Biphenyl-indanones: Allosteric potentiators of the metabotropic glutamate subtype 2 receptor

Article abstract of DOI:10.1016/j.bmcl.2005.06.062

We have identified and synthesized a series of biphenyl-carboxylic acid indanones as allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward improving the potency and the brain to plasma ra

Full text of DOI:10.1016/j.bmcl.2005.06.062

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4354–4358
Biphenyl-indanones: Allosteric potentiators
of the metabotropic glutamate subtype 2 receptor
a,
a
a
a
*
´
Celine Bonnefous, Jean-Michel Vernier, John H. Hutchinson, Michael F. Gardner,
Merryl Cramer,a Joyce K. James,a Blake A. Rowe,b Lorrie P. Daggett,b
b
Herve Schaffhauser and Theodore M. Kamenecka
a
´
aDepartment of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court,
San Diego, CA 92121, USA
bDepartment of Neuropharmacology, Merck Research Laboratories, , MRLSDB1, 3535 General Atomics Court,
San Diego, CA 92121, USA
Received 22 April 2005; revised 13 June 2005; accepted 13 June 2005
Available online 19 July 2005
Abstract—We have identified and synthesized a series of biphenyl-carboxylic acid indanones as allosteric potentiators of the metab-
otropic glutamate receptor 2. Structure–activity relationship studies directed toward improving the potency and the brain to plasma
ratio of the initial lead led to the discovery of 5 and 23 (EC50 = 111 and 5 nM, respectively).
Ó 2005 Elsevier Ltd. All rights reserved.
Glutamate, one of the most abundant neurotransmit-
ters in the brain, plays a dual role in a wide variety
of central nervous system functions. It activates both
ionotropic glutamate receptors (iGluRs), which are
glutamate-gated ion channels, and the metabotropic
glutamate receptors (mGluRs) which belong to the
family of G-protein coupled receptors.1,2 Currently,
mGluRs are divided into eight subtypes and three main
groups (I–III). Group II (mGluR2 and 3) mGluRs
are mainly localized presynaptically and generally
inhibit neurotransmission. Therefore, agents targeting
group II mGluRs may have utility in a variety of
clinical conditions,3–5 including epilepsy, anxiety, and
schizophrenia.6
gy for selectivity involves the discovery of allosteric
modulators (potentiators) that do not bind at the
glutamate binding site.12–14 Furthermore, a recent study
demonstrated that potentiators may overcome the
desensitization of GPCR observed after repeated dosing
of agonists.15 Previously published work on potentiators
from our laboratories16–19 and from Eli Lilly20–23 has
yielded moderately potent compounds. Herein, we re-
port the discovery of a new series of indanone potenti-
ators with improved potency, potentiation, and
selectivity which also, at times, gave significant brain
penetration.
Compound 1 was identified as a racemate from an inter-
nal screen24,25 as a weak mGluR2 potentiator with poor
rat pharmacokinetic properties characterized by high
plasma clearance (Clp = 502 mL/min/kg) and a short
half life (t1/2 = 0.3 h). Indanone 1 displayed no activity
in the absence of glutamate, as well as no activity at
mGluR324 in the presence or absence of glutamate, con-
firming it was a selective mGluR2 modulator. Com-
pounds 2 and 3 were subsequently identified as potent
alternatives via structure–activity relationship (SAR)
studies on a second lead containing an acetophenone
moiety.26 Unfortunately, these two compounds were
plagued with either poor brain/plasma ratio
(B/P = 0.1% for 2) or reduced potentiation (44% for
Recently, nonselective mGluR2/3 agonists7–9 have
shown activity in numerous animal models as well as
clinical trials.10,11 However, compounds selective for
mGluR2 over mGluR3 have not been discovered using
this approach, probably due to the high degree of se-
quence homology between group II mGluRs, especially
at the glutamate binding site. Therefore, another strate-
Keywords: mGluR2; Indanone; CNS; Schizophrenia.
*
Corresponding author. Tel.: +1 858 202 5207; fax: +1 858 202 5752;
e-mail: celine_bonnefous@yahoo.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.06.062

