Novel cyclopentane dicