Synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as mGluR5 (metabotropic glutamate receptor 5) antagonists

Article abstract of DOI:10.1016/j.bmcl.2015.11.012

We described here the synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as potential mGluR5 antagonists. We found that a series of thiazole derivatives 6 showed better inhibitory activity against mGluR5. Compounds 6bc and 6bj have been identified as potent antagonists (IC₅₀ = 274 and 159 nM) showing excellent in vitro stability profile. Molecular docking study using the crystal structure of mGluR5 revealed that our compounds 6bc and 6bj fit the allosteric binding site of mavoglurant well.

Full text of DOI:10.1016/j.bmcl.2015.11.012

Accepted Manuscript
Synthesis and biological evaluation of picolinamides and thiazole-2-carboxa-
mides as mGluR5 (metabotropic glutamate receptor 5) antagonists
Vu Hoang Nam, Ji Young Kim, Ahmed H.E. Hassan, Kihang Choi, Jong-Hyun
Park, Ki Duk Park, Jae Kyun Lee, Ae Nim Pae, Hyunah Choo, Sun-Joon Min,
Yong Seo Cho
PII:
S0960-894X(15)30221-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.11.012
BMCL 23268
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 September 2015
1 November 2015
5 November 2015
Please cite this article as: Nam, V.H., Kim, J.Y., Hassan, A.H.E., Choi, K., Park, J-H., Park, K.D., Lee, J.K., Pae,
A.N., Choo, H., Min, S-J., Cho, Y.S., Synthesis and biological evaluation of picolinamides and thiazole-2-
carboxamides as mGluR5 (metabotropic glutamate receptor 5) antagonists, Bioorganic & Medicinal Chemistry
Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.11.012
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Synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as
mGluR5 (metabotropic glutamate receptor 5) antagonists
Vu Hoang Nam,a,b Ji Young Kim,a,c Ahmed H. E. Hassan,a,b Kihang Choi,c Jong-Hyun Park, a
Ki Duk Park,a,b Jae Kyun Lee,a,b Ae Nim Pae,a,b Hyunah Choo,a,b Sun-Joon Min, d,* Yong Seo
Choa,b,*
aCenter for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and
Technology (KIST), 5 Hwarangno 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea
bDepartment of Biological Chemistry, Korea University of Science and Technology (UST),
217 Gajungro, Yuseong-gu, Daejeon,34113, Republic of Korea
cDepartment of Chemistry, Korea University, Seoul,02841, Republic of Korea
dDepartment of Applied Chemistry, Hanyang University, Ansan, Gyeonggi-do, 15588,
Republic of Korea
Email: ys4049@kist.re.kr;sjmin@hanyang.ac.kr
Abstract: We described here the synthesis and biological evaluation of picolinamides and
thiazole-2-carboxamides as potential mGluR5 antagonists. We found that a series of thiazole
derivatives 6 showed better inhibitory activity against mGluR5. Compounds 6bc and 6bj
have been identified as potent antagonists (IC50 = 274 and 159 nM) showing excellent in vitro
stability profile. Molecular docking study using the crystal structure of mGluR5 revealed that
our compounds 6bc and 6bj fit the allosteric binding site of mavoglurant well.
Keywords: metabotropic glutamate receptor, antagonist, picolinamides, thiazole-2-
carboxamides, molecular docking
1

