Spiro-oxindole Piperidines and 3-(Azetidin-3-yl)-1 H-benzimidazol-2-ones as mGlu2 Receptor PAMs

Article abstract of DOI:10.1021/acsmedchemlett.9b00350

Starting from two weak mGlu₂ receptor positive allosteric modulator (PAM) HTS hits (4 and 5), a molecular hybridization strategy resulted in the identification of a novel spiro-oxindole piperidine series with improved activity and metabolic sta

Full text of DOI:10.1021/acsmedchemlett.9b00350

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Letter
Spiro-oxindole piperidines and 3-(azetidin-3-yl)-1H-
benzimidazol-2-ones as mGlu2 receptor PAMs
Ana Isabel de Lucas, Juan Antonio Vega, Encarnación Matesanz, María Lourdes Linares, Aránzazu
García Molina, Gary Tresadern, Hilde Lavreysen, Andrés A. Trabanco, and José María Cid
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00350 • Publication Date (Web): 10 Oct 2019
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Spiro-oxindole piperidines and 3-(azetidin-3-yl)-1H-benzimidazol-2-
ones as mGlu2 receptor PAMs
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Ana Isabel de Lucas,‡,*Juan Antonio Vega,‡ Encarnación Matesanz,‡ María Lourdes Linares,‡ Aránzazu
‖
García Molina, ‡ Gary Tresadern, § Hilde Lavreysen, Andrés A. Trabanco, ‡ and José María Cid‡,*
‡ Discovery Chemistry, Janssen Research & Development, Division of Janssen-Cilag S.A., Jarama 75A, Toledo 45007, Spain
§Computational Chemistry, Discovery Neuroscience, Janssen Research & Development, Division of Janssen Pharmaceutica
NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
‖Discovery Neuroscience, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-
2340 Beerse, Belgium
KEYWORDS. Metabotropic glutamate receptor 2, mGlu2, mGluR2, GRM2, positive allosteric modulators, PAMs, scaffold
hopping
ABSTRACT: Starting from two weak mGlu2 receptor positive allosteric modulator (PAM) HTS hits (4 and 5) a molecular
hybridization strategy resulted in the identification of a novel spiro-oxindole piperidine series with improved activity and metabolic
stability. Scaffold hopping around the spiro-oxindole core identified the 3-(azetidin-3-yl)-1H-benzimidazol-2-one as bioisoster.
Medicinal chemistry optimization of these two novel chemotypes resulted in the identification of potent, selective, orally bioavailable
and brain penetrant mGluR2 PAMs.
INTRODUCTION
We have previously reported on a series of pyridones originated
from a high throughput screening (HTS) campaign of the Addex
Pharmaceuticals compound collection.11
Metabotropic glutamate (mGlu) receptors represent a family of
G protein-coupled receptors (GPCRs) that are activated by the
excitatory neurotransmitter glutamate.1,2 To date, eight mGlu
receptor subtypes have been identified and classified into 3
groups based on sequence homology, pharmacologic profile
and preferential signal transduction pathway.3 The mGlu2 and
mGlu3 receptors are the members of group II that couple
negatively to adenylyl cyclase through Gi/Go proteins.
Activation of the mGluR2 results in reduced glutamate release
and decreases excitability. mGluR2 activation can be achieved
with orthosteric agonists or can be modulated by positive
allosteric modulation of the receptor. A positive allosteric
modulator (PAM) can increase the affinity and/or efficacy of
the endogenous neurotransmitter glutamate binding to a site
topologically distinct from the orthosteric (glutamate) ligand
binding sites. PAMs of mGluR2 have emerged as promising
novel therapeutic agents for the treatment of several central
nervous system (CNS) disorders.4-6 The mGluR2 is expressed
on presynaptic glutamatergic nerve terminals where it functions
as an autoreceptor for glutamate. Thus, a mGlu2 PAM can
normalize excessive glutamatergic neurotransmission, which
may be of benefit in disorders such as epilepsy7,8 and
schizophrenia.9.10
O
NC
1
, HTS hit
N
mGlu2 PAM EC50 = 8 M
mGlu2 PAM EMAX (%) = 117
O
N
N
Cl
F3C
N
N
N
N
2
3
, JNJ-42153605
, JNJ-40411813
mGlu2 PAM EC50 = 147 nM
mGlu2 PAM EMAX (%) = 273
mGlu2 PAM EC50 = 17 nM
mGlu2 PAM EMAX (%) = 285
Figure 1. Previously reported mGlu2 PAM hit 1 and subsequent
lead molecules 2 and 3.
