Azetidinyl oxadiazoles as potent mGluR5 positive allosteric modulators

Article abstract of DOI:10.1016/j.bmcl.2012.08.044

A novel series of aryl azetidinyl oxadiazoles are identified as mGluR5 positive allosteric modulators (PAMs) with improved physico-chemical properties. N-substituted cyclohexyl and exo-norbornyl carboxamides, and carbamate analogs of azetidines are moderate to potent mGluR5 PAMs. The aryl, lower alkyl carboxamides analogs and sulfonamide analogs of azetidines are moderate mGluR5 negative allosteric modulators (NAMs). In the aryl oxadiazole moiety, substituents such as fluoro, chloro and methyl are well tolerated at the meta position while para substituents led to either inactive compounds or NAMs. A tight pharmacophore and subtle 'PAM to NAM switching' with close analogs makes the optimization of the series extremely challenging.

Full text of DOI:10.1016/j.bmcl.2012.08.044

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6469–6474
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Azetidinyl oxadiazoles as potent mGluR5 positive allosteric modulators
Mathivanan Packiarajan a, , Christine G. Mazza Ferreira a, Sang-Phyo Hong a, Andrew D. White a,
⇑
Gamini Chandrasena a, Xiaosui Pu b, Robbin M. Brodbeck b, Albert J. Robichaud a
a Chemical & Pharmacokinetic Sciences, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA
b Synaptic Transmission, Disease Biological Unit, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of aryl azetidinyl oxadiazoles are identified as mGluR5 positive allosteric modulators
(PAMs) with improved physico-chemical properties. N-substituted cyclohexyl and exo-norbornyl carbox-
amides, and carbamate analogs of azetidines are moderate to potent mGluR5 PAMs. The aryl, lower alkyl
carboxamides analogs and sulfonamide analogs of azetidines are moderate mGluR5 negative allosteric
modulators (NAMs). In the aryl oxadiazole moiety, substituents such as fluoro, chloro and methyl are well
tolerated at the meta position while para substituents led to either inactive compounds or NAMs. A tight
pharmacophore and subtle ‘PAM to NAM switching’ with close analogs makes the optimization of the
series extremely challenging.
Received 29 June 2012
Revised 2 August 2012
Accepted 13 August 2012
Available online 25 August 2012
Keywords:
mGluR5 positive allosteric modulators
Azetidinyl oxadiazoles
Azetidinyl N-cyclohexyl carboxamides and
carbamates
Ó 2012 Elsevier Ltd. All rights reserved.
Azetidinyl N-sulfonamides
PAM to NAM switching
Glutamate is the major excitatory neurotransmitter in the
mammalian central nervous system, where it mediates its effects
through three ionotropic (AMPA, kainate and NMDA) and eight
metabotropic receptors (mGluR1-8).1 The metabotropic glutamate
receptors (mGluRs) are class C GPCRs and contain two distinct do-
mains. A large extracellular domain binds glutamate while the
heptahelical transmembrane (7TM) domain binds a variety of
ligands at one or more allosteric binding sites.2 The mGluRs struc-
turally and pharmacologically associate with the NMDA receptor
to modulate roles in synaptic plasticity, cognition, and learning
and the memory process.3 The mGluR5 receptors are primarily lo-
cated post synaptically and are highly expressed in the limbic brain
regions.4 Activation of the mGluR5 receptor potentiates NMDA
receptor function and thus positive allosteric activation of mGluR5
could indirectly correct NMDA hypo-function. It has been postu-
lated that positive modulation of mGlu5 receptor could treat the
positive symptoms and cognitive deficits in schizophrenia,5–9 and
also improve spatial learning10,11 and cognition.12
used extensively as mGluR5 PAM tools. Compounds 317f and 418c
have been shown to reverse amphetamine induced hyperlocomo-
tion and conditioned avoidance responding (Fig. 1). We recently
reported the discovery of several novel classes of mGluR5 PAMs
including nicotinamides 5a,19b lactams 5b19c and N-aryl pyrrolidi-
nonyl oxadiazoles 6.19d
The compound 6 exhibits high potency at mGluR5 (EC50 = 10.7
nM) but poor solubility is an issue for this class of compounds. In
continuing our efforts to identify novel compounds with improved
physio-chemical properties, we initiated the optimization of the
pyrrolidinonyl oxadiazole analog 6. We postulated that the core
pyrrolidinone ring could be replaced with a smaller azetidine ring,
coupled with exocyclic transposition of the carbonyl group. The
resulting 4-fluorobenzamide analog 7a is devoid of mGluR5 PAM
potency and exhibits weak NAM potency (IC50 = 4000 nM) with
improved solubility (47 lM). However, replacement of the chlorine
atom with a methyl group on the aryl moiety in compound 7d
results in a moderately active PAM (Fig. 2). A benzamide was found
not to be crucial for PAM activity as the cyclohexyl amide 13a has
similar activity to the benzamide 7d. In this Letter, we report our
efforts towards the optimization of azetidinyl oxadiazoles as novel
mGluR5 positive allosteric modulators.
