Discovery of biological evaluation of pyrazole/imidazole amides as mGlu5 receptor negative allosteric modulators

Article abstract of DOI:10.1016/j.bmcl.2013.01.116

Development of SAR in a 5-aryl-3-acylpyridinyl-pyrazoles and 1-aryl-4-acylpyridinyl imidazoles series of mGlu5 receptor negative allosteric modulators (mGluR5 NAMs) using a functional cell-based assay is described in this Letter. Analysis of the Ligand-lipophilic efficiency (LipE) of compounds provided new insight for the design of potent mGluR5 negative allosteric modulators with anti-depressant activities.

Full text of DOI:10.1016/j.bmcl.2013.01.116

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2134–2139
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of biological evaluation of pyrazole/imidazole amides
as mGlu5 receptor negative allosteric modulators
⇑
Eunhee Chae , Yong-Je Shin, Eun-Ju Ryu, Mi Kyung Ji, Nahm Ryune Cho, Ki-Ho Lee, Hyun Ji Jeong,
Soo-Jin Kim, Yeonjung Choi, Kyung Seok Oh, Chun-Eung Park, Young Soo Yoon
CNS Drug Discovery, Drug Development Center, SK Biopharmaceuticals, Daejeon 305-712, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Development of SAR in a 5-aryl-3-acylpyridinyl-pyrazoles and 1-aryl-4-acylpyridinyl imidazoles series of
mGlu5 receptor negative allosteric modulators (mGluR5 NAMs) using a functional cell-based assay is
described in this Letter. Analysis of the Ligand-lipophilic efficiency (LipE) of compounds provided new
insight for the design of potent mGluR5 negative allosteric modulators with anti-depressant activities.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 25 November 2012
Revised 23 January 2013
Accepted 24 January 2013
Available online 4 February 2013
Keywords:
Ligand-lipophilic efficiency (LipE)
Metabotropic glutamate receptor 5 (mGluR5)
Negative allosteric modulators
Antidepressant
Pyrazole amide
Imidazole amide
The metabotropic glutamate receptors (mGluRs) are members
of the GPCR-C family and classified into Group I (mGlu1 and
mGlu5), Group II (mGlu2 and mGlu3), or Group III (mGlu4, 6, 7,
8). All mGlu receptors have allosteric binding sites which are
topologically distinct and less conserved within the subtypes in
comparision to glutamate (orthosteric) binding sites.1 Beyond the
classical approach targeting the orthosteric binding site of these
receptors, the development of allosteric modulators represents
an emerging class of orally available small molecules offering
greater selectivity and better modulatory control at disease medi-
ating receptors.2 In recent years, a number of mGluR5 negative
allosteric modulators (NAMs) have reported positive data from
clinical studies in psychiatric disorders such as anxiety, depression,
pain, migraine, drug abuse and addiction.3 Since the discovery of
the diarylalkynes MPEP, many alkyne-based mGluR5 NAMs have
been developed as illustrated in Figure 1. Also, bioisosteric replace-
ment of the ethynyl bond, which keeps the molecular topology and
the established SAR within the alkyne series, have been published
in recent reviews.4
[d]isoxazole-3-carboxylic acid (5-chloro-2-hydroxy-phenyl)-amide
(HTS hit 1, Fig. 2) was identified as a potential starting point. Con-
ceptually, this scaffold is related to previously reported scaffolds as
exemplified in Carboxamide A6 (Fig. 1). So we could easily perform
a preliminary SAR (structure–activity relationship) as described in
Figure 2.