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Figure 2. Structure and primary activity of hits 4 and 5 and hybrid
molecule 6.
As previously described, starting from the HTS hit 1 (Figure 1),
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3
4
5
6
7
8
potency and druglike properties were significantly improved to
deliver the clinical lead JNJ-40411813 (2).12 Subsequent back
up programs focused on novel chemical series identified by
pharmacophore overlays and scaffold hopping using the
pyridone core as template.13-14 Additional leads, such as JNJ-
42153605 (3),15,16 with improved potencies and druglike related
attributes were found. Later, we confirmed these series bind in
the 7-transmembrane domain of the receptor17 and the discovery
of the first covalent PAM, an analogue of 3, helped confirm our
overlay and binding mode hypotheses.18 Using modeling and
mutagenesis a mechanism was proposed for how PAMs initiate
their functional effect.19
As part of a continuing effort to identify and develop novel
mGluR2 PAMs from structurally different scaffolds a second
HTS campaign, now using the Janssen compound library, was
conducted. Nine hit series with structurally distinct chemotypes
were found. Hit triaging using mGlu2 receptor PAM potency
and in vitro ADME profiling prioritized two novel series,
exemplified by hits 4 and 5 (Figure 2) as the most promising.
We hypothesized that the phenylpiperidine motif of hit 4 was
embedded into the structure of the spiro-oxindole piperidine hit
5, suggesting that hybrid analogues could be worth exploring.
To validate the hypothesis the hybrid compound 6 was
synthesized. Pleasingly, compound 6 showed a two-fold
increase in potency with respect to hit 4 (6: EC50 = 1.02 M vs
4: EC50 = 2.29 M) and a significant increase in the EMAX of
232% indicating a substantial increase in the glutamate
response. Herein, we report on the synthesis, SAR exploration
and medicinal chemistry optimization of this novel series as
well as on the initial pharmacokinetic evaluation of selected
early leads.
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O
O
HN
N
N
Cl
O
N
N
F3C
Br
4
5
mGlu2 PAM EC50 = 2.29 M
mGlu2 PAM EC50 ~ 10 M
mGlu2 PAM EMAx = 128 %
mGlu2 PAM EMAX = 120 %
Hit
hybridization
RESULTS AND DISCUSSION The initial exploration of
compound 6 focused on two main aspects: study the effect of
substituents on the indolone core ring and piridazinyl ring.
Functional activity and microsomal stability data for spiro-
oxindole piperidine 6 along with new derivatives 7-26 are
summarized in Table 1 and 2.
O
HN
N
Cl
N
N
Br
6
mGlu2 PAM EC50 ~ 1.02 M
mGlu2 PAM EMAX = 232 %
Table 1. Functional activity and metabolic stability data for representative spiro-oxindole piperidine mGluR2 PAMs 6-20
O
HN
N
N
N
(7)
(6)
X
R2
(4)
R1
(5)
mGlu2 EC50 (nM)a
(95% CI)
mGlu2
mGlu2
% effect @ 1 µMb ± SD
HLM
(%)c
RLM
(%)c
compd
X
R1
R2
EMAX (%)b ± SD
232 ± 64
217 ± 6
65 ± 4
6
5-Br
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
1,020 (822-1257)
100 ± 17
24 ± 13
9 ± 2
8
45
n.t.e
n.t.
n.t.
8
25
95
7
n.d.d
3,090e
8
7-Br
6-Br
4-Br
5-Cl
5-F
Cl
n.t.
n.t.
n.t.
76
9
Cl
n.d.
183 ± 2
108d
76 ± 7
31 ± 5
80 ± 8
31 ± 4
105 ± 22
7 ± 3
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11
12
13
14
15
16
17
Cl
n.d.
Cl
1,000 (904-1132)
n.d.
187 ± 14
184 ± 17
169 ± 5
141d
Cl
11
45
n.t.
17
4
57
5-Cy
5-Br
5-Br
5-Br
5-Br
Cl
630 (317-1285)
n.d.
100
n.t.
