl
Cl
O
Cl
O
Cl
a,b
HO
NC
34
33
Cl
O
Cl
c,d
N
N
10
N
HN
Scheme 3. Reagents and conditions: (a) PhNTf2, Cs2CO3, CH3CN/DMF 9/1, 88%; (b) 4-cyanoethynylbenzene, PdCl2(PPh3)2, CuI, Et3N, 65 °C,
41%; (c) TMS–N3, Bu2SnO, toluene, reflux, 63%; (d) H2, 10% Pd/C, MeOH, quant.
Cl
O
Cl
Cl
O
c, d
Cl
a,b
O
HO
HO2C
22
33
Cl
O
Cl
O
H
N
23-24
R
O
Scheme 4. Reagents and conditions: (a) methyl-4-(bromomethyl)benzoate, K2CO3, acetone, 45 °C, 88%; (b) LiOH, THF/water 1/1, 99%; (c)
(COCl)2, DMF, CH2Cl2; (d) RNH2, NaH, THF, 0 °C.
22. This was then converted into compounds 23–24 by
first converting the acid into the acid chloride then react-
ing the acid chloride with the appropriate anion pre-
pared via the amide or sulfonamide and sodium
hydride. Compound 21 was prepared via an alkylation
in a similar manner as with 22, using the appropriate
sulfonamide benzyl bromide. Compound 20 was ac-
cessed via alkylation of compound 9 with methyl iodide.
Lastly, compound 25 and the compounds in Table 4
were synthesized under Mitsunobu type conditions with
an appropriately substituted indanone (35) and benzylic
alcohol 36, which was made as described previously.
Reaction of these two precursors with di-tert-butylazo-
dicarboxylate and triphenylphosphine in THF gave the
desired compounds. In this fashion 25–30 were obtained
in generally good yields (Scheme 5).
R
O
N
R
R'
a
+
S
OH
R"
HO
35
26
R
O
R
O
N
R'
R"
S
25-30
Scheme 5. Reagents: (a) DTAD, PPh3, THF.

A. B. Pinkerton et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1565–1571
1571
11. Grillon, C.; Cordova, J.; Levine, L. R.; Morgan, C. A.,
III. Psychopharmacology 2003, 168, 446; Schoepp, D. D.;
Wright, R. A.; Levine, L. R.; Gaydos, B.; Potter, W. Z.
Stress 2003, 6, 189.
12. Knoflach, F.; Mutel, V.; Jolidon, S.; Kew, J. N. C.;
Malherbe, P.; Viera, E.; Wichmann, J.; Kemp, J. A. Proc.
Natl. Acad. Sci. U.S.A. 2001, 98, 13402.
5. Conclusion
In conclusion, a new class of indanone mGlu2 receptor
potentiators has been described. Optimization of the ser-
ies has led to compounds such as 28, which shows activ-
ity after systemic dosing in rodent models with relevance
to schizophrenia. This result helps validate the potential
application of mGlu2 receptor potentiators in a variety
of CNS disorders. Further optimization and application
of this series of compounds will be reported in due
course.
13. (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) Barda, D. A.; Wang, Z.; Britton, T. C.; Henry, S.
S.; Jagdmann, G. E.; Coleman, D. S.; Johnson, M. P.;
Andis, S. L.; Schoepp, D. D. Bioorg. Med. Chem. Lett.
2004, 14, 3099; (c) Hu, E.; Chua, P. C.; Tehrani, L.;
Nagasawa, J. Y.; Pinkerton, A. B.; Rowe, B. A.; Vernier,
J.-M.; Hutchinson, J. H.; Cosford, N. D. P. Bioorg. Med.
Chem. Lett. 2004, 14, 5071.
14. 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.
15. The effect of these compounds was characterized in the
[35S]-GTPcS binding assay using a cell line expressing
human mGlu2 receptor. See Ref. 14 for a detailed
description of this assay. First, an EC10 (1 lM) of
glutamate was added to the cell line followed immediately
by the test compound at varying concentrations. The
response was then compared to a response using a
saturating amount of glutamate (1 mM) to give both an
EC50 and a percent potentiation (the response normalized
to the maximum response of glutamate alone). The same
experiment was carried out in the absence of glutamate to
test if the compound was truly a positive allosteric
modulator. Nonspecific binding was determined by addi-
tion of 10 lM unlabeled GTPcS.
16. Pinkerton, A. B.; Vernier, J.-M.; Schaffahuser, H.; Rowe,
B. A.; Campbell, U. C.; Rodriguez, D. E.; Lorrain, D. S.;
Baccei, C. S.; Daggett, L. P.; Bristow, L. J. J. Med. Chem.
2004, 47, 4595.
17. Pinkerton, A. B.; Cube, R. V.; Hutchinson, J. H.; Rowe,
B. A.; Schaffhauser, H.; Zhao, X.; Daggett, L. P.; Vernier,
J.-M. Bioorg. Med. Chem. Lett. 2004, 14, 5329.
18. Pinkerton, A. B.; Cube, R. V.; Hutchinson, J. H.; James,
J. K.; Gardner, M. F.; Rowe, B. A.; Schaffhauser, H.;
Daggett, L. P.; Vernier, J.-M. Bioorg. Med. Chem. Lett.
2004, 14, 5867.
19. 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.; Pinkerton, A. B.; Vernier,
J.-M.; Bristow, L. J. Neuropsychopharmacology 2003, 28,
1622.
Acknowledgments
We thank Merryl Cramer for assistance in measuring
the PK parameters for 1, 9, 12, and 28.
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