Substituted biaryl oxazoles, imidazoles, and thiazoles as sodium channel blockers

Article abstract of DOI:10.1016/j.bmcl.2010.07.064

Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. With a goal to develop potent peripherally active sodium channel blockers, a series of low molecular weight biaryl substituted imidazoles, oxazoles, and thiazole ca

Full text of DOI:10.1016/j.bmcl.2010.07.064

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5536–5540
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Substituted biaryl oxazoles, imidazoles, and thiazoles as sodium
channel blockers
a,*
a
a
a
a
Sriram Tyagarajan , Prasun K. Chakravarty , Bishan Zhou , Michael H. Fisher , Mathew J. Wyvratt ,
b
b
b
b
c
c
c
Kathy Lyons , Tracy Klatt , Xiaohua Li , Sanjeev Kumar , Brande Williams , John Felix , Birgit T. Priest ,
c
c
c
c
c
Richard M. Brochu , Vivien Warren , McHardy Smith , Maria Garcia , Gregory J. Kaczorowski ,
d
d
d
d
a
William J. Martin , Catherine Abbadie , Erin McGowan , Nina Jochnowitz , William H. Parsons
a
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Rahway, NJ 07065, USA
Department of Ion Channels, Merck Research Laboratories, Rahway, NJ 07065, USA
Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, USA
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. With a goal
to develop potent peripherally active sodium channel blockers, a series of low molecular weight biaryl
substituted imidazoles, oxazoles, and thiazole carboxamides were identified with good in vitro and
in vivo potency.
Received 19 February 2010
Revised 14 July 2010
Accepted 16 July 2010
Available online 21 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Neuropathic pain
Voltage-gated sodium channel
v
Na 1.7 blockers
Biaryl oxazoles
Biaryl imidazoles
Biaryl thiazoles
Neuropathic pain is a complex pain state, that is, usually caused
by injury to the peripheral or central nervous system. It causes per-
sistent debilitating pain long after the acute injury or disease. Such
pain states are associated with hyper-excitability and spontaneous
action potential firing in peripheral sensory neurons. Neuropathic
pain is associated with shingles, peripheral nerve injury (phantom
limb), diabetic neuropathy chemotherapy, post-herpetic neuralgia,
dependent sodium channel blocker may provide functional selec-
tivity with minimal CNS and cardiac effects.
Form bond
H- acceptor
C
O
A
H
N
S
F
O
1
N
B
NH
and chronic back pain.
NH
2
Many sodium channels subtypes exist in the nervous system.
O
O
B
H-donor
OCF3
Subtype Na
v
1.7 and Na
1.7 is primarily expressed in the peripheral nervous
system. Recent human genetic evidence implicates the crucial role
of Na 1.7 in noccieptive signaling. Indeed, a loss of function muta-
tion in Na 1.7 has been associated with congenital insensitivity to
v
1.8 are over expressed at the sites of nerve
Cleave bond
V102862
injuries. Na
v
2
2
C
v
v
3
painful stimuli.
R2
Several of the marketed drugs used in the treatment of neuro-
pathic pain are weak sodium channel antagonists. The efficacy of
these drugs is limited by poor tolerability. We believe that a state
X
N
R1
X, = NH, S or O
3
*
Corresponding author. Tel.: +1 732 594 6226; fax: +1 732 594 5350.
E-mail address: sriram_tyagarajan@merck.com (S. Tyagarajan).
Figure 1. Design concept.