69
H
Me
CF3
OEt
n.d.
228d
36 ± 18
46 ± 6
5 ± 0
400 (242-654)
>10,000
53 ± 2
20
52 ± 11
7
31
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20
5-Br
5-Br
5-Br
NHEt
OEt
Cl
Cl
240 (110-535)
210 (150-309)
130 (96-164)
394d
380d
263 ± 18
203 ± 42
160 ± 23
8
11
9
65
58
43
1
2
3
OEt
CF3
216 ± 35
4
5
6
7
a
b
Values are the mean of at least two experiments and within confidence interval of >95%. Values are the median of at least two
experiments with standard deviation. c HLM and RLM data refer to % of compound metabolized after incubation with microsomes for 15
min at a 5 uM concentration. d n.d.: absolute EC50 could not be calculated since no obvious upper plateau of the concentration-response curve
was reached. e no tested.
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9
Removing the bromine atom (7) from the indolone core led to
decrease in potency and worsened metabolism. Moving the
bromine atom from C-5 to other positions of the aromatic ring
was also detrimental for activity. Thus compound 8 (7-Br) was
3-fold less potent showing a low EMAX and isomers 9 (6-Br) and
10 (4-Br) weakly active. The role of the bromine atom at C-5
was assessed by exploring alternative substituents. For instance,
a chlorine substituent was equipotent (11, EC50 = 1,000 nM),
however it displayed higher metabolism in rat liver microsomes
(11, RLM 76% vs 6. RLM 25%). The smaller and less lipophilic
fluorine (12) was not tolerated leading to an inactive molecule.
Nevertheless, the mGluR2 PAM activity was recovered with the
introduction of the more lipophilic cyclopropyl substituent (13)
having comparable potency but lacking good stability in both
HLM and RLM. Moreover, SAR on the pyridazine ring showed
that removing the chlorine atom (14) resulted also in a decrease
in activity. Next, several replacements for the chlorine group of
the pyridazine such as methyl (15), trifluoromethyl (16), and
ethoxy (17) were explored. These modifications turned out to
be unfavorable leading to either low EMAX (16, 53%) or loss of
activity (15 and 17, %effect at 1 M 36% for 15 and 5% for 17,
EC50 > 10 M for 17). Introduction of a second substitution on
the pyridazine ring was explored with compounds 18-19.
Incorporation of an ethylamino (18) or ethoxy (19) adjacent to
the chlorine atom led to a 4 and 5-fold increase in potency
respectively compared to 6 but also with some decrease of the
metabolic stability in RLM. In the continued effort to find
alternatives for the chlorine group of the pyridazine, we went
back to the CF3 group, which resulted in compound 20 having
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an additional improvement in potency (EC50 = 130 nM; EMAX
=
216%). Thus compound 20 is 2-fold more potent than 19 and
7.5-fold more potent than the initial hit 6, keeping the in vitro
metabolic profile in an acceptable range.
Figure 3. Comparison of the 3D conformation and electrostatic
surfaces for spiro-oxindole piperidine (18) and a new hit containing
a 1H-benzimidazol-2-one core (21) with azetidine substitution. The
red surface represents region of negative electrostatic charge and
the blue surface is positive charge.
We next focused on finding replacements of the central spiro-
oxindole core. To that end, a scaffold hopping exercise looking
for non-spirocyclic bicyclic cores was conducted. We applied
computational techniques based on 3D shape and electrostatic
similarity. Such approaches are well suited to scaffold hopping
as similarity is assessed using properties important for
biological recognition and not the underlying atom
connectivity. We have previously assessed these techniques in
detail20 and applied them to identify mGlu2 PAM scaffolds.13
Here we performed a similar approach aimed at replacing the
central piperidine with alternative secondary amines and we
also searched databases of pre-fragmented compounds. The
ROCS21 and EON software from Openeye Scientific22 were
used which assess shape and electrostatic similarity
respectively. Amongst the best computational hits was the
benzimidazolone core (21) with an azetidine substituent, Figure
3. The shape and electrostatic similarity between the two were
high suggesting this as a strong candidate for follow-up
chemistry.