Based on prior SAR knowledge for mGluR5 NAMs, the initial
focus was centered on a 3-chlorophenyl derivative (2), which
resulted in the desired direction as demonstrated for meta-substi-
tution preference on aryl group in the previous literatures.3,4 Also,
amide N–H is thought to be a key part to target potencies of this
series as depicted in compounds 3 and 3a.7 It might be a pharma-
cophoric feature in which a conformational lock is provided by
intramolecular hydrogen bonds between proximal amide NH and
nitrogen on the pyrazole ring as shown in compound 3.8 Com-
pound 4 proved to be inactive and it was assumed that it could
not participate in an intramolecular hydrogen bonding interaction
or insufficient hydrophobic interaction between target and aro-
matic ring due to its appropriately constrained structure whereas
We conducted a high-throughput screening (HTS) with a FLIPR
Ca2+ mobilization assay in a human mGluR5/HEK293 to find novel
mGluR5 NAMs lacking the alkyne moiety which might be relevant
to chemical or metabolic liability as reported in the case of
ADX10059.5 With an IC50 of 373 nM, 5, 6-dihydro-4H-cyclopenta
compound 5 had moderate in vitro potency. Unfortunately,
compound 5 was very unstable in rat plasma (T1/2 <1 h) and it
prompted us to investigate factors that increase in plasma stability,
which resulted in compound 6. The improved rat plasma stability
in compound 6 (T1/2 >3 h) may stem from steric occlusion of the
potentially hydrolysable amide linkage.9 Furthermore, the intro-
duction of methyl group on the pyrazole ring of compound 6
offered additional beneficial effect in terms of mGluR5 target
⇑
Corresponding author.
E-mail address: Eunhee.chae@sk.com (E. Chae).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.116

E. Chae et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2134–2139
2135
(a)
N
N
N
F
F
N
NH2
(b)
N
Cl
RG-7090 Series
H
N
N
(Roche,Phase II)
MPEP
ADX 10059
F
N
Depression, Fragile X syndrome
(Novartis, Clinical hold)
(Addex, Clinical hold)
S
O
F
H
N
N
HO
O
Carboxamide A(NIH)
Unknown
N
N
H
CN
N
F
N
O
Dipraglurant
F
Mavoglurant
ADX 48621 Series
(Addex, Phase II)
PD-LID
STX107 Series
(Novartis, Phase II/III)
Fragile X syndrome
PD-LID
(Seaside Therapeutics, Phase II)
Fragile X syndrome
Figure 1. (a) mGluR5 NAMs structural template, (b) a structure of carboxamide A.
Cl
O
N
N
O
O
N
H
N
O
N
N
H
N
H
OH
H
N
O
N
N
N
N
N
N
3
1(HTS hit)
4
mGlu5 IC50 27nM
5
mGlu5 IC50 373nM
mGlu5 IC50 >1uM
mGlu5 IC50 95nM
N
O
Cl
O
N
N
H
N
N
O
6
H
N
O
mGlu5 IC50 4.4nM
N
3a
N
H
2
mGlu5 IC50 >1uM
N
mGlu5 IC50 63nM
N
ring B linkage core ring A
Figure 2. Preliminary exploration from HTS hit 1 to compound 6.
potency. A pharmacophoric overlay of compound 6 and references
(MPEP, RG-7090 series10 and Carboxamide A6 in Fig. 3) demon-
strated that there is a remarkable similarity between references
and compound 6. In addition, ring A segment of compound 6 is able
to mimic in those of RG-7090 series with slightly torsional
changes.
Before starting an investment of chemical resources on this
template, its overall selectivity profile was checked. Compound 6
was profiled against a battery of in vitro assays including human
at the 5HT2C, dopamine re-uptake transporter (DAT) and noradren-
aline re-uptake transporter (NET) (66%, 60% and 63% inh@10 M,
l
respectively). In order to deliver a candidate compound suitable
for in vivo investigation, it was thought to be crucial to balance tar-
get potency and lipophilicity. Over the past few years, lipophilic li-
gand efficiency (LLE or LipE, defined as pIC50–cLogP) concept
which correlates potency and lipophilicity has been utilized by
medicinal chemists to retrospectively evaluate compounds poten-
cies to properties.12 LipE is increased when the pIC50 is increased
by more than the increase in cLogP. This value of cLogP is often
consistent with reasonable in vivo clearance, solubility and protein
binding. An important point to note from LipE concept is that hav-
ing a design strategy targeting increased LipE values in a series of-
ten encounters compounds which have high metabolic clearance
even at lower lipophilicity. Thus, we focused a strategy on maxi-
mizing LipE values and improving the metabolic stability. These
considerations, together with the structural diversity of compound
6 (Three sites of diversity; ring A, B and core ring) encouraged us to
consider this series for further development.