0
960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.064

S. Tyagarajan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5536–5540
5537
Our goal is to develop potent, state dependent hNa
for neuropathic pain. Recently, scientists at Cocensys/Purdue Phar-
ma reported the discovery of the semicarbazone sodium channel
v
1.7 blockers
The compounds were synthesized and evaluated for their abil-
ity to block voltage-gated hNa 1.7 via an in vitro functional mem-
v
brane potential FRET based assay, details of which have recently
6
blocker V102862 (hNa
v
1.7, K
i
= 0.36
lM), and this compound was
been described in a separate Letter. Selected compounds were
considered as a template to design non-semicarbazone based so-
also screened for activity against ancillary targets including hERG
(MK-0499 binding), CYP inhibitions and Cav 1.2 (diltiazem (DLZ)
binding). Those compounds that were found to be selective in
dium channel blockers.4
7
As shown in Figure 1, the phenoxy group of the semicarbazone
of V102862 can be replaced by a biphenyl group and a rigid ring
closed analog could be derived via pathways B and C. Pathway B
gives a novel series of biphenyl thiazolidin-2,4-diones with potent
these ancillary assay were then examined in the rat spinal nerve
ligation (Chung) model of neuropathic pain and their pharmacoki-
8
netic profiles were evaluated.
hNa
v
1.7 activity (hNa
v
1.7, K
i
= 0.02
l
M) and has been described
The syntheses of the biphenyl heterocyclic compounds are out-
lined in Scheme 1. These analogs were constructed from the biphe-
nyl bromoketone 6, a common key intermediate. The intermediate
6 was prepared via a palladium catalyzed Suzuki cross-coupling
reaction of the aryl bromide 4 with the commercially available
5
separately. Pathway C could give rise to a series of five-membered
heterocycles 3 as a potential replacement for the semicarbazone of
V102862. This modification has led us to the discovery of a series
of a new biphenyl heterocycles.
Our exploration focused on three different five-membered het-
erocyclic replacements of the semicarbazone moiety in V1028662:
the oxazoles, imidazoles, and thiazoles. These are three different
heterocycles with different basic properties.
3-acetophenone boronic acids
bromination.
With the bromoketone derivative 6 in hand, the biphenyl
heterocycles were synthesized using condensation chemistry.
5
followed by acid-catalyzed
9
Oxazoles
d
O
O
O
N
N
N
9
7
8
R
R
NH
2
R
NH
2
O
c
NH
b
N
10
R
e
Imidazoles
Br
+
a
O
HO
B
OH
COMe
h
R
Br
6
4
5
R
f
NH
NH
N
R
S
11
2
j
g
O
S
N
i
N
R
15
S
S
NHSO Me
NH
2
N
N
R
12
O
14
R
NH2
R
13
2
Thiazoles
O
k
l
S
Br
Br
OH
NH
2
1
6
17
S
m
S
Br
N
N
R
19
18
NH
2
CO
2
Et
O
Scheme 1. Reagents and conditions: (a) (i) Ph
ii) BF -Et O, MeCONH , xylene; (d) (i) SeO , pyridine; (ii) CDI, NH
toluene, reflux; (h) H NCSNH , toluene, reflux; (i) MeSO Cl, pyridine, THF; (j) (i) ethyl thioxamate, EtOH; (ii). ammonia, EtOH; (k) (i) CDI, NH
THF; (l) ethyl bromopyruvate, dioxane; (m) (i) ArB(OH) , Ph P, Pd(OAc) , n-propanol, H O, 2 M Na CO , reflux; (ii) ammonia, MeOH.
3
P, Pd(OAc)
2
, n-propanol, H
2
O, 2 M Na
2
CO
3
, reflux; (ii) Br
, 210 °C; (f) (i) methyl glyoxalate, NH
2
, HBr (cat), MeOH; (b) urea, t-BuOH; (c) (i) AcOH, K
OAc, MeCN; (ii) ammonia, EtOH; (g) MeCSNH
OAc; (ii) Lawesson’s reagent,
2 3 2
CO , EtOH, H O;
(
3
2
2
2
4
OAc, THF; (e) HCONH
2
4
2
,
2
2
2
4
2
3
2
2
2
3

5
538
S. Tyagarajan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5536–5540
Cyclization of the bromo ketone 6 with urea afforded the 2-amino
oxazoles 7. Biphenyl oxazole 9 was prepared from the 2-methyl
oxazole analog 8, which was, in turn derived from the correspond-
ing acetate. Cyclization of the bromo ketone 6 with formamide
gave the biphenyl imidazole, 10. The 2-carboxamide imidazole
Initial SAR efforts were directed towards the biphenyl oxazoles.