Glutamate, the principal excitatory neurotransmitter in the brain, regulates neuronal signal
transmission through either inotropic or metabotropic glutamate receptors (iGluRs or
mGluRs). The mGluRs belong to class C of the G-protein-coupled receptors (GPCRs), which
are categorized into three groups (I, II and III) based on sequence homology, signal
transduction mechanism and pharmacology. mGluR5, one of the group I receptors, is
expressed postsynaptically and is mainly found in limbic brain areas including forebrain,
striatal regions, and amygdala. Interaction of glutamate with mGluR5 results in activation of
phospholipase C via Gq protein to release intracellular calcium ions, which leads to a variety
of cellular responses.1
Figure 1. Representative mGluR5 antagonists
Regulation of mGluR5 has therapeutic potential in numerous preclinical models of diseases,
including anxiety,2 gastroesophageal reflux disease (GERD),3 drug addiction,4 and
neuropathic pain.5 Furthermore, recent study has demonstrated clinical evidence of the
potential utility of mGluR5 antagonists. For example, basimglurant 3, an mGluR5 negative
allosteric modulator developed by Roche, is in phase II clinical trial for the treatment of
depression and fragile X syndrome (Figure 1).6 Novartis researchers also developed
mavoglurant 4 as a non-competitive mGluR5 inhibitor, which is currently in phase II clinical
trial for Levodopa-induced dyskinesia.7
2

Figure 2. Structures of picolinamides 5 and thiazol-2-carboxamides 6
Up to date, a number of mGluR5 antagonists containing an alkyne subunit as a key structural
motif have been reported and known to show high affinity to mGluR5 receptor.8 Inspired by
their therapeutic potentials, alkynylquinoline analogues have been investigated in our
laboratory.9 In fact, we have discovered 2-(pyridin-2-ylethynyl)quinoline, which has high
inhibitory activity against mGluR5 showing excellent stability profile. Furthermore, this
compound exhibited favorable in vivo activity in a behavior test of neuropathic pain mouse
model. Despite the high potencies of acetylenic analogues, we have attempted to search for
new nonalkynyl mGluR5 antagonists because an alkyne moiety is metabolically unstable to
cause unfavorable side effects.10 Recently, several groups reported that a series of
arylcarboxamides or arylureas proved to be potent mGluR5 antagonists, which indicated that
amide or urea functional group could be appropriate structural motif as a replacement of
alkyne linkage.11 On the basis of the arylamide structure, therefore, we designed a new class
of mGluR5 antagonists as shown in Figure 2. Compared to the previously reported
compounds, we envisioned that meta-substituted pyrdine of 5 or meta-substituted thiazole of
6 would occupy the binding pocket of terminal aryl pharmacophore of most mGluR5
antagonists. In addition, incorporation of substituted aromatic ring to the other side of the
amide linker would provide molecular diversity in this series of compounds to explore
structure-activity relationship (SAR) and stability profile.
Herein we report the synthesis and in vitro evaluation of picolinamides and thiazole-2-
carboxamides as potent mGluR5 antagonists including structural insight resulting from
3

computational docking study of our compounds in the crystal structure of mGluR5.
Scheme 1. Synthesis of picolinamides 5 and thiazole-2-carboxamides 6.
Reagents and conditions: (a) aminopyridines, HBTU, TEA, DMF, rt or 70 °C, 27-94%; (b)
aminopyridine, CDI, THF or DMF, rt, 57-68%; (c) chloroacetone, EtOH, reflux, 12 h, 37%;
(d) LiOH, H2O/MeOH/THF(1:1:1), rt, 1 h, 42%; (e) iPrMgCl, THF, 0 °C, 15 min, then ethyl
cyanoformate, rt, 15 min, 56% (2 steps); (f) LiOH, MeOH, rt, 2 h, 89%; (g) thioglycolic acid,
pyridine, 80 °C, 3 h, 24%; (h) Tf2O, TEA, DCM, rt, 18 h, 49%; (i) Zn(CN)2, Pd2(dba)3, dppf,
DMF, 65 °C, 3 h, 80%; (j) NaBH4, EtOH, 0 °C to rt, 3 h, 87%; (k) PDC, DMF, rt, 5 h, 59%; (l)
i) ClCO2i-Bu, NMM, THF, -5 °C, 1 h; ii) anilines or aminopyridines, THF, rt, 18 h, 20-80%;
(m) i) oxalyl chloride, DCM, rt; ii) anilines or aminopyridines, DIEA, DCM, rt, overnight,
40-90%.
A series of picolinamide analogues 5 were easily synthesized through an amide coupling
reaction using HBTU as a coupling reagent, as described in Scheme 1. In order to synthesize
4