mGluR1 at the compound concentration of 10 lM. Of 11 receptors
screened (Ricerca Biosciences),11 only weak, but detectable activity
The synthesis of this class of compounds was straightforward as
shown in Scheme 1. The pyrazole analogs were started with vari-
ous propiophenones via Claisen condensation to give the corre-
sponding diketo esters. Following cyclization with hydrazine
derivatives afforded the corresponding 3-substituted-pyrazole-
5-carboxylic acid ethyl esters. Almost all of esters were treated
with various anilines in the presence of AlMe3 (2 M solution in
Figure 3. Pharmacophoric alignment with references and compound 6 (Compound
6 is shown in yellow color; references in grey; oxygen in red, nitrogen in blue;
chlorine in green, fluorine in turquoise blue).

2136
E. Chae et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2134–2139
O
O
O
O
Y
N
N
R
c
N
N
N
b
a
O
O
z
Y, Z = N or C
X
X
O
X
R= Me,F,Cl,CF3
O
X
O
6-18, 26-40
O
OH
b
a
c
d
e
19
H
O
O
N
N
N
N
N
c
N
f
N
b
N
N
N
O
O
R1
O
O
HO
HO
O
O
O
O
20-25
Hydroxyl pyrazole
intermediate
Scheme 1. General preparation of pyrazole analogs. Reagents and conditions: (a) EtO2CCO2Et, LiHMDS, THF, À78 °C or EtO2CCO2Et, Na, EtOH, À78 °C, 75–83%; (b) MeN–NH2,
acetic acid, EtOH, rt, 80%; (c) AlMe3(2 M solution in toluene), dioxane, 110 °C, various anilines, 20–45%; (d) CH3CH2MgBr, THF, À78 °C to rt, 58%; (e) pyridium chlorochromate,
CH2Cl2, 80%; (f) K2CO3, KI, CH3CN/DMF, R1Br, reflux or microwave, 100 °C, 10 min, 24–56%.
toluene) to produce their corresponding amides. For the synthesis
of the compounds 20–25, diethyl oxalpropionate with methyl
hydrazine were preferably irradiated quickly in a microwave
reactor to produce intermediate which was converted to hydroxyl
pyrazole. Subsequently, coupling of hyrdoxyl pyrazole with various
partners (R1–X) afforded the target compounds (20–25).
Replacement of the amide moiety of compound 6 with –CH2O–
,–CH2N–, –NC@O–, –NC@ON– produced no active compounds
(data not shown). Furthermore, the upper methyl group on the
pyrazole ring thought to be optimal for receptor interaction from
the result that the larger group such as ethyl, propyl and phenyl
microsomes (HLM) with the exception of di-substituted fluorine
analogs (10–12). Since our in vivo models are rodent based, we
hoped to increase the stability of these molecules to both MLM
and RLM by blocking the metabolic sites. Having the optimal sub-
stituent as 4-fluoro, we quickly optimized ring B. In terms of target
potency, altering the position of the methyl group of compound 7
was still tolerated in potency exemplified in 26 and 27, whereas it
is not the same case in the thiazole ring (39 and 40). The metabolic
blocking effects were observed in both electron withdrawing group
(EWG) and electron donating group (EDG) substituted analogs.
However, the magnitude was greater in analogs having EWG in
either meta or para position in all species (28, 29, 32, 33, 36, and
37) whereas analogs having EDG such as methyl group did not ex-
ert metabolic improvement, which assumed to be involved methyl
hydroxylation (26, 27, and 35). The most pronounced effect was
found in pyrimidine analog 38, which potentially improved meta-
bolic stabilities in all species. It was thought that as the number of
nitrogen atom in the ring increases, the pi-electrons of ring become
less energetic, which led to less N-oxidation in pyrimidine ring. At
this point, it appeared that the strategy of both blocking metabolic
sites and introduction of EWG on ring B through modification of
ring A and B would deliver a compound with the desired balance
of properties. However, in conjunction with LipE values, it indi-
cated that the introduction of halogens to block metabolic sites
had impact for improving the metabolic stability but it rendered
compounds having greater cLogP than the corresponding un-
substituted analog, bringing the lipophilicity higher and LipE val-
ues lower.
Next, we investigated core modifications using the preferred aro-
matic substitution pattern both in ring A and B on the basis of the
result of Table 1. The preparation of the imidazole analogs 41–53
is depicted in Scheme 2. The commercially available oxo-esters
were reacted with sodium nitrite (NaNO2) to furnish the oximes.
Subsequent catalytic reductive acetylation with acetic anhydride
afforded the crude compounds, which were cycloaromatized with
various anilines in acetonitrile under microwave irradiation to
obtain the corresponding imidazole esters. The target compounds
41–53 were obtained from via amidation reactions in the presence
of coupling reagent AlMe3 as the same as described in the synthesis
of pyrazole analogs.14
group resulted in loss of potency (IC50: 27 nM, 37% inh@2
lM,
26% inh@10 M, respectively). All functional activities were mea-
l
sured by the ability of the compound to inhibit calcium mobiliza-
tion caused by an EC80 concentration of glutamate in HEK293 cells
expressing the human mGlu5 receptor using MTEP as a reference
compound.13
It was observed that ring A analogs yielded comparatively ac-
tive antagonists as highlighted by the 4-fluoro analog 7, which is
the most potent mGlu5 receptor antagonist (IC50 = 1.1 nM) having
the highest LipE (6.28) in the series. Small lipophilic substituents
(e.g., F, Cl and Me) are more preferred with no dependency on their
electronic properties while a larger group such as N(CH3)2 was not
favored for functional potency. Reduction of the aryl ring of com-
pound 6 to cyclohexyl ring analog 19 did not significantly alter
affinity. However, oxygen linked compounds 20–25 failed to
furnish potent antagonists. Likewise, insertion of one methylene
linker into the compound 7 provided analog 25, which led to a
reduction of target potency. In addition, an analog removing
aromatic ring had almost no efficacy at the mGluR5 receptor (com-
pound not shown). From these observations, it was hypothesized
that a well restrict phenyl group may occupy a hydrophobic pocket
in the mGluR5 binding site with a very limited tolerance in this
region of the receptor.
Our initial focus during hit evaluation was also to assess
whether the metabolic stability could be increased within this