C. Bonnefous et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4354–4358
Table 1. Binding affinities for compounds 4–23
4355
Entry
–COOH (C3 or C4)
R1
X
Y
hmGluR2 GTP-cS EC50 (nM)
% potentiation
4
5
C3
C4
H
H
CH3
CH3
CH3
CH3
69
111
118
114
6
C3
C3
C3
C3
C3
C3
C3
C3
2-CH3
4-Cl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
252
24
94
109
81
7
8
4-OCH3
4-OH
5-F
202
62
9
113
124
100
97
10
11
12
13
91
6-CH3
6-F
6-OMe
140
176
36
114
14
15
16
17
C4
C4
C4
C4
2-CH3
2-F
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
353
416
158
119
103
119
98
3-CH3
3-Cl
97
18
19
C3
C4
H
H
CH3
CH3
Cl
Cl
64
49
122
110
20
21
C3
C3
4-Cl
5-F
CH3
CH3
Cl
Cl
67
41
121
161
22
23
C4
C3
H
Cl
Cl
Cl
Cl
240
5
98
4-Cl
117
3), with potentiation being defined as the response ob-
tained using the test compound up to 10 lM plus an
EC10 of glutamate normalized to the maximal response
obtained with glutamate alone. Additionally, com-
pounds 2 and 3 were not selective for mGluR2 over
mGluR3. In the present communication, SAR of a
new class of compounds based on a combination of 1,
2, and 3 will be discussed.
sis with aqueous lithium hydroxide in warm ethanol.
When R was a cyano group, compounds 25 and 26 were
obtained via a tin catalyzed tetrazole formation using
trimethylsilyl azide in refluxing toluene in generally
good yield. The acyl sulfonamide 27 was obtained by
reacting the acyl chloride of 4 with the sodium salt of
methanesulfonamide.
The indanone class of compounds incorporating the
biphenyl carboxylic acid of 3 revealed that, unlike the
acetophenones, they are inactive against mGluR3.25
Importantly, as shown with previous work, the presence
of an acidic proton is crucial for maintaining for good
levels of potency and potentiation.17 SAR results
around this new class of compounds are shown in
Tables 1 and 2. All compounds synthesized showed
good levels of potentiation (81–165%), so binding affin-
ities were used to drive the SAR.
The compounds described in Tables 1 and 2 (4–27) were
synthesized following the synthetic route outlined in
Scheme 1.27 The synthesis began with the initial forma-
tion of boronic esters 30 by alkylation of a hydroxyl-
indanone28 (29, racemic mixture) with 2-[3-(bromo
methyl)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane
28.
Suzuki coupling with the desired bromo-aryl derivatives
(31) afforded compounds 32. In the case where R was an
ester, the final products 4–24 were accessed via hydroly-