thiazole-2-carboxamides 6, thiazole-2-carboxylic acids containing different substituents at the
2-position were required as substrates for amide coupling reactions. First, 4-methyl thiazole-
2-carboxylic acid 9 was prepared by condensation of ethyl 2-amino-2-thioxoacetate 8 with
chloroacetone followed by hydrolysis. Selective carbonylation of 2,4-dibromothiazole 10 via
metal-halogen exchange produced the corresponding thiazole-2-carboxylate, which was also
hydrolyzed to afford carboxylic acid 11. Based on the Negishi type coupling reaction,12 the
synthesis of 4-cyano thiazole derivative 15 was achieved. Thus, thiazoletriflate 13, derived
from condensation of thioglycolic acid 12 with ethyl cyanoformate followed by triflation,
was treated with Zn(CN)2 in the presence of palladium catalyst to produce ester 14, which
was converted to desired acid 15 by reduction and oxidation. Finally, a series of thiazole-2-
carboxamides 6 were synthesized via either mixed anhydride or acid chloride intermediate.
In vitro antagonistic activities of picolinamides 5 against mGluR5 were evaluated using a
fluorescence-based calcium mobilization assay.13 The results of the in vitro assay of these
compounds were shown in Table 1. Although plicolinamides 5 showed relatively low
inhibitory activity against mGluR5 at the concentration of 10 µM and 1 µM, we found that
the inhibition values of compounds 5a, 5f, 5l, and 5m were over 50% at 10 µM. Regarding
the SAR of aromatic group on the left hand side, it seemed that the 2-pyridyl ring (5a and 5b)
was superior to the 3-pyridyl group (5c-5i). Most importantly, the meta-substituted phenyl
ring was preferred when R2 is methyl group (5l and 5m). On the basis of this initial SAR, we
decided to use 3-substituted phenyl and 6-substituted-2-pyridyl groups on the left hand side
of thiazole derivatives for the next phase of SAR study.
5

Table 1. In vitro inhibitory activity of picolinamide derivatives 5 against mGluR5
% Inhibition (mGluR5)a
compds
X
Y
R1
R2
10 µM
65.46
30.68
30.28
17.72
25.52
51.04
35.40
23.10
33.42
18.57
43.38
52.08
68.07
33.35
33.99
1 µM
34.45
16.18
25.62
16.06
13.99
13.77
3.85
5a
5b
5c
5d
5e
5f
CH
CH
N
N
H
5-Cl
H
H
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
H
H
N
2-Cl, 4-Me
6-MeO
2,5-diCl
2,6-diCl
H
H
N
H
N
H
5g
5h
5i
N
H
N
OMe
Cl
Cl
Cl
Me
Me
F
22.79
19.11
15.65
18.48
10.51
18.42
13.13
3.20
N
H
5j
N
2-Cl, 4-Me
6-MeO
3-Cl
5k
5l
N
CH
CH
CH
CH
5m
5n
5o
3-CN
3-Cl
3-CN
F
aCa2+ flux assay using glutamate as agonist.
Next, thiazole-2-carboxamide derivatives 6 were tested for their inhibitory activity against
mGluR5 and the result is summarized in Table 2. At this time, the calcium-based functional
assay was performed at the concentration of 1µM because higher selection criteria were
necessary due to searching for more potent lead compounds.14 Among the tested compounds,
eight compounds have more than 40% inhibitory activity against mGluR5. When R2 is
methyl group, compounds 6af, 6ah, and 6ai bearing hydrogen, chloro and methyl groups on
the pyridine ring showed potent inhibitory activity, comparable to the corresponding
picolinamide 5a. In case of 4-bromothiazole derivatives 6b, substitution of either pyridyl ring
or phenyl ring at the meta-position resulted in significant enhancement of potency. In
particular, compounds 6bc and 6bj exhibited high antagonistic effect against mGluR5 at 1
6