Azetidinyl oxadiazole analogs (7,12–14, 16 and 17) were synthe-
sized as outlined in Scheme 1. Coupling of N-Boc protected azetidine
carboxylic acid 9a–b with aryl-N-imidoximes 8a–c using HBTU in
the presence of Et3N followed by heating under microwave irradia-
tion or refluxing condition affords the aryl oxadiazoles 10a–c in
moderate yield (40–60%).20a Alternatively, the oxadiazoles can be
There has been considerable interest recently in identification
of positive allosteric modulators (PAMs) of the mGlu5 receptor.13
Over the last few years, structurally distinct chemotypes of
mGluR5 PAMs have been reported from various groups.14–19
Compounds such as 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-
yl)benzamide (1, CDPPB)15a,b and ADX47273 (2)16a–c have been
⇑
Corresponding author. Tel.: +1 201 820 1971; fax: +1 201 261 0623.
E-mail address: packiara@yahoo.com (M. Packiarajan).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.08.044

6470
M. Packiarajan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6469–6474
N
O
F
Cl
N
H
N
F
N
N
H
N
N
N
N
N
N
O
CN
O
O
O
N
1: CDPPB
2: ADX47273
3
4
F
O
N
O
O
O
Cl
N
N
N
HN
N
N
5a
5b
6
F
Figure 1. mGluR5 positive allosteric modulators.
O
N
O
N
N
O
O
O
O
N
N
N
H3C
Cl
N
Cl
N
N
F
F
F
7d: EC50 1400 nM (60%)
6: EC50 10.7 (55%)
7a: IC50 4000 nM (60%)
Figure 2. Azetidinyl oxadiazoles as mGluR5 positive allosteric modulators.
O
OH
O
O
N
N
O
N
OH
N
R1
O
O
N
NH
R
N
R
b
N
N
a
c
R
N
N
R
+
O
NH2
N
7: R1 = Aryl
13: R1 = Alkyl
17: R1 = Bicyclic
R = F, Cl Me
10 a - c
8 a - c
R = F, Cl and Me
11a - c
9a
O
O
d
e and f
and
O
S
O
R
N
O
R1
O
N
N
R
R
N
Cl
N
N
12
14
O
O
N
O
N
N
OH
O
N
N
R
a and b
c
N
R
N
H
8 a - c
+
O
R'
O
O
9b
15a
15b
16
R = F and Me
and
R = F and Me
Scheme 1. Reagents and conditions: (a) HBTU, Et3N, DMF, 5 min, rt, then add 9a or 9b, microwave, 190 °C, 15 min, 40–60%; (b) 4 M HCl in dioxan, rt, >99%; (c) RCOOH, HBTU,
DIEA, DMF, rt or RCOCl, Et3N, CH2Cl2, rt, 20–70%; (d) Et3N, CH2Cl2, R1SO2Cl, rt, 50–75%; (e) trisphosgene, CH2Cl2, 0 °C to rt or 4-nitrochloroformate, CH2Cl2, Et3N, 0 °C and (f)
R0R0NH, CH2Cl2, rt, 30–55%.
