Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor

Article abstract of DOI:10.1016/j.bmcl.2009.11.008

Imidazo[1,2-a]pyridines were identified via their shape and electrostatic similarity as novel positive allosteric modulators of the metabotropic glutamate 2 receptor. The subsequent synthesis and SAR are described. Potent, selective and metabolically stable compounds were found representing a promising avenue for current further studies.

Full text of DOI:10.1016/j.bmcl.2009.11.008

Bioorganic & Medicinal Chemistry Letters 20 (2010) 175–179
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive
allosteric modulators of metabotropic glutamate 2 receptor
b
c
b
b
Gary Tresadern a, , Jose María Cid , Gregor J. Macdonald , Juan Antonio Vega , Ana Isabel de Lucas ,
*
Aránzazu García b, Encarnación Matesanz b, María Lourdes Linares b, Daniel Oehlrich c, Hilde Lavreysen d,
Ilse Biesmans d, Andrés A. Trabanco b,
*
a Research Informatics, Johnson & Johnson, Pharmaceutical Research & Development, Janssen-Cilag S.A., Calle Jarama 75, Poligono Industrial, Toledo 45007, Spain
b Medicinal Chemistry, Johnson & Johnson, Pharmaceutical Research & Development, Janssen-Cilag S.A., Calle Jarama 75, Poligono Industrial, Toledo 45007, Spain
c Medicinal Chemistry, Johnson & Johnson, Pharmaceutical Research & Development, Janssen Pharmaceutica N.V., Turnhoutsweg 30 B-2340, Beerse, Belgium
d Neuroscience, Johnson & Johnson, Pharmaceutical Research & Development, Janssen Pharmaceutica N.V., Turnhoutsweg 30 B-2340, Beerse, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Imidazo[1,2-a]pyridines were identified via their shape and electrostatic similarity as novel positive allo-
steric modulators of the metabotropic glutamate 2 receptor. The subsequent synthesis and SAR are
described. Potent, selective and metabolically stable compounds were found representing a promising
avenue for current further studies.
Received 7 October 2009
Revised 3 November 2009
Accepted 3 November 2009
Available online 10 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The authors dedicate this Letter to the
memory of Dr. Hassan Imogai, Addex
Pharmaceuticals SA
Keywords:
mGluR2
Metabotropic
Chemotype hopping
Glutamate
Allosteric
PAM
The metabotropic glutamate type 2 receptor (mGluR2) is a G-
protein coupled receptor (GPCR) expressed on presynaptic nerve
terminals where it negatively modulates glutamate and GABA re-
lease.1 Mixed mGluR2/mGluR3 agonists such as LY354740 (1) have
shown activity in a range of preclinical animal models of anxiety
and schizophrenia (see Fig. 1).2,3 Early clinical work with
LY354740 demonstrated activity in a CO2 inhalation study suggest-
ing the usefulness for the treatment of anxiety related disorders.4
Subsequently, a related prodrug LY2140023 (2) demonstrated
improvements in positive and negative symptoms in patients
suffering from schizophrenia.5 These molecules exhibit combined
mGluR2/mGluR3 activity although there is evidence from knock-
out studies that preclinical anti-psychotic effects may be mediated
via the mGluR2 receptor.6
An alternative avenue for modulating GPCRs is to act via alloste-
ric mechanisms, binding at a different site from the orthosteric
agonist.7 Positive allosteric modulators (PAMs) of mGluR2 have
been claimed and reported, Figure 2.8 PAMs may offer benefits over
orthosteric agonists. The orthosteric site is highly conserved across
the mGluR family therefore targeting alternative sites assists the
identification of selective compounds.9 Allosteric ligands will in
general be more brain penetrant as they would not be amino acid
analogues. The allosteric modulator exerts its effect when gluta-
mate is present allowing the receptor to respond to physiological
O
CO2H
NH2
H
O
H
CO2H
S
H
N
H
SMe
H
O
HO2C
HO2C
NH2
2, LY2140023
Figure 1. Structures of mixed mGluR2/3 agonists LY354740 and LY2140023.
* Corresponding authors. Tel.: +34 925 245792 (A.T.); +34 925 245782; fax: +34
925 245771 (G.T.).
E-mail addresses: gtresade@its.jnj.com (G. Tresadern), atrabanc@its.jnj.com (A.A.
Trabanco).