The 3-(azetidin-3-yl)-1H-benzimidazol-2-one core exemplified
with compound 21, stood out as an optimal bioisosteric
replacement of the spiro-oxindole piperidine. Pleasingly, the
new subclass represented by 21 showed comparable mGlu2
PAM activity and interestingly better metabolic stability when
compared to its corresponding match pair 18. This encouraging
result triggered a focused exploration in which the 3-(azetidin-
3-yl)-1H-benzimidazol-2-one core was kept as template to
explore SAR on both left- and right-hand side. The most
relevant examples prepared along with their primary activity
and metabolic stability data are summarized in Table 2. In
contrast to the previous subclass, removal of the 6-bromine
atom on the benzimidazolone scaffold (22) did not have any
effect on the potency or the metabolic stability. Replacement of
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the pyridazine for pyridine (23) resulted in a ~2.3-fold potency
increase compared to 22 although the compound was found to
be metabolically less stable in both HLM and RLM.
Substitution of the aminoethyl group on 23 by an ethoxy moiety
was unfavorable and compound 24 showed decreased potency
(24, EC50 = 270 nM vs 23, EC50 = 120 nM). Pleasingly, mGlu2
PAM activity was significantly improved by the introduction of
a trifluoromethyl group at the 5 position of the benzimidazolone
Page 4 of 7
scaffold (25) resulting in ~3.4-fold increase in potency
compared to the unsubstituted analogue 24 (25, EC50 = 80 nM
vs 24, EC50 = 270 nM) and excellent metabolic stability in
human and rat liver microsomes (HLM = 4% and RLM = 12%).
Interestingly, the pyrimidine analogue 26 displayed comparable
activity to 25 and no metabolites could be seen after incubation
with HLM and RLM.
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5
6
7
8
9
Table 2. Functional activity and metabolic stability data for representative 3-(azetidin-3-yl)-1H-benzimidazol-2-one mGluR2
PAMs 21 -26a.
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O
HN
N
N
Z
N
Cl
Y
(5)
X
(6)
R
mGlu2 EC50a (nM)
(95% CI)
mGlu2 EMAX (%)b
± SD
HLM
(%)c
RLM
(%)c
comp
X
R
Y
Z
21
22
23
24
25
26
6-Br
H
NHEt
NHEt
NHEt
OEt
CH
CH
CH
CH
CH
N
N
230 (200-262)
280 (229-345)
120 (97-160)
270 (202-368)
80 (57-113)
241 ± 71
291 ± 43
381 ± 80
259 ± 38
218 ± 32
220 ± 16
9
26
N
0
23
H
CH
CH
CH
CH
27
15
4
88
H
46
5-CF3
5-CF3
OEt
12
OEt
150 (130-189)
BQLd
BQLd
a Values are the mean of at least two experiments and within confidence interval of >95%. b Values are the median of at least two
experiments with standard deviation. c HLM and RLM data refer to % of compound metabolized after incubation with microsomes for 15
min at a 5 uM concentration. d Below Quantification Limit.
Based upon their overall in vitro profile (e.g. good balance
between potency and metabolism) and with the aim to maximize
the potential to identify suitable in vivo probes, compounds 19, 20,
21, 22, 24 and 25 were evaluated after oral dose in a PK study in
rat and for their ability to cross the blood−brain barrier (BBB).
Thus, plasma and brain levels measured 2 and 4 h after dosing at
10 or 30 mg/kg are shown in Table 3. With the exception of 19,
compounds display relevant plasma exposures after 4 hours
administration reflecting low to moderate clearance, in line with the
in vitro rat metabolism previously shown. Moreover, the brain
penetration was generally low for most of the compounds with Kp
values below 0.4, with the exception of compound 20 (Kp = 1.4).
To rule out potential interaction with the glycoprotein P (P-gp), the
efflux ratio of compounds 24 and 25 was evaluated in LLC-PK1
cell lines transfected with MDR1 showing no indication for P-gp
efflux with values of 1.18 and 1.24 x 10-6 cm/s for both 24 and 25
respectively. Likewise, both compounds possessed moderate
permeability (13 and 9 x 10-6 cm s for 24 and 25 respectively).