µM. On the other hand, a set of 4-cyanothiazole derivatives 6c showed a loss in potency. The
overall SAR results indicated that the inhibitory activity of this series is highly sensitive to
substitution at the 4-position of thiazole.
Table 2. In vitro inhibitory activity of thiazole-2-carboxamides 6 against mGluR5
% Inhibition
(mGluR5, 1µM)a
compds
Y
R1
R2
6aa
6ab
6ac
6ad
6ae
6af
CH
CH
CH
CH
CH
N
F
Cl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Br
3.1
32.2
18.0
11.6
16.6
47.1
-21.2
45.0
50.1
-22.6
13.7
58.1
71.1
40.9
-0.1
Br
Me
CN
H
6ag
6ah
6ai
N
F
N
Cl
N
Me
CN
F
6aj
N
6ba
6bb
6bc
6bd
6be
6bf
6bg
6bh
6bi
CH
CH
CH
CH
CH
N
Cl
Br
Br
Me
CN
H
Br
Br
Br
Br
-20.4
27.6
60.0
19.8
81.0
9.6
N
F
Br
N
Cl
Br
N
Br
Me
CN
Cl
Br
6bj
6bk
6ca
6cb
6cc
6cd
6ce
6cf
N
Br
N
Br
CH
CH
CH
CH
N
CN
CN
CN
CN
CN
CN
CN
CN
CN
-7.3
Br
Me
CN
F
19.5
-32.7
-23.0
-0.4
N
Cl
-9.4
6cg
6ch
6ci
N
Br
Me
CN
-21.5
24.7
8.3
N
N
aCa2+ flux assay using glutamate as agonist.
To further investigate pharmacological properties of the most potent compounds 6bc and 6bj,
7

we examined their IC50 values, hERG inhibition, microsomal stability, and CYP inhibition.
The results are summarized in Table 3. IC50 values of compounds 6bc and 6bj were obtained
by measuring inhibition values against mGluR5 at varied concentrations. In the hERG assay,
depolarization potential inhibited by our compounds was measured using automated patch
clamp device. The microsomal stability was determined by analysis of the remaining amount
of compounds incubated in the human liver microsomes. For the CYP assay, the % remaining
activity values of five human CYP450 isozymes after treatment with compounds 6bc and 6cj
were obtained. The data confirmed that compounds 6bc and 6bj have excellent inhibitory
activity against mGluR5 with IC50 values of 274 and 159 nM, which is comparable to that of
mavoglurant 4 (IC50 = 110 nM in Ca2+ assay).16 With regard to in vitro safety and stability,
compound 6bc had relatively higher % remaining activity of all the tested CYP isozymes
compared to compound 6bj, which suggested that 6bc has better CYP stability than 6bj. In
addition, both compounds showed low blocking activity of hERG channel at three different
concentrations. Compound 6bc exhibited considerably good microsomal stability, whereas
6bj was found to be rapidly metabolized in hepatic microsomes.
Table 3. The results of IC50 (mGluR5), hERG channel inhibition, microsomal stability, and
CYP inhibition
HLM
CYP (% remaining @ 10µM)
mGluR5
IC50
hERG
% inhibition
@ 10/1/0.1 µMb
%remaining
@ 1µM after
30 min
compds
(µM)a
1A2
38.3
2D6
2C9
3A4
2C19
6bc
6bj
0.274
0.159
39.6/29.3/16.3
34.8/19.4/15.0
37.31
102.1
99.2
99.0
88.2
84.9
87.3
86.3
7.4
7.25
11.0
b
aIC50 value ( SD) was obtained from a dose-response curve. Only % inhibition values at 10, 1, and 0.1 µM
were provided due to low inhibitory activity.
In order to rationalize the structure-activity relationship of thiazole derivatives, the binding
modes of the most potent compounds 6bc and 6bj were evaluated using docking simulation
with the crystal structure of the mGluR5 receptor recently reported by Heptares
8