1, LY354740
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.008

176
G. Tresadern et al. / Bioorg. Med. Chem. Lett. 20 (2010) 175–179
OH
O
Br
N
S
O
O
O
O
O
N
N
CF3
N
N
N
4
H
3, 2,2,2-TEMPS
O
Cl
O
N
O
N
N
N
O
N
5, BINA
6
7
CO2H
O
N
O
NC
N
N
N
N
N
O
H
N
N
N
H
O
N
F
Cl
9
10
8
Cl
Figure 2. Reported mGluR2 positive allosteric modulators.
changes in endogenous agonist levels. In addition, it is expected
that PAMs will not produce the same degree of receptor desensiti-
zation.10 The first allosteric modulators of mGluR2 were a series of
sulfonamides developed by Lilly that include the 2,2,2-TEMPS 3
which inhibited ketamine evoked norepinephrine release in rats.11
BINA 5 has shown anxiolytic and antipsychotic effects in behav-
ioral models in mice.12 Finally, compound 10 was active in a meth-
amphetamine induced hyperlocomotion model in mice.8h
In this Letter we present the discovery of imidazo[1,2-a]pyri-
dines as a new series of mGluR2 PAMs. With the need to identify
new hit matter for this target we applied computational tech-
niques based on 3D shape and electrostatic similarity. Such ap-
proaches are well suited to scaffold hopping as similarity is
assessed using properties important for biological recognition not
the underlying atom connectivity. We demonstrate that examples
from the imidazopyridine series, show good in vitro mGluR2 PAM
activity, selectivity and metabolic stability.
An overlay hypothesis for mGluR2 PAMs 4–8 is shown in Fig-
ure 3. This was derived with flexible alignment in MOE, the
MMFF94x force field, Born solvation, internal dielectric equal to 4
and all other settings as defaults.13,14 We do not present a fully val-
idated mGluR2 PAM pharmacophore here yet the plausible align-
ment serves to highlight shared features. Firstly, the molecules
have a central scaffold with an often exocyclic H-bond acceptor,
adjacent to which is a small substituent such as –Cl, –Br, –Me or
–CN. Secondly, a larger lipophilic group is pendant from the
scaffold, examples include isopentyl, cyclopentyl, phenyl and
benzyl. Finally, there is a scaffold substituent with greater extent
of structural variation, ranging from pyridyl and phenylpiperidine
to larger and more flexible substituted ethers as in 4 and 5. In
summary, inspection of the molecules in Figure 2 and overlay in
Figure 3 helped identify conserved features of mGluR2 PAM
molecules and suggested that alternative scaffolds with suitable
features and decoration would yield new hits.
Figure 3. Overlay of molecules 4–8. Selected conserved features are highlighted
with dotted spheres, H-bond acceptor, small scaffold substituent and larger
lipophilic scaffold group. Molecule color-coding: 4—yellow, 5—magenta, 6—green,
7—black, 8—blue.
been implemented.15 In this project a similar approach was ap-
plied. Search queries were defined as scaffold fragments of mole-
cules 6–8 with phenyl, ethyl and chloro decoration to mimic the
complete molecules, see pyridone query in Figure 4. The search
database was constructed from two sources: ideas from the project
team and scaffolds generated in an automated fashion via frag-
mentation of in-house and external compound collections. Data-
base fragments were capped in an analogous manner to the
queries using phenyl, ethyl and chloro at each open valence. The
database contained 115,647 fragments and 3D conformations were
generated with Omega.16 The lowest energy conformer was used
Within our labs a process of scaffold hopping using annotated
fragment databases and 3D shape and electrostatic similarity has

G. Tresadern et al. / Bioorg. Med. Chem. Lett. 20 (2010) 175–179
177
shown in Figure 4. Overall they have similar shape, size and distri-
bution of substituent groups. The negative region of the carbonyl
acceptor is well reproduced by the imidazo nitrogen. The phenyl
groups are both twisted yielding very similar regions of negative
charge above and below the ring. In addition the positive regions
produced by –CH moieties on the scaffold are well matched. Before
synthesis a virtual library of imidazopyridines was enumerated
and target compounds including examples from Tables 1 and 2
with the best overall shape and feature similarity compared to
molecule 8 were prioritized.