synthesized via activation of the acid 9a with CDI at room temper-
ature followed by treatment with amidoximes 8 under refluxing
conditions.20b The N-Boc group was removed by treatment with
10% TFA in DCM or 4 M HCl in methanol in quantitative yield. In
an analogous manner, the 2S-(ꢀ) enantiomer of the azetidinyl-2-
carboxylic acid 9b was converted into the corresponding azetidinyl
oxadiazoles (15) in two steps.
The azetidine salts (11a–11c and 15) were treated with suitable
aryl or alkyl carboxylic acid chlorides in the presence of Et3N to af-
ford the amide analogs (7, 13 and 16). Alternatively, treatment of
alkyl carboxylic acid with HBTU in the presence of DIEA affords
the azetidine carboxamides analogs (13 and 17). In analogous
manner, the azetidines HCl (11) were treated with aryl sulfonyl
chlorides at room temperature affording azetidinyl sulfonamides
(12a–12h) in good yield. The carbamate analogs were synthesized
in a two-step process by reaction of azetidines 11a with triphos-
gene or 4-nitrophenyl chloroformate followed by treatment with
cyclic amines in the presence of base to afford azetidinyl carba-
mate analogs (14a–14j).
The SAR of the peripheral aryl rings is shown in Table 1.
Replacement of the chloro substituent of compound 7a with a
methyl group resulted in compound 7d having moderate PAM

M. Packiarajan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6469–6474
6471
Table 1
The in vitro mGluR5 functional affinities of aryl carboxamide analogs 7
Table 3
SAR of azetidinyl amide analogs 13
O
N
O
N
N
R1
O
R
N
R
N
N
R1
O
13
7
a
a
Compound
R
R1
EC50
(nM)
Emax
(%)
IC50
Inh.a
(%)
a
a
(nM)
Compound
R
R1
EC50 (nM) Emax (%) IC50 (nM) Inh.b (%)
7a
7b
7c
7d
7e
7f
7g
7h
7i
Cl
Cl
Cl
4-F
3-F
2-F
>10000
>10000
>10000
1400
>10000
>10000
7100
2400
2500
6800
3200
ꢀ12
ꢀ12
ꢀ12
32
15
5
33
40
62
27
4000
780
670
>10000
2100
1400
>10000
>10000
>10000
>10000
>10000
60
87
86
50
62
64
ꢀ6.3
ꢀ6
ꢀ82
ꢀ30
ꢀ50
13a
13b
CH3
CH3
950
45
68
>10000
ꢀ20
CH3 4-F
CH3 3-F
CH3 2-F
CH3 4-Cl
F
F
F
F
970
500
>10000
>10000
ꢀ49
ꢀ19
4-F
4-Cl
4-CH3
3,4-Di F
13c
CH3
46
7j
7k
35
13d
13e
13f
13g
CH3
CH3
CH3
CH3
1000
>10000
>10000
>10000
36
ꢀ7
3
>10000
2500
3
70
77
80
CF3
a
The mGluR5 EC50 and IC50 functional FLIPR data were generated using a human
mGluR5 cell line.21
b
A negative % inhibition value represents positive allosteric modulation.