Interestingly, the Kp values followed a trend with log P, excluding
25, in which its higher lipophilicity, may not account for its poor
brain penetration. Thus, for example, increasing the lipophilicity by
replacing the chlorine atom in the pyridazine ring (19) by a
trifluoromethyl group (20) led to an increase in Kp that translated
into higher brain exposures. Conversely, the reduction of
lipophilicity in compound 21 by removing the bromine atom on the
benzimidazolone ring led to compound 22 which displayed lower
Kp value. In view of these data, compounds 20, 24 and 25 displayed
the best combination of low plasma clearance and relevant brain
concentrations maintained at least for 4 h.
In addition, all compounds displayed a high level of selectivity
toward all mGlu receptor subtypes: mGlu1 and mGlu3-8 (see
compound 20 as example in supporting information). Likewise,
potential off-target interactions were explored in a limited CEREP
panel containing 18 different targets and also in the DiscoverX
kinase panel (see supporting information) showing overall clean
selective profiles with the exception of A2B (IC50 0.79 uM) for
compound 20.
Collectively, our data show that compounds 20, 24 and 25 are
suitable tools derived from novel templates to further explore
the therapeutic potential of mGlu2 PAMs in biological models
of CNS disorders. In vivo studies to confirm their in vitro
activity are in progress and will be reported in due course.
Table 3. Brain and Plasma kinetics in rat after a single oral
dose.a
Plasma level
b
Brain level (ng/g)
Kp
ALogP
2.94
(ng/mL)
2 h
49
compd
4 h
17
2 h
18
4 h
2 h
19c
BQLd
0.37
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20c
21c
22
260
254
220
416
310
18
290
18
1.4
3.43
2.64
1.9
The general synthetic schemes for the preparation of spiro-
oxindole piperidines (6-20) and 3-(azetidin-3-yl)-1H-
benzimidazol-2-ones (21-26) are outlined in Scheme 1 and
Scheme 2 respectively. The precursor compounds 27a-e, 28a-
d, 28f and 31a-b were commercially available. For the
preparation of compounds 6-20 the general procedure involves
a nucleophilic aromatic substitution on a 3,6-dichoropyridazine
heterocycle (28a-g) with the corresponding spirocyclic
piperidine derivative (27a-g) using DIPEA or K2CO3 (Scheme
1) as base. The benzimidazole azetidines 21-26 were prepared
following a similar reaction procedure, starting in this case from
the corresponding benzimidazole derivative 31a-c and chloro-
heterocycle 28e, 32a-c (Scheme 2).
1
2
3
4
5
6
7
8
0.07
0.03
0.36
0.14
1,480
5,770
2,660
842
48
31
24
5,780
2,050
2,374
2.14
25
5,090
371
996
3.1
a Study in male Sprague Dawley rat (n= 1) dosed at 30 mg/kg
b
p.o. in suspension (20% HP--CD at pH 7). Kp is partition
coefficient between brain and plasma after 2 hours. c10 mg/kg
dose p.o. d Below Quantification Limits.
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CHEMISTRY
Scheme1. General synthesis of spiro-oxindole piperidines 6-20a
O
O
Cl
HN
HN
N
N
a
N
N
NH
N
(7)
(6)
+
R2
R1
(4)
X
R2
R1
X
(5)
: X = 5- Br
: X = H
: X = 7-Br
: X = 4-Br
: X = 5- Cl
: R1 = H; R2 = Cl
: R1 = R2 = H
: R1 = H; R2 = Me
: R1 = H; R2 = CF3
: R1 = N(Boc)Et; R2 = Cl
: R1 = OEt; R2 = Cl
: R1 = OEt; R2 = CF3
: X = 5-Br; R1 = H; R2 = Cl
27a
27b
27c
27d
27e
27f
28a
28b
28c
28d
28e
28f
6
: X =R1 = R2 = H;
7
: X = 7-Br; R1 = H; R2 = Cl
8
: X = 4-Br; R1 = H; R2 = Cl
: X = 5-Cl; R1 = H; R2 = Cl
: X = 5-F; R1 = H; R2 = Cl
: X = 5-CyPr; R1 = H; R2 = Cl
10
11
12
13
14
15
16
17
29
18
19
20
: X = 5- F
: X = CyPr
b
27g
28g
1
: X = 5-Br; R = R2 = H