The synthesis of the final imidazo[1,2-a]pyridines19 is depicted
in Schemes 1 and 2. Microwave promoted thermal condensation of
Figure 4. Electrostatic fields of (a) pyridone query and (b) imidazopyridine hit
commercially available pyridine derivative 11 with an a-bromoal-
fragment. Negative field is red and positive blue.
dehyde 12 afforded in moderate to good yields the 8-cyano-7-
hydroxyimidazo[1,2-a]pyridines 13. Subsequent reaction of 13
with P(O)Cl3 led to the corresponding chloro derivatives 14 which
were then transformed into the final compounds 16 by nucleo-
philic substitution of the chlorine atom with secondary amine 15
in the presence of diisopropylethylamine (DIPEA) under micro-
wave irradiation (Scheme 1).
for each query whilst default settings generated multiple 3D
conformers of each database fragment. Firstly, searches were
performed with ROCS17 using comboscore ranking to align and
identify shape and feature similar database fragments. Subse-
quently the top 500 hits were re-ranked by their electrostatic field
similarity to the query using EON.18
From the search using the pyridone query the imidazopyridine
was identified among the best ranked hits. The Poisson–Boltzmann
electrostatic Tanimoto similarity was 0.87. The query and hit are
In the case of aryl substituted imidazo[1,2-a]pyridines 18 the
target compounds were obtained by Suzuki coupling of the corre-
sponding boronic esters 17 with the chloroimidazopyridine 14a.
Table 1
Functional activity and metabolic stability in rat (RLM) and human liver microsomes (HLM) of representative mGluR2 PAMs (general structure 16)a
R1-
R2-
mGluR2 pEC50
mGluR2 EMAX (%)
RLMb,c (%)
HLMb,c (%)
a
a
Compds
3
5
8
—
—
—
—
—
—
7.51
7.56
6.20
124
213
235
nd
nd
nd
nd
nd
nd
16a
16b
16c
16d
16e
16f
6.01
<5.5
<5.5
<5.5
5.96
6.07
241
73
88
nd
nd
nd
nd
26
71
nd
nd
nd
57
32
N
214
248
229
231
N
N
N
N
N
N
CF3
N
N
16g
16h
16i
5.64
6.19
6.35
142
179
128
nd
nd
nd
70
70
57
N
N
N
N
N
CF3
a
b
c
Values are means of three experiments.
RLM and HLM data refer to % of compound metabolized after 15 min at 5
nd: not determined.
lM concentration.

178
G. Tresadern et al. / Bioorg. Med. Chem. Lett. 20 (2010) 175–179
Table 2
Functional activity and metabolic stability in rat (RLM) and human liver microsomes (HLM) of representative mGluR2 PAMs (general structure 18)a
R1-
Ar-
mGluR2 pEC50
mGluR2 EMAX (%)
RLMb,c (%)
HLMb,c (%)
a
a
Compds
CF3
CF3
18a
6.35
272
123
21
32
18b
6.63
nd
nd
N
Cl
CF3
18c
18d
6.85
6.73
187
200
38
23
28
23
N
H
CF3
CF3
O
18e
6.80
222
nd
nd
O
a
b
c
Values are means of three experiments.
RLM and HLM data refer to % of compound metabolized after 15 min at 5
nd: not determined.
l
M concentration.
NH2
N
N
the bicyclic imidazopyridine core (Table 1). Thus lipophilic alkyl
and aryl groups such as n-propyl (16a, 16d and 16h), phenyl
(16b), ethyl (16c and 16g), cyclopropylethyl (16e) and 2,2,2-tri-
fluoroethyl (16f and 16i) were introduced. It was pleasing that
amongst the first molecules synthesized with the new scaffold,
mGluR2 PAM activity was found. This suggested that the scaffold
replacement strategy was successful. However, not all combina-
tions were well tolerated. The n-propyl group was active in com-
pounds 16a and 16h yet 16d, although delivering an increase in
glutamate response, EMAX 248%, did not have a pEC50 greater than
the concentration limit. The highest pEC50 was observed for the
more lipophilic groups as seen in the trend within the two subser-
ies 16c–f and 16g–i.21 The 2,2,2-trifluoroethyl was the most active
group in combination with both pyrimidylpiperazinyl groups in
compounds 16f and 16i with pEC50 values of 6.07 and 6.35, respec-
tively. For compound 16c having the less lipophilic ethyl residue a
pEC50 could not be measured despite showing an increase in gluta-
mate signal. In mGlu2 binding experiments 16f displaced a triti-
ated analogue from the pyridone series with a pIC50 of 6.4
offering further experimental support for the scaffold hopping
replacement of pyridone by imidazopyridine. Overall interesting
functional activity was found in a similar range to the analogous
pyridone 8, pEC50 = 6.20 and EMAX 235%. However, the compounds
were less active than reference compounds 3 and 5 in the same as-
say, 7.51 and 7.56, respectively.