class of compounds while maintaining potency. Aromatic substitu-
ents at para position on ring A had slight effect on the metabolic
stability, which demonstrated that oxidation occurred on aromatic
ring A. It was observed that the introduction of an electron with-
drawing group such as Cl and CF3 may help to stabilize the
electronic rich phenyl group, thereby improving metabolic stability
(8, 13, 15). Many of analogs we prepared showed high functional
potencies for the mGlu5 receptor and interestingly these analogs
proved to be much more stable in the presence of human liver
Representative examples in imidazole analogs are shown in
Table 2. Imidazole core replacement rendered compounds 41–53,
which were generally less potent than pyrazoles and had a cLogP
values greater than 0.5 unit higher than the corresponding pyra-
zole analogs, bringing the LipE values lower. The microsomal

E. Chae et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2134–2139
2137
Table 1
Structure–activity relationships for pyrazole analogs 6–40
Ring A
N N
2
N
3
O
Ring B
Ring A
O
O
X
4
6
Q
O
5
F
19
20(Q=C)
6-17
21
25
22(Q=O)
23(Q=NH)
24(Q=NMe)
Compound
Ring A
Ring B
mGlu5a IC50 (nM)
cLogPb
LipEc
Metabolic stability T1/2 (min)
Mice
Rat
Human
6
7
H
4-F
4.4
1.1
2.53
2.68
6.28
5.17
18
36
34
56
66
82
N
8
9
4-Cl
3-Cl
3,4 F2
2,4 F2
3,5 F2
3,4 Cl2
4-Me
4-CF3
3.8
4.7
4.3
3.7
5.3
2.3
5.3
38
17
645
71
25
92
3.25
3.25
2.75
2.82
2.82
3.84
3.03
3.42
2.46
2.70
1.05
3.08
2.66
5.08
5.62
5.61
4.20
4.80
5.25
3.99
5.31
3.49
6.10
4.52
4.38
64
32
42
38
18
195
45
194
71
87
55
149
76
64
148
22
>300
95
128
122
46
67
32
107
118
>300
>300
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4-OMe
4-N(Me)2
4-Pyridyl
See diagram
See diagram
See diagram
See diagram
See diagram
See diagram
See diagram
8
28
37
8
42
83
1.3
lM
11.6% inh@1
l
lM
l
M
5.6% inh@2
À7.7% inh@1
911
M
2.54
2.68
3.50
4.36
N
N
26
4-F
90.8
13
10
67
26
91
27
4-F
82.3
2.68
4.40
119
N
Cl
28
29
4-F
4-F
16.4
130
2.93
3.19
4.86
3.69
116
98
108
58
115
269
N
N
CF3
30
31
4-F
4-F
28
2.86
2.93
4.69
3.81
99
24
166
143
213
126
F
N
195
Cl
N
32
33
4-F
4-F
10.3
184
2.36
2.93
5.63
3.78
39
16
>300
219
>300
>300
F
N
Cl
#
#
#
#
#
34
35
36
37
38
39
4-F
4-F
4-F
4-F
4-F
4-F
300.5
94.5
56.3
41.6
7.1
2.18
2.68
2.93
2.36
2.17
2.76
4.34
4.34
4.32
5.02
5.98
5.03
N
84
76
77
N
N
N
N
Cl
>300
>300
>300
45
161
114
>300
61
>300
>300
>300
122
F
N
Cl
N
#
16.4
S
(continued on next page)

2138
E. Chae et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2134–2139
Table 1 (continued)
Compound
Ring A
4-F
Ring B
mGlu5a IC50 (nM)
cLogPb
2.76
LipEc
Metabolic stability T1/2 (min)
Mice
Rat
Human
N
#
40
2700
12
S
N
S
MTE
2.12
5.80
13
60
108
N
a
mGluR5 assay data are presented as % inhibition at remarked concentration or IC50. Assay reproducibility was monitored by the use of the mGlu5 negative modulator
MTEP (IC50 = 12 5 nM).
b
cLogP was calculated using ChemBioDraw Ultra version 12.0.
Ligand-lipophilicity efficiency (LipE) = pIC50–cLogP.
c
R
z
O
O
Y
O
O
a
N
N
b
d
O
O
O
O
N
O
c
O
O
O
N
N
O
N
N
X
X
OH
Compounds 41-53
Y, Z = N or C
R = Me, F, Cl, CF, CN
3
Scheme 2. General preparation of imidazole analogs. Reagents and conditions: (a) NaNO2, H2O, 4 °C, 2 h, 68%; (b) H2, Pd/C, 1 atm, Ac2O, rt, 20 h, 51%; (c) various anilines, TFA,
acetonitrile, microwave, 140 °C, 45 min (30–42%); (d) AlMe3 (2 M solution in toluene), dioxane, 110 °C, various anilines, 20–45%.