Earlier work in the area of biphenyl thiazolidine-2,4-diones had
shown that meta arrangement of the biphenyl (1,3) is preferred
5
,11
to the para biphenyl (1,4).
In case of the biphenyl heterocycles,
the same relationship was maintained.
1
1 was derived from condensation with methyl glyoxalate. The thi-
As shown in Table 1, biphenyl oxazoles were found to be mod-
est sodium channel blockers. Liphophilic substituents such as the
trifluoromethyl or the trifluoromethoxy were found to be optimal
azoles were prepared according to the method described by Wright
1
0
and coworkers. The biphenyl thiazoles 12 were derived from the
cyclization of bromo ketone 6 with ethanethioamide. Similarly,
thiourea cyclization afforded the 2-thiazolamine 13 which was
then functionalized to the sulfonamide 14. Cyclization of 6 with
ethyl thioxamate afforded the ester which was converted to the
2
at the R position of the biphenyl group. The trifluoromethoxy
derivative 21 had improved hNa
to the trifluoromethyl analog 20. Introduction of a methyl substitu-
ent 22 maintained the same level of hNa 1.7 functional block while
a basic amino group 23 had diminished hNa 1.7 block. Introduc-
tion of a carboxamide group 24 at the C-2 position of the oxazole
improved the hNa 1.7 functional block. In the imidazoles series,
the trifluoromethyl analog 25 was more potent on hNa 1.7 than
the trifluoromethoxy analog 26. Imidazole analogs 25 and 27
blocked hNa 1.7 in a state dependent manner with a K of 15 nM
v
1.7 functional block compared
v
2
-thiazolecarboxamides 15. A different synthetic route was uti-
v
lized to synthesize 4-thiazolecarboxamides 19. Commercially
available 3-bromo acetic acid 16 was converted to the thioamide
1
v
7 which was cyclized to 4-thiazole ethyl ester 18. The carboxam-
v
ide 19 was prepared from the corresponding ester 18.
v
i
and 270 nM, respectively. Substitution of the central ring with a
8
Table 1
fluoro group in the R position 30 diminished potency, but potency
7
SAR of the oxazoles and imidazoles
was significantly improved by fluoro substitution in R as in 31.
R7
R8
The thiazole series displayed improved hNa
compared to the corresponding oxazoles and imidazoles. As shown
v
1.7 block when
R2
Z
R3
R4
v
in Table 2, the unsubstituted thiazole, 32 displayed good hNa 1.7
functional block.
X
N
Y
Introduction of a methyl group 33 retained the same level of
activity, but introduction of a basic amine group at C-2 position
Entry
R2
CF
OCF
OCF
OCF
OCF
CF
OCF
CF
CF
CF
R7
R8
Z
X
Y
Na
v
1.7 VIPRa
3
4 again led to a diminished hNa
mide 35 and the urea 37 analogs were not tolerated. The thiazole
analog 38 with a carboxamide at C-2 displayed excellent hNa 1.7
functional block. A secondary carboxamide 39 or an acetamide
1 at the same position resulted in a diminished hNa 1.7 activity.
Analogs with a hydroxymethyl 42 or the nitrile 44 exhibited re-
duced hNa 1.7 functional block. Introduction of a heterocycle at
C-2 position of the thiazole, 45–49, diminished hNa 1.7 activity.
As shown in Table 2, a primary carboxamide at the 2-position of
the thiazole imparts good hNa 1.7 functional block in this series.
v
1.7 activity. The methylsulfona-
20
21
22
23
24
25
26
27
28
29
30
31
3
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
Cl
H
H
H
O
O
O
O
O
NH
NH
NH
NH
H
H
Me
NH
CONH
H
5.31
1.94
2.14
3
3
3
3
v
b
2
37%
2.36
2.1
4
v
2
3
b
3
H
14%
55%
v
b
3
3
3
CONH
CONH
CONH
CONH
CONH
2
2
2
2
2
v
2.77
1.25
NMe
NMe
NMe
b
OCF
OCF
3
3
15%
v
H
0.49
The SAR around the phenyl ring with a thiazole carboxamide at
C-2 position was explored. Consistent with earlier results in the
other heterocyclic series, the meta biphenyl thiazole (1,3) 38 dis-
a
IC50
,
l
M.