4356
C. Bonnefous et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4354–4358
Table 2. Binding affinities for compounds 24–27
does not matter as both compounds may have similar
potencies.
The potency could further be improved by adding a sub-
stituent on the terminal phenyl ring. Extensive SAR
with the acid at C3 and X = Y = CH3 revealed that elec-
tron-withdrawing groups at the C4 position or electron-
donating groups at C6 position were favored (7 and 13,
respectively). Substitutions at C2 and C5 positions (6
and 10) were tolerated but resulted in a moderate loss
of potency compared to 4. Preliminary SAR with the
C4 acid led to moderate losses in potency with most sub-
stitution patterns investigated (14–17). The potencies
were not affected by substitution when X = CH3,
Y = Cl (20 and 21). Combining the potency enhancing
4-Cl substituent in the dichloro indanone series resulted
in an unexpected large boost in potency. To date, com-
pound 23 (as a racemic mixture) is the most potent
mGluR2 potentiator synthesized. The racemic mixture
could be separated into enantiomers using chiral chro-
matography (Chiralcel OD column) at the ester stage,
but racemization was observed during the LiOH hydro-
lysis step.31
Entry
R
hmGluR2 GTP-cS
EC50 (nM)
%
potentiation
24
38
87
111
107
103
43
25
26
27
73
369
Previous SAR on the indanone moiety and the middle
ring revealed that (1) X and Y cannot both be hydro-
gens,29 (2) cyclopentyl/hydrogen is one of the best
combinations for the a position of the ketone,19 (3)
unsubstituted phenyl is the best option for the middle
ring,30 and (4) the benzyl linker does not tolerate
substituents.30
A number of acid bioisosteres were also investigated
(Table 2). The m-tetrazole (25) was essentially equipo-
tent to acid 4, while the acyl sulfonamide (27) lost signif-
icant potency. Additionally, compounds containing a
terminal pyridine with a tetrazole or a carboxylic acid
(24 and 26, respectively) (Table 2) were made to alter
the physical properties of the molecules. These, too,
were potent with good levels of potentiation.
New SAR around the indanone and the terminal phen-
yl can be summarized as follows. When X = Y = CH3,
the acid at the C3 position appears to be preferred (4
vs 5, 6 and 11 vs 14, and 12 vs 15). When X = CH3
and Y = Cl (18 vs 19), the position of the acid group
As previously suspected,19 the tetrazole is partially
responsible for the low B/P (2, 25, and 26). Substitution
Scheme 1. Reagents and conditions: (a) K2CO3, acetone, 50 °C, 18 h, 75–92%; (b) PdCl2(PPh3)2, K2CO3, toluene/MeOH (10:1), 80 °C, 18 h, 59–76%;
(c) LiOH (1 M in H2O), THF, 50 °C, 48 h, 82–89%; (d) TMSN3, n-Bu2SnO, toluene, 110 °C, 18 h, 62–83%; (e) (COCl)2, THF, DMF, rt, 5 h, 85%;
(f) MeSO2NH2, NaH, THF, 65 °C, 18 h, 71%.

C. Bonnefous et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4354–4358
4357
Table 3. Rat brain and plasma levels and B/P ratio for compounds 2–
5, 18, and 24–27
8. Monn, J. A.; Valli, M. J.; Massey, S. M.; Hansen, M. M.;
Kress, T. J.; Wepsiec, J. P.; Harkness, A. R.; Grutsch, J.
L., Jr.; Wright, R. A.; Johnson, B. G.; Andis, S. L.;
Kingston, A.; Tomlinson, R.; Lewis, R.; Griffey, K. R.;
Tizzano, J. P.; Schoepp, D. D. J. Med. Chem. 1999, 42,
1027.
9. Nakazato, A.; Kumagai, T.; Sakagami, K.; Yoshikawa,
R.; Suzuki, Y.; Chaki, S.; Ito, H.; Taguchi, T.; Nakanishi,
S.; Okuyama, S. J. Med. Chem. 2000, 43, 4893.
10. Levine, L.; Gaydos, B.; Sheehan, D.; Goddarg, A. W.;
Feighner, J.; Potter, W. Z.; Schoepp, D. D. Neurophar-
macology 2002, 43, 294.
Entry
Brain level (lM)a
Plasma level (lM)a
B/P
2
0.06
0.89
12
6
5.5
36
16
4.5
1.5
9
0.01
0.16
0.33
0.75
0.67
0.04
0.001
0.008
0
3
4
5
12
3
18
24
25
26
27
0.06
0.01
2
<LOQb
264
2
11. (a) Grillon, C.; Cordova, J.; Levine, L. R.; Morgan, C. A.,
III Psychopharmacology 2003, 168, 446; (b) Schoepp, D.
D.; Wright, R. A.; Levine, L. R.; Gaydos, B.; Potter, W.
Z. Stress 2003, 6, 189.
a Dosed 20 mpk ip, levels at 2 h.
b LOQ = limit of quantification.
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.
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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.
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.; Linda, J.; Bristow, L. J.;
Varney, M. A.; Daggett, L. P. Pharmacology 2003, 64,
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of the tetrazole with a carboxylic acid (i.e., 2 ! 3,
25 ! 4, and 26 ! 24) did improve the B/P (0.01–0.16,
0.001–0.33, and 0.008–0.04, respectively), while substitu-
tion with an acyl sulfonamide (27) did not (no
compound could be detected in the brain) (Table 3).
Replacement of the terminal phenyl with a pyridine
(24 and 26), while leading to potent compounds, did
not improve the B/P (0.0076 and 0.04, respectively) as
hoped. Replacement of one of the methyl groups by a
chlorine atom on the indanone ring (18) led to excellent
B/P (0.67), however, lower plasma levels resulted in
lower brain level.
15. Pin, J. P.; Parmentier, M. L.; Prezeau, L. Mol. Pharmacol.
2001, 60, 881.
In conclusion, a new class of biphenyl-indanone
mGluR2 potentiators has been described. Optimization
of the original lead led to compounds such as 23 which
are, to date, the most potent mGluR2 selective (over
mGluR3) potentiators from our laboratories. Addition-
ally, potent compounds such as 4 and 5 were identified
with good to excellent plasma exposure (16–36 lM)
and brain exposure (12 lM) upon ip dosing in rats at
20 mpk. Finally, preliminary in vivo data32 suggest that
these allosteric modulators may have therapeutic
potential for the treatment of schizophrenia and will
be described in a future communication.
16. (a) Pinkerton, A. B.; Vernier, J.-M.; Shaffhauser, 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; (b) 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.
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.; Schaffhauser, H.; Rowe, B. A.;
Daggett, L. P.; Vernier, J.-M. Bioorg. Med. Chem. Lett.
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References and notes
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24. Screening of compounds was carried out using a Ca2+ flux
functional (FLIPR384) assay using a stable cell line co-