1000
Table 2
SAR of azetidinyl sulfonamide analogs 12
ꢀ7
1300
O
13h
CH3
>10000
3
1900
79
R1
O
N
N
O
R
N
S
13i
13j
13k
13l
CH3
CH3
Cl
O
>10000
590
ꢀ2
36
43
ꢀ7
1800
>10000
>10000
1500
74
ꢀ3
O
O
12
F
F
Compound
R
R1
EC50 (nM)
Emax (%)
IC50 (nM)
Inh. (%)
a
a
12a
12b
12c
12d
12e
12f
Cl
Cl
Cl
Cl
CH3
CH3
CH3
CH3
4-CH3
4-Cl
4-F
3-CH3
4-CH3
4-Cl
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
2
7
ꢀ7
ꢀ2
1
3
6
ꢀ4
920
170
130
390
670
1100
950
650
75
79
85
82
80
75
74
76
520
ꢀ35
75
Cl
>10000
12g
12h
4-F
3-CH3
13m
Cl
>10000
ꢀ3
890
79
O
a
The mGluR5 EC50 and IC50 functional FLIPR data, see footnote in Table 1.21
F
F
13n
13o
Cl
Cl
180
75
75
>10000
ꢀ3
1500
>10000 ꢀ120
potency at the mGlu5 receptor. However, moving the fluoro group
of the benzamide from the para to the meta or ortho positions
caused loss of PAM activity and the analogs (7b, 7c, 7e and 7f) be-
came weak NAMs. The fluoro substituted aryl oxadiazole analogs
(7h–7k) retain moderate PAM potency. To our disappointment,
azetidinyl sulfonamide analogs (12a–12h) exhibit NAM activity at
the mGluR5 receptor (Table 2).
Since the amide analog 7d was promising, we decided to inves-
tigate further with non-aromatic carboxamides. Interestingly,
introduction of a cyclohexyl group (13a) resulted in an improve-
ment of PAM potency. This result led us to further investigate cyclo-
alkyl rings (13a–13x) and the results are summarized in Table 3.
Groups such as cyclobutyl, cyclopentyl, tetrahydrofuranyl and
tetrahydropyranyl results in compounds with varying degrees of
NAM potency at mGlu5 receptor. On the other hand, substituted
cyclohexyl carboxamide analogs are mGluR5 PAMs with moderate
potency. The 4,4-difluoro cyclohexyl carboxamide analogs are po-
tent mGluR5 PAMs (13j, 13n and 13u Table 3). In the cyclohexyl
moiety, substituents such as methyl, trifluoromethyl and a spirocy-
cle are tolerated, but groups such as methoxy or hydroxyl groups
cause complete loss of PAM or NAM potency (data not shown). In
addition, introduction of the smaller acyclic carboxamides such
as cyclopropyl, difluorocyclopropyl, fluorocyclopropyl, methyl
13p
Cl
410
53
>10000
ꢀ34
13q
13r
Cl
Cl
CF3
1000
1100
1000
40
40
46
>10000
>10000
>10000
ꢀ5
ꢀ24
ꢀ19
13s
13t
Cl
F
13u
F
540
87
>10000
ꢀ48
F
F
13v
13w
13x
F
F
F
520
2200
680
53
47
56
>10000
>10000
>10000
11
ꢀ11
ꢀ37
CF3
The mGluR5 EC50 and IC50 functional FLIPR data, see footnote in Table 1.21
a

6472
M. Packiarajan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6469–6474
Table 4
Table 5
SAR of azetidinyl carbamate analogs 14
The in vitro mGluR5 functional affinities of amide analogs 16
R1
R
O
O
N
N
R
O
N
Cl
N
N
N
R
O
N
16
14
a
a
Compound HNRR
EC50
Emax
(%)
IC50
Inh.a
(%)
Compound
R
R1
EC50
Emax
(%)
IC50
Inh.a
(%)
a
a
(nM)
(nM)
(nM)
(nM)
14a
14b
HN
HN
370
44
66
>10000
>10000
ꢀ87
16a
16b
F
F
1200
29
52
>10000
ꢀ12
ꢀ75
865
>10000
990
n/a
F
F
14c
14d
6
3400
69
2400
>10000
920
HN
HN
F
41
>10000
ꢀ61
F
16c
16d
F
>10000
>10000
57
68
58
HN
14e
200
51
>10000
ꢀ81
F
F
CH3
6.2
1800
14f
HN
HN
OCH3 >10000
11
>10000
1830
n/a
80
F
14g
>10000
ꢀ14
16e
16f
16g
CH3
CH3
CH3
1500
51
88
24
>10000
1400
ꢀ92
72
OCH3
F
>10000
1900
CN
14h
HN
O
>10000
n/a
990
51
>10000
ꢀ30
F
HN
HN
14i
14j
47
44
88
>10000
>10000
ꢀ41
The mGluR5 EC50 and IC50 functional FLIPR data, see footnote in Table 1.21
a
>10000
80
n/a = not available
a
The mGluR5 EC50 and IC50 functional FLIPR data, see footnote in Table 1.21
Table 6
The in vitro mGluR5 functional affinities of bicyclic amide analogs 17
substituted cyclopropyl or linear alkyl groups with or without tri-
fluoromethyl group causes loss of mGluR5 activity (data not
shown). In the aryl oxadiazole moiety, the substituents chloro,
fluoro and methyl at the meta position result in PAMs while these
groups at the para position result in analogs with NAM potency
(data not shown).