b
%
inh @ 1 lM.
v
played significantly better hNa 1.7 functional block than the para
biphenyl thiazole (1,4) 50 (Table 3). Liphophilic substitutents such
as the trifluoromethyl or the trifluoromethoxy were found to be
optimal at the R position of the biphenyl group. Compound 38 is
Table 2
SAR around the thiazole ring
2
one of the most potent thiazoles investigated.
Z
A representative group of compounds were evaluated for
S
hNa
to the Ikr channel and CYP enzymes were evaluated (Table 4). The
unsubstituted imidazole 25 though fairly potent on hNa 1.7, exhib-
v
1.7 block using electrophysiology and their binding inhibition
N
OCF3
Y
v
ited strong CYP inhibition of all the three isoforms tested. Reducing
Entry
Z
Y
v
Na 1.7 VIPR (IC50, lM or % inh @ 1 lM)
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
H
H
H
H
H
H
H
H
Me
H
H
Me
H
H
H
H
H
H
H
2.16
2.99
84%
65%
5%
6.6%
0.23
1.37
0.43
0.62
1.80
8%
Me
NH
NH
NHCOMe
NHCONMe
CONH
CONMe
CONH
CH
CH
Table 3
2
2
Meta versus para thiazole carboxamides
SO
2
Me
v
Na 1.7 VIPR IC50 (lM) or % inh at 10 lM
2
2
H N
2
2
N
O
2
6.1%
2
CONH
OH
2
S
2
OCF3
5
0
CO
CH
2
Et
2
CN
8%
2,3-Pyrazine
2-Pyridyl
Oxazole
Imidazole
Pyrimidine
1.26
À21%
27%
0.95
6.3%
NH
2
N
0.228
O
S
OCF
38
3

S. Tyagarajan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5536–5540
5539
Table 4
Pharmacokinetic data for selected compounds
R2
Z
Entry
R2
CF
Z
Na
V
1.7 VIPRa
Na
v
1.7 EPa
MK-0499a
75%
CYP 3A4b
<0.05
CYP 2C9b
<0.05
CYP 2D6b
<0.05
Rat dosec
1.0/2.0
F%
AUC d
N
Clpe
32
t1/2 (h)
25
27
38
51
3
3
N
NH
2.1
0.15
0.27
0.015
0.05
71
1.81
2.23
0.36
0.27
0.63
0.5
H
N
N
N
NH
CF
55%
25%
0.5%
55%
>40
18
>40
16
>40
48
1.0/3.0
1.0/2.0
1.0/3.0
46
20
22
23
52
CONH
2
S
OCF
OCF
3
3
0.23
1.33
0.74
CONH
2
S
0.26
>50
8.79
>50
112
CONH
2
a
b
c
IC50
IC50
mg/kg.
mMh/mpk.
mL/min/kg.
(
l
M) or % inh at 1
lM.
,
lM.
d
e
Na channel blocker
+
1
20%
Other MOA
Rat
Duration of effect (hr)
Dog
Monkey
Human
Acute dose (mg/kg)
Lidocaine (5-iv)
Mexiletine (30)
100%
0.25
*
8
6
0%
0%
n.s.
n.a.
2
(100)
*
Lamotrigine (100)
*
>1
1
Carbamazepine (100)
Amitriptyline (10)
*
40%
20%
n.s.
n.a.
2
Gabapentin (30)
Thiazole 38 (10)
*
0
%
0
10
20
30
40
Time (min)
50
60
70
2
*
0
20
40
60
80
100
Maximal Possible Effect (%)
Figure 3. Compound 38 in microsomal incubation.