4358
C. Bonnefous et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4354–4358
expressing the human mGlu2 receptors coupled to a
Campbell, U. C.; Rodriguez, D. E.; James, J. K.;
Bristow, L. J.; Daggett, L.; Kamenecka, T. M. Present-
ed at the 229th National Meeting of the American
Chemical Society, San Diego, CA, March 2005; poster
MEDI-37.
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Rao, S. P.; Sacaan, A.; Lin, F. F.; Bleicher, L.; Santori, E.
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27. All final compounds displayed spectral data (NMR, MS)
that was consistent with the assigned structure.
28. DeSolm, J. S.; Woltersdorf, O. W.; Cragoe, E. J.; Watson,
L. S.; Fanelli, G. M. J. Med. Chem. 1978, 21, 437.
29. When X = Y = H, EC50 > 10 lM.
30. Kamenecka,T. M.; Bonnefous, C.; Hutchison, J. H.;
Gardner, M. F.; Cramer, M.; James, J. K.; Rowe, B. A.;
Daggett, L. P.; Schaffhauser, H.; Vernier, J.-M., manu-
script in preparation.
25. The effect of these compounds were confirmed and further
characterized in the [35S]-GTPcS binding assay. See Ref.
11 for a detailed description of this assay. First, an EC10
(0.5 lM) of glutamate was added to the cell line (express-
ing hmGluR2 or hmGluR3) 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 exper-
iment was carried out in the absence of glutamate to test if
the compound was truly a positive allosteric modulator.
Non-specific binding was determined by addition of
10 lM unlabeled GTPcS.
31. The potency was shown to reside in the (ꢀ) isomer. See
Ref. 19 for more details.
32. (a) Vernier, J.-M.; Kamenecka, T. M.; Bonnefous, C.;
Schaffhauser, H.; Rowe, B. A.; Campbell, U. C.;
Rodriguez, D. E.; Gardner, M. F.; James, J.; Bristow,
L. J.; Daggett, L. P.; Hutchinson, J. H., manuscript in
preparation.; (b) Rodriguez, D.; Bonnefous, C.; Kam-
enecka, T.; Vernier, J.-M.; Bristow, L.; Campbell, U.
Presented at the 34th Annual Meeting of the Society for
Neuroscience, San Diego, CA, October 2004; poster
798.8.
26. Bonnefous, C.; Vernier, J-.M.; Hutchinson, J. H.;
Gardner, M. F.; Rowe, B. A.; Schaffhauser, H.;