Therapeutics.17 The energy-minimization of compounds 6bc and 6bj in the mGluR5 crystal
structure confirmed that these compounds comparatively fit the allosteric binding site of
mavoglurant 4, as shown in Figure 3.18 The 3-bromophenyl ring of compound 6bc docks to
the hydrophobic pocket formed by the 3-methylphenyl ring of 4 and the amide linker moiety
sits well in a narrow channel surrounded by Pro655, Tyr659, Val806, and Ser809. The
carbonyl group of 6bc forms a hydrogen bond with Tyr659, which is likely to compensate for
a loss of binding affinity in this region, where the hydrogen bonding between Ser809 and the
hydroxyl group of 4 exists. Interestingly, the binding mode of compound 6bj is opposite to
that of compound 6bc. Thus, the 4-bromothiazole segment of 6bj sits in a cavity defined by
several hydrophobic residues such as Ala813, Ala810, Ile625 and Pro655, which corresponds
to the binding site of the 3-bromphenyl moiety of 6bc. The hydrogen bonding between
Tyr659 and the carbonyl oxygen of 6bj was also observed. In addition, the methylpyridine
tail of 6bj favorably docks to the other side of hydrophobic binding pocket, which is
contributed to a slight rotational twist of C-N bond between pyridine and amide for proper
positioning.
Figure 3. Superimposed binding modes of compounds 6bc and 6bj in the allosteric binding
site of mavoglurant 4 complexed with mGluR5 (PDB code 4oo9). This docking study was
peformed by using CDocker in Discovery Studio 3.1.
9

In conclusion, we have synthesized pincolinamides 5 and thiazole-2-carboxamides 6 as
potential mGluR5 antagonists. The in vitro evaluation of these compounds turned out that a
series of thiazole derivatives showed better inhibitory activity against mGluR5. Among them,
compounds 6bc and 6bj were identified as most potent mGluR5 antagonists with IC50 values
of 274 and 159 nM. Additionally, the in vitro stability experiments of these compounds
proved that these compounds have excellent hERG selectivity and CYP stability, but they
should be further improved with regard to microsomal stability. Molecular docking study
using the mGluR5 crystal structure elucidates that the binding modes of compounds 6bc and
6bj are well correlated with the allosteric binding site of mavoglurant 4 although they are
located in the opposite direction. Based on the current study, compound 6bc and 6bj will be
optimized as potential lead compounds and further applied to preclinical evaluation of
mGluR5 associated diseases.
Acknowledgments
This research was supported by the Korea Institute of Science and Technology (KIST,
2E25580, 2E25473, 2E25240, 2V03970) and by a grant of the National Research Foundation
of Korea (NRF-2013R1A1A2005550 and NRF-2015M3A9A8030034) funded by the the
Ministry of Science, ICT and Future Planning.
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Graphical Abstract
Leave this area blank for abstract info.
Synthesis and biological evaluation of
picolinamides and thiazole-2-carboxamides
as mGluR5 (metabotropic glutamate
receptor 5) antagonists
Vu Hoang Nam,a,b Ji Young Kim,a,c Ahmed H. E. Hassan,a,b Kihang Choi,c Jong-Hyun Park, a Ki Duk
Park,a,b Jae Kyun Lee,a,b Ae Nim Pae,a,b Hyunah Choo,a,b Sun-Joon Min, d,* Yong Seo Choa,b,*
aCenter for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Seoul 02792, South
b
Korea, Biological Chemistry, Korea University of Science and Technology (UST), Daejeon, 34113,
c
d
South Korea, Department of Chemistry, Korea University, Seoul 136-701, South Korea, Department
of Applied Chemistry, Hanyang University, Ansan, 15588, South Korea
14