Table 2
Structure–activity relationships for imidazole analogs 41–53
Ring B
N
N
Cl
N
N
Cl
N
Q
N
N
Ring B
N
N
X
F
F
O
51
50
41-49
53
52
Compound
X
Ring B
Q = Me
mGlu5a IC50 (nM)
cLogPb
LipEc
Metabolic stability T1/2(min)
Mice
Rat
106
134
87
Human
41
42
43
44
45
46
47
48
49
50
51
52
53
4-F
13
5.8
3.17
4.34
3.89
3.02
3.94
3.74
2.86
3.64
2.42
3.36
3.43
2.86
2.57
4.72
3.90
3.95
3.40
3.40
4.03
4.76
3.12
4.69
3.50
3.78
4.19
4.82
18
93
70
44
122
76
3,4-Cl2
3-Cl,4-F
4-OMe
4-CF3
4-Cl
14.5
147
46.2
17.1
24.2
173
77
139
62
88.3
40.4
>300
81
37
>300
59
>300
54
4-F
Q = F
Q = CF3
Q = CN
See diagram
See diagram
See diagram
See diagram
68
96
158
72
196
86
300
32
44
94
60
225
110
165
>300
283
278
a
mGlu5 assay data are presented as% inhibition at remarked concentration or IC50. Assay reproducibility was monitored by the use of the mGlu5 negative modulator MTEP
(IC50 = 12 5 nM).
b
cLogP was calculated using ChemBioDraw Ultra version 12.0.
Ligand-lipophilicity efficiency (LipE) = pIC50–cLogP.
c
stability pattern is similar to those of pyrazoles. Given the high
functional potency of some analogs, we were interested to see if
this would translate into in vivo efficacy. To evaluate antidepres-
sant activity of the interesting compounds, several analogs were
chosen based on the outcomes of LipE values, target potencies
and metabolic stabilities. Antidepressant activity was assessed as
percentage decrease in immobility duration in the forced swim-
ming test (FST) and data has been presented as mean SEM. The
obtained data on the antidepressant activity of the compounds
and references (MTEP, ADX48621 series15) are given in Table 3.
Majority of the synthesized compounds exhibited considerable
antidepressant potential as evident from their% decrease of immo-
bility duration values whereas our references was found to be less
active than our analogues. Compound 6 was virtually not active at
the dose of 10 mg/kg due to low metabolic stability in mice (MLM
stability T1/2: 18 min), despite its high LipE value. And compound
15 having low LipE value showed weak in vivo efficacy even it
had high metabolic stability in mice. Therefore, compounds with
low metabolic stabilities and low LipE’s were not screened
in vivo test. The representative compound 7 in the pyrazole

E. Chae et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2134–2139
2139
Table 3
10 lM). A single dose-exposure study in Sprague–Dawley rats re-
Anti-depressant activities of selected analogs
vealed that 1 h after an intraperitoneally at a dose of 10 mg/kg,
they had moderate plasma and brain concentrations, and a brain/
plasma ratio of 1.63 0.39.
a
Compound
mGlu5 IC50 (nM)
m-FST
% Decrease in immobility
duration at 10 mg/kg(p.o.)
In summary, we report a new series of mGluR5 antagonists
identified through HTS hit. During preliminary hit-to-lead, the rep-
resentative pyrazole and imidazole amides have been described
and evaluated by monitoring LipE’s. In vitro functional potencies
were correlated well with our series and their SAR was found to
be tractable and majority of the synthesized compounds exhibited
considerable anti-depressant potential. However, despite con-
trolled LipE values, some analogs showed weak activities in vivo
model, which emphasizes on the importance of initial evaluations
of other parameters such as aqueous solubility,metabolic stability,
PK/exposure as well as LipE.16 The continued optimization of this
series of mGluR5 NAMs will be to improve physicochemical prop-
erty by further modification of structural features and will be pre-
sented in due course.
6
7
8
10
11
13
14
15
16
28
32
36
37
38
39
41
4.4
1.1
3.8
4.3
3.7
2.3
5.3
38
17
16.4
10.3
56.3
41.6
7.1
16.4
13
5.8
(53.3 21.5⁄50 mg/kg, p.o.)