: X = 5-Br; R1 = H; R2 = Me
: X = 5-Br; R1 = H; R2 = CF3
: X = 5-Br; R1 = H; R2 = OEt
: X = 5-Br; R1 = N(Boc)Et; R2 = Cl
: X = 5-Br; R1 = NHEt; R2 = Cl
: X = 5-Br; R1 = OEt; R2 = Cl
: X = 5-Br; R1 = OEt; R2 = CF3
O
O
N
c
Boc
HN
d, e
N
N
N
NH
Cl
Br
Br
30
9
aReagents and conditions: (a) DIPEA or K2CO3, solvent, 85 - 150 ºC. Y: 2 - 78%, see Supporting Information for
28a
detailed protocol; (b) NaOEt, EtOH, 0 to 100 ºC, 48h. Y: 40%; (c) TFA, DCM, rt, 1h. Y: 42%; (d)
DMEDA, K2CO3, DMF, 120 ºC, 12h; (e) HCl, MeOH, rt, 1h. Y: 5% (two steps)
, CuI,
Scheme2. General synthesis of 3-(azetidin-3-yl)-1H-benzimidazol-2-ones 21-26a
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O
N
O
Cl
Cl
HN
(6)
1
2
3
4
HN
N
N
a
Z
NH
Y
N
Z
N
+
Cl
(5)
Y
R
X
X
R
5
6
7
8
9
33
21:
34
22:
35
: X = 6-Br; Y = CH; Z = N; R = N(Boc)Et
X = 6-Br; Y = CH; Z = N; R = NHEt
: X = H; Y = CH; Z = N; R = N(Boc)Et
X = H; Y = CH; Z = N; R = NHEt
: X = H; Y = Z = CH; R = CF3C(O)NEt
X = H; Y = Z = CH; R = NHEt
: X = H; Y = Z = CH, R = OEt
: X = 5-CF3; Y = Z = CH, R = OEt
: X = 5-CF3; Y = N; Z = CH, R = OEt
31a
31b
31c
28e
32a
32b
32c
: X = 6-Br
: X = H
: X = 5-CF3
: Y = CH; Z = N; R = N(Boc)Et
: Y = Z = CH, R = CF3C(O)NEt
: Y = Z = CH, R = OEt
b
b
: Y = N; Z = CH, R = OEt
c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
23:
24
25
26
aReagents and conditions: (a) DIPEA or K2CO3, solvent, 85 - 130 ºC. Y: 15 - 85%, see Supporting Information
for detailed protocol; (b) TFA, DCM, rt, 1h. Y 32 - 39%; (c) K2CO3, MeOH, H2O, 50 ºC, 4h. Y: 23%
mGlu2, metabotropic glutamate 2; PAM, positive allosteric
modulator; GPCR, G protein-coupled receptor, CNS, central
nervous system; HTS, high throughput screening; SAR,
structure-activity relationship. RLM, rat liver microsomes;
HLM, human liver microsomes.
CONCLUSIONS
In summary, we have outlined the medicinal chemistry
strategies employed in the optimization of micromolar HTS hits
to the identification of two novel mGlu2 PAM series. A hybrid
design approach that combined the two HTS hits gave quick
access to a novel series that after systematic SAR studies
including a scaffold hopping approach, delivered compounds
with good in vitro potency, selectivity and appropriate
pharmacokinetic attributes to progress to in vivo PD studies.
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ASSOCIATED CONTENT
*Supporting Information
Assay protocols, experimental procedures, and analytical data
for compounds 6-26, 27f-g, 28e, 28g, 29, 30, 31c, 32a, 33, 34
and 35 (PDF)
AUTHOR INFORMATION
Corresponding Authors
*for A.I.L: phone, +34 925 245770; e-mail:
adelucas@its.jnj.com
*for J.M.C: phone, +34 925 245767; e-mail: jcid@its.jnj.com.
Author Contributions
The manuscript was written through contributions of all
authors. / All authors have given approval to the final version
of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(9) Lavreysen, H.; Langlois, X.; Ver Donck, L.; Cid Nuñez, J. M.;
Pype, S.; Lütjens, R.; Megens, A. Preclinical evaluation of the
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allosteric modulator of mGluR2, in two randomised, double-blind
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The authors thank Dr Manuela Ariza, Dr Miriam Ciordia and
Dr María Morón for their synthetic contributions and members
of the purification and analysis team from Toledo, the biology
and ADMET team from Janssen R & D. The authors further
thanks Ilse Biesmans for data management support.
a positive
ABBREVIATIONS
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