NC
NC
HO
Br
R1
(i)
N
+
OHC
12
R1
MeO
11
13
N
NH
N
NC
R1
NC
Cl
N
R1
N
N
R2
15
(ii)
N
(iii)
N
R2
14
16
Scheme 1. Reagents and conditions: (i) EtOH,
l
W, 150 °C, 40 min, 50–82%; (ii)
P(O)Cl3,
97%.
lW, 150 °C, 15 min, 70–85%; (iii) DIPEA, CH3CN, mW, 180 °C, 15 min, 67–
O
N
N
CF3
CF3
B
O
NC
Cl
NC
Ar
Ar
N
N
17
(i)
14a
18
Some of the compounds shown in Table 1 were tested for single
point microsomal stability in rat and human liver microsomes.
Examples containing linear alkyl chains such as n-propyl 16a suf-
fered from extensive metabolism 88% and 71% metabolized after
15 min in rat and human liver microsomes, respectively. Com-
pound 16f with the 2,2,2-trifluoroethyl substituent was better,
being 26% metabolized in rat and 32% in human microsomes.
With the aim of expanding the SAR and the hope of improving
in vitro activity and metabolic stability, the amines present in the
structures of 16a–i were replaced by different substituted aryl
groups leading to the arylimidazo[1,2-a]pyridines 18a–e shown
in Table 2. The 2,2,2-trifluoroethyl substituent on the imidazole
Scheme 2. Reagents and conditions: (i) Pd(PPh3)4, NaHCO3 (aq)/1,4-dioxane,
150 °C, 15 min 71–88%.
The functional activity20 and microsomal stability data for a set
of selected imidazo[1,2-a]pyridines are listed in Tables 1 and 2.
Two activity data are reported for each molecule: the maximum
% effect increase in glutamate response (EMAX) and the pEC50 for
the modulatory effect.
Based on data from our previous hit 88f we initially decided to
use different phenylpiperazinyl and pyrimidylpiperazinyl groups
to study the influence of substitution on the imidazole ring of

G. Tresadern et al. / Bioorg. Med. Chem. Lett. 20 (2010) 175–179
179
6. Fell, M. J.; Svensson, K. A.; Johnson, B. G.; Schoepp, D. D. J. Pharmacol. Exp. Ther.
2008, 326, 209.
ring was fixed as it had delivered improved pEC50 activity and met-
abolic stability. In general a diverse range of substituents were well
tolerated in the aromatic ring (chloro-, alkyl-, amino-, aryloxy-
groups) and a good level of activity was retained. As observed in
the case of the aminoimidazo[1,2-a]pyridines 16 the 2,2,2-trifluo-
roethyl substituent led to improved metabolic stability in both
HLM and RLM (18a and 18c,d). These compounds were more active
than the examples in Table 1 and in all cases more active than the
pyridone compound 8. Increase in the EMAX glutamate response
was also good.
As mentionedearlier, oneadvantage of allosteric modulationis to
facilitate the identification of selective compounds. To examine the
selectivity of this new series, examples from both the aminoimi-
dazo[1,2-a]pyridines 16 and arylimidazo[1,2-a]pyridines 18 were
profiled in a panel of mGluR assays.22 Examples such as 16f, 16h
and 18d showed no activity in either agonism or antagonism assays
of mGluR1, mGluR3, mGluR4, mGluR5, mGluR6, mGluR7 or mGluR8
7. Jeffrey Conn, P.; Christopoulos, A.; Lindsley, C. W. Nat. Rev. Drug Disc. 2009, 8, 41.
8. Compound 3: (a) Barda, D. A.; Wang, Z. Q.; 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; compound 4: (b) 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; compound 5: (c) Pinkerton, A. B.;
Cube, R. V.; Hutchinson, J. H.; James, J. K.; Gardner, M. F.; Rowe, B. A.;
Schaffhauser, H.; Rodriguez, D. E.; Campbell, U. C.; Daggett, L. P.; Vernier, J. M.
Bioorg. Med. Chem. Lett. 2005, 15, 1565; (d) compound 6: Empfield, J.; Folmer, J.