Figure 2. Comparison of thiazole 38 with standards: SNL model of neuropathic
pain.
son, thiazole 38 had significantly better reversal of allodynia than
most commercial sodium channel blockers.
the basicity of the imidazole with the introduction of a carboxam-
ide group 27 improved the selectivity against CYPs and IKr channel
significantly but also had vastly diminished Na 1.7 potency. The
v
Pharmacokinetic metabolite analysis of compound 38 revealed
significant in vivo hydrolysis of the amide to the corresponding
acid. When subjected to rat, dog, and human liver S9 microsomal
incubation for 60 min, thiazole 38 had 68%, 10%, and 47% of the
parent remaining ( Fig. 3). Biphenyl thiazole 38 is extensively
metabolized in dog hepatocytes (2 h, 10 lM substrate), with very
small amount (<5%) of the parent remaining.
In summary, a new class of biphenyl heterocyclic sodium chan-
nel blockers has been developed. Biphenyl oxazoles are modest
sodium channel blockers. Biphenyl imidazoles exhibit improved
in vitro and in vivo efficacy but have CYP related issues. In compar-
thiazole 38 exhibited selectivity against various isoforms of CYPs
and the IKr channel. Thiazole 51 was more selective towards IKr
channel. The pharmacokinetic properties of the compounds in Ta-
ble 4 were also evaluated in rats. Imidazole 27 exhibited better
clearance and exposure compared to imidazole 25 but was consid-
erably less potent on hNa 1.7. In comparison to compound 51, thi-
v
azole 38 displayed significantly lower clearance and improved half
life.
In the rat spinal nerve ligation (Chung) model of neuropathic
pain (SNL), thiazole 38 exhibited excellent efficacy.8 When dosed
orally in rats at 10 mg/kg, 38 reversed mechanical allodynia by
v
ison, biphenyl thiazoles displayed increased hNa 1.7 functional
block. Biphenyl thiazole 38 is a potent state dependent sodium
channel blocker with good in vivo efficacy in the Chung model.
However, this thiazole analog undergoes extensive hydrolysis of
the amide and is rapidly metabolized in dog hepatocytes.
6
1% (p <0.05) (at 2 h post-dose) significantly more than mexiletine,
12
lamotrigine or carbamazepine at 100 mg/kg (Fig. 2). In compari-

5
540
S. Tyagarajan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5536–5540
Improvements to the pharmacokinetics and pharmacodynamics of
this thiazole series will be focus of future work and will be
reported in due course.
Br. J. Pharmacol. 2005, 144, 801; (c) Ramu, K.; Lam, G. N.; Hughes, H. Drug Metab.
Dispos. 2000, 28, 1153.
5
.
.
Chakravarty, P.; Kuo, C. H.; Tyagarajan, S.; Ayer, M.; Meinke, P. T.; Parsons, W.
H.; Fisher, M. H.; Wyvratt, M. J.; Lyons, K. A.; Priest, B. T.; Brochu, R. M.; Dick, I.
E.; Kaczorowski, G. J.; McGowan, E.; Jochnowitz, N.; Tarpley, J. W.; West, S.;
Reiseter, B. S.; Martin, W.J. Abstracts of Papers, 232nd National Meeting of the
American Chemical Society, San Francisco, CA, Sept 10–14, 2006; American
Chemical Society: Washington, DC, 2006; MEDI 45.
Felix, J. P.; Williams, B. S.; Priest, B. T.; Brochu, R. M.; Dick, I. E.; Warren, V. A.;
Yan, L.; Slaughter, R. S.; Kaczorowski, G. J.; Smith, M. M.; Garcia, M. L. Assay
Drug Dev. Technol. 2004, 2, 260.
Acknowledgment
6
The authors thank Dr. Joseph Duffy and Dr. Tesfaye Biftu for
proof-reading the manuscript.
7
8
.
.
Schoemaker, H.; Hicks, P.; Langer, S. J. Cardiovasc. Pharmacol. 1987, 9, 173.
Chaplan, S. R.; Bach, F. W.; Pogrel, J. W.; Chung, J. M.; Yaksh, T. L. J. Neurosci.
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12. Treatment with compound 38 (10 mg/kg) 14 days after surgery in the Chung
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