61.1 10.6%⁄
51.4 8.1%⁄
58.8 13.7%⁄
25.7 6.6%⁄
45.8 7.3%⁄
30.8 13.4%⁄
18.5 6.4⁄
14.4 3.4%
12.6 6.2%
36.8 7.1%⁄
39.1 13.4%⁄
15.5 6.0%⁄
31.2 10.0%⁄
32.8 3.4%⁄
52.1 11.8%⁄
85.2 31.4%⁄
65.3 17.1%⁄
14.0 4.8%
42
53
40.4
12
20
References and notes
MTEP
ADX48621 seriesb
(44.3 12.2⁄50 mg/kg, p.o.)
1. (a) Foord, S. M.; Bonner, T. I.; Neubig, R. R.; Rosser, E. M.; Pin, J. P.; Davenport, A.
P.; Spedding, M.; Harmar, A. J. Pharmacol. Rev. 2005, 57, 279; (b) Behan, D. P.;
Chalmers, D. T. Nat. Rev. Drug Disc. 2002, 1, 599; (c) Topiol, S.; Sabio, M.; Uberti,
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2. (a) Kenakin, T. Trends Pharmacol. Sci. 2007, 28, 407; (b) Christopoulos, A.;
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3. (a) Rocher, J. P.; Bonnet, B.; Bolea, C.; Lutjens, R.; Le Poul, E.; Poli, S.; Epping-
Jordan, M.; Bessis, A. S.; Ludwig, B.; Mutel, V. Curr. Top. Med. Chem. 2011, 11,
680; (b) Emmitte, K. A. ACS Chem. Neurosci. 2011, 2, 411; (c) Chaki, S.
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a
Drugs(10 mg/kg, p.o.) were administered to ICR mice 1 h before the test, and the
duration of immobility was measured during 4 min following training for 2 min.
Data was expressed in mean SEM (n = 8) and analyzed by Dunnett’s multiple
comparisons following one-way ANOVA(⁄p <0.05).
b
6-Fluoro-2-[4-(pyridin-2-yl)but-3-yn-1-yl]imidazo[1,2-a]pyridine as shown in
Figure 1.
analogues showed potent in vivo efficacy in animal model,
which was found to decrease immobility duration as high as
61.1 10.6%. To distinguish antidepressant effect from hyperactiv-
ity of animals, compound 7 was conducted in locomotor activity
tests in mice. When the compound 7 was administrated intraperi-
toneally (ip), it showed hypoactivity at a dose range from 1 mg/kg
to 30 mg/kg. Therefore, the efficacy in immobility of compound 7
(ED50 = 1.1 mg/kg, ip) was not caused by hyperactivity of animal
indicating that the locomotor activity fell within the normal range.
However, compound 7 demonstrated from moderate bioavailabil-
ity in mice (F = 31%) to poor in rat (F < 2%). It is likely that its poor
solubility (vehicle: 5% DMSO + 5% Cremophore) resulted in insuffi-
cient oral exposure especially in rats, which was in agreement with
weak activity in rats (10.9%⁄ at the dose of 10 mg/kg, ip) against
the forced swimming test.
For comparision with pyrazole analogs, imidazole analogues
(41, 42 and 53) were chosen and evaluated. The antidepressant
efficacy of compound 42 proved to be caused by hyperactivity, that
is, false positive results. On the other hand, compound 41 and 53
showed potent antidepressant efficacy without hyperactivities. Ta-
ken LipE values and metabolic profiles, compound 53 was further
evaluated. Contrary to compound 7, compound 53 also showed
statistically significant efficacious activity in rats with MEDs of
1 mg/kg after oral administration in the forced swimming test. It
assumed that imidazole analogs were seemingly more soluble than
pyrazoles in our test vehicle, which may contribute to efficacies in
rats. In addition, compound 53 showed no appreciable inhibition
4. (a) Burdi, D. F.; Hunt, R.; Fan, L.; Hu, T.; Wang, J.; Guo, Z.; Huang, Z.; Wu, C.;
Hardy, L.; Detheux, M.; Orsini, M. A.; Quinton, M. S.; Lew, R.; Spear, K. Y. J. Med.