O
N
R
N
N
O
H
17
a
Next we examined carbamate analogs of the azetidinyl oxadiaz-
oles (Table 4). Piperidinyl carbamate analogs (14a, 14b, 14d and
14e) retain mGlu5 PAM potency similar to carboxamide analogs.
Methoxy substituted piperidinyl carbamates (14f and 14g) or a
morpholinyl analog 14h cause complete loss of PAM or NAM po-
tency similar to the corresponding carboxamide analogs. Replace-
ment of the piperidine with an azepine (14i) results in a potent
PAM. On the other hand, incorporation of a substituted pyrrolidine
analog (14j) caused loss of PAM and NAM potency.
Compound
R
Conf.
EC50 (nM)
Emax (%)
cLogPb
17a
17b
17c
17d
17e
17f
H
H
F
F
Cl
Cl
2S
2R
2S
2R
2S
2R
120
400
72
100
74
160
88
140
110
120
66
2
2
2.1
2.1
2.7
2.7
98
The mGluR5 EC50 functional FLIPR data, see Table 1.21
cLogP was calculated using ChemBioDraw Ultra version 12.0.
a
b
We investigated the regio isomeric 2-azetidinyl oxadiazole ana-
logs (Table 5) with aryl, alkyl and cycloalkyl carboxamides. We no-
ticed that both aryl and cycloalkyl carboxamide analogs exhibit
moderate NAM activity with the exception of the 3,4-difluoro benz-
amide analog (16e) which shows PAM activity. However, elonga-
tion of the benzamides to arylacetamides results analogs 16a,
16b and 16g with intermediate PAM potency.
Interestingly, by increasing the lipophilicity of the amide moi-
ety in 3-azetidinyl oxadiazole series, via incorporation of an exo-
norbornyl carboxamide results in compounds (17a–f) having more
consistent PAM activity (Table 6). For example, the ‘2S’ enantio-
mers (17a, 17c and 17e) exhibit higher PAM potency and efficacy
than the corresponding ‘2R’ enantiomers (17b, 17d and 17f).
Compounds 13n, 13u and 17c (Fig. 3) were profiled further and
the data is sown in Table 7. The selected compounds have reason-
able cLogPs, lipophilic efficiencies (LLE) and solubility. Compound
13n exhibits moderate PAM potency at mGlu5 receptor
(EC50 = 180 nM) with a weak binding affinity of 3800 nM in the
radiolabelled binding assay and has moderate solubility
(130 lM). Compound 13n is highly selective among the other
mGluR subtypes tested (mGluR1, mGluR2, mGluR4 and mGluR7)
in agonist, PAM and NAM mode. It does not show significant inhi-
bition of the 2D6 and 3A4 cytochrome P450 (CYP) isoforms
(IC50 >25 lM). Compound 13n has moderately high rat (96.9%)

M. Packiarajan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6469–6474
6473
O
O
O
O
N
O
N
O
N
N
N
Cl
F
N
N
N
F
F
F
H
N
F
F
13n
13u
17c
Figure 3. Key compounds.