WO2007/095024 A1; (e) compound 7: Balestra, M.; Bunting, H; Chen, D.; Egle,
I.; Forst, J.; Frey, J.; Isaac, M.; Ma, F.; Nugiel, D.; Slassi, A.; Steelman, G.; Sun, G.;
Sundar, B.; Ukkiramapandian, R.; Urbanek, R.; Walsh, S. WO2006/071730 A1;
(f) compound 8: Cid-Nuñez, J. M.; Andrés-Gil, J.; Trabanco-Suárez, A. A.,
Oyarzábal-Santamarina, J.; Dautzenberg, F.; Macdonald, G.; Pullan, S.; Lutjens,
R.; Duvey, G.; Nhem, V.; Finn, T.; Melikyan, G. WO2007/104783 A1; compound
9: (g) Zhang, L.; Rogers, B. N.; Duplantier, A. J.; McHardy, S. F.; Efremov, I.;
Berke, H.; Qian, W.; Zhang, A. Q.; Maklad, N.; Candler, J.; Doran, A. C.; Lazzaro,
J.; Ganong, A. H. Bioorg. Med. Chem. Lett. 2008, 18, 5493; compound 10: (h)
Duplantier, A. J.; Efremov, I.; Candler, J.; Doran, A. C.; Ganong, A. H.; Haas, J. A.;
Hanks, A. N.; Kraus, K. G.; Lazzaro, J.; Lu, J.; Maklad, N.; McCarthy, S. A.;
O’Sullivan, T. J.; Rogers, B. N.; Siuciak, J. A.; Spracklin, D. K.; Zhang, L. Bioorg.
Med. Chem. Lett. 2009, 19, 2524.
at 10 lM.
In summary, a series of imidazo[1,2-a]pyridines with mGluR2
PAM activity have been presented. The scaffold was identified via
shape and electrostatic similarity to a known pyridone family pre-
viously reported by our team.8f Such approaches can be of value for
providing new chemical series in medicinal chemistry programs.
Incorporating side chains from our other pyridone series led to
the rapid identification of hits. The reported compounds show
comparable in vitro activity to reference compounds and examples
displayed favorable metabolic stability. Imidazo[1,2-a]pyridines
represent a promising avenue for current exploration.
9. Recasens, M.; Guiramand, J.; Aimar, R.; Abdulkarim, A.; Barbanel, G. Curr. Drug
Targets 2007, 8, 651.
10. Gjoni, T.; Urwyler, S. Neuropharmacology 2008, 55, 1293.
11. 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.
12. Galici, R.; Jones, C. K.; Hemstapat, K.; Nong, Y.; Echemendia, N. G.; Williams, L.
C.; de Paulis, T.; Conn, P. J. J. Pharmacol. Exp. Ther. 2006, 318, 173.
13. Chemical Computing Group Inc. Molecular Operating Environment (MOE),
1010 Sherbrooke St. W, Suite 910, Montreal, QC, Canada; available from
Chemical Computing Group Inc. at http://www.chemcomp.com. 2009.
14. mGluR2 PAM binding data generated in house via displacement of a tritiated
compound from our internal pyridone series (structure not disclosed) provides
support that some examples share a common binding site. Example 5 had a
pIC50 of 6.8 and another member of the isoindolone series displayed pIC50 of
6.6.
Acknowledgements
15. Oyarzábal, J.; Howe, T.; Alcazar, J.; Andrés, J. I.; Alvarez, R. M.; Dautzenberg, F.;
Iturrino, L.; Martínez, S.; Van der Linden, I. J. Med. Chem. 2009, 52, 2076.
16. OMEGA. OpenEye Scientific Software, Inc.; http://www.eyesopen.com. 2006.
17. Grant, J. A.; Gallardo, M. A.; Pickup, B. T. J. Comput. Chem. 1996, 17, 1653.
18. Nicholls, A.; MacCuish, N. E.; MacCuish, J. D. J. Comput. Aided Mol. Des. 2004, 18,
451.
The authors thank collaborators from Addex pharmaceuticals;
members of the purification and analysis group; and the in vitro
metabolism team from the discovery ADME/Tox group.
19. Trabanco-Suárez A. A.; Tresadern G. J.; Vera-Ramiro J. A.; Cid-Nuñez J. M.
WO2009/062676 A2.
References and notes
20. The effect of these compounds on the [35S]-GTP
cS binding induced by 4 lM
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glutamate (ꢀEC20) was characterized using a CHO cell line expressing the
human mGluR2 receptor. See Ref. 19 for a detailed description of this assay.
21. The calculated Alog P for 16c–f were 1.2, 1.6, 2.0 and 1.6, respectively, and 1.8,
2.2 and 2.2 for 16g–i.
22. Compounds were tested for agonist or antagonist activity on mGlu receptors in
fluorescent Ca2+ assays using HEK293 cells expressing human mGluR1,
mGluR5, mGluR3, mGluR7 or mGluR8. Effects on the human mGluR4 and rat
mGluR6, expressed in L929 or CHO cells, were assessed in
functional assays.
[ cS
35S]-GTP