Chem. 2010, 53, 7107; (b) Lindsley, C. W.; Bates, B. S.; Menon, U. N.; Jadhav, S.
B.; Kane, A. S.; Jones, C. K.; Rodriguez, A. L.; Conn, P. J.; Olsen, C. M.; Winder, D.
G.; Emmitte, K. A. ACS Chem. Neurosci. 2011, 2, 471.
5. Development of ADX10059 ended for long-term use. http://www.
addexpharma.com/press-releases/press-release-details/article/development-
of-adx10059-ended-for-long-term-use/ accessed on October 15, 2010.
6. (a) Newman, A. H. Bioorg. Med. Chem. Lett. 2007, 17, 2074; (b) WO2008092072.
7. These structures (3 and 3a) could be identified by 1H NMR and 2D–1H/13C NMR
(HMBC, Hetero nuclear Multiple Bond Correlation). 1H–HMC correlates
chemical shifts of protons with carbons separated with two or three bonds.
(Compound 3a: Hydrogen of methyl group on the pyrazole ring crosspeaks
with adjacent quaternary and carbonyl carbons, whereas compound
displayed the absence of crosspeaks with two carbons).
3
8. Bonnefous, C.; Vernier, J. M.; Hutchinson, J. H.; Chung, J.; Reyes-Manalo, G.;
Kamenecka, T. Bioorg. Med. Chem. Lett. 2005, 15, 1197.
9. Kerns, E. H; Di, L. In Drug-Like Properties: Concepts, Structure Design and
Methods: from ADME to Toxicity Optimization; Academic Press: Burlington,
Massachusetts, 2008. Chapter 12.
[10]. For information, we refer to following patents (WO2005118568,
WO2009024491).
11. Compound 6 has no significant off-target effect regarding to following 11
targets at 10
histamine H1, muscarinic M1, M2, 5-HT2C
norepinephrine, serotonin (DAT, NET, SERT, respectively).
l
M; Monoamine oxidase A, B, adenosine A2A, adrenergic a1D
,
,
transporter for dopamine,
12. (a) Leeson, P. D.; Springthorpe, B. Nat. Rev. Drug Disc. 2007, 6, 881; (b)
Ryckmans, T.; Edwards, M. P.; Horne, V. A.; MonicaCorreia, A.; Owen, D. R.;
Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Bioorg. Med. Chem. Lett. 2009, 15,
4406; (c) Edwards, M. P.; Price, D. A. Annu. Rep. Med. Chem. 2010, 45, 381; (d)
Bembenek, S. D.; Tounge, B. A.; Reynolds, C. H. Drug Discovery Today 2009, 14,
278; (e) BemHopkins, A. L. Drug Discovery Today 2004, 9, 430.
13. O’Brian, J.; Lemaire, W.; Chen, T. B.; Chang, R.; Jacobson, M.; Ha, S.; Lindsley, C.;
Schaffhauser, H.; Sur, C.; Pettibone, D.; Conn, P.; Williams, D. Mol. Pharmacol.
2003, 64, 731.
14. Lange, J. H. Bioorg. Med. Chem. Lett. 2010, 1084, 20. For the synthesis of pyrazole
analogs and imidazole analogs, we refer to the following patents
(WO2001029007, WO2006087355, respectively).
15. For information, we refer to a following patent (WO2005123703)
16. Gilbert, A. M. Bioorg. Med. Chem. Lett. 2011, 21, 195.
against CYP1A2, CYP2D6, CYP 2C9, CY2C19 and CYP3A4 at 10
and were highly stable in human hepatocytes (Clint 0.99 L/min/
106 cells). The activity of compound 53 in the hERG potassium
channel assay was determined to be low (13% at 10 M) and dis-
played selectivity over mGluR1 receptor (10% inhibition at
lM
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