Table 7
Profiling data of selected key compounds (in vitro metabolic clearance, CYP inhibition and rat in vivo pharmacokinetic data)
Solb
(mM)
cLogPc LLEd hClint
rClint
hPPB
(%)
rPPB
(%)
CYP3A4
(IC50, mM)
CYP2D6
(IC50, mM)
Brainf
(ng/g)
Plasmaf
(ng/mL)
Brain to plasma
ratiof (B/P)
e
e
Compound mGluR5
a
EC50 (nM)
(L/min)
(mL/min)
13n
13u
17c
180
520
72
130
180
54
1.8
1.2
2.1
5.1
5.1
5.1
0.9
1.6
59
24
13
16
98.7
96.6
99.3
96.9
94.5
99.2
25
25
n/a
33
40
n/a
280
n/a
84
160
n/a
36
1.75
n/a
2.33
a
b
c
For the mGluR5 EC50 functional FLIPR data see Table 1.21
The solubility (l
g/mL) was measured using DMSO stock solution22
cLogP was calculated using ChemBioDraw Ultra version 12.0
d
e
Lipophilic ligand efficiency (LLE).24 = pEC50–cLogP
The hClint and rClint are human (L/min) and rat (mL/min) intrinsic clearances, respectively, and were determined according to Obach et al.,23 rat and human liver blood
flow corresponds to 20 mL/min and 1.5 L/min, respectively.
f
Exposure was determined in brain and plasma after a single oral dose (10 mg/kg po, n = 2).25
3. (a) Anwyl, R. Neuropharmacology 2009, 56, 735; (b) Neisewander, J. L.; Baker, D.
and human (98.7%) plasma protein binding. In rat PK studies, the
compound 13n exhibits a moderate exposure in brain 1 h, follow-
ing a 10 mg/kg oral (po) dose (brain = 280 ng/g; plasma = 160 ng/
mL) with a brain to plasma (B/P) ratio of 1.75. Compound 13u
exhibits moderate PAM potency but with improved properties.
On the other hand, compound 17c is highly protein bound (rPB
and hPB are 99.2% and 99.3%, respectively) with lower brain
A.; Fuchs, R. A.; Tran-Nguyen, L. T.; Palmer, A.; Marshall, J. F. J. Neurosci. 2000,
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exposure at 1 h, following
a
10 mg/kg oral (po) dose
(brain = 84 ng/g; plasma = 36 ng/mL) with a brain to plasma (B/P)
ratio of 2.33.
In summary, we have described a new series of azetidinyl oxa-
diazoles (13 and 17) which are mGluR5 positive allosteric modula-
tors (PAMs). The azetidine carboxamides are low molecular weight
(<350) optimal cLogP (<3) compounds with improved physico-
chemical and PK properties versus the N-aryl pyrrolidinonyl
oxadiazole lead 6. Substituted cyclohexyl and exo-norbornyl
carboxamides, and carbamate analogs are mGluR5 PAMs whereas
the aryl, lower alkyl carboxamide and sulfonamide analogs are
moderate mGluR5 negative allosteric modulators (NAMs). The opti-
mization of initial lead 6 led to the identification of the potent
compounds 13n and 17c with improvements in the solubility,
cLogP, LLE and acceptable PK properties. However, the moderate
potency remains an issue for this series of compounds. Also, simple
structural modifications lead to PAM/NAM switching, thus making
optimization a challenge.
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Acknowledgments
We thank our colleagues Manual Cajina, Megan E. Nattini and
Kimloan Nguyen (Bioanalysis, pharmacokinetics metabolic stabil-
ity and CYP inhibition); Xu Zhang, Qing-Ping Han and Chi Zhang
(chiral separation and physico-chemical property determination);
Michelle B. Uberti and Christina L. Bonvicino (functional data) for
providing experimental data to support this work. We thank Dipt-
endu Goswami (Chembiotek, India) for synthetic support for this
work.
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of the EC80 response to
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l
l
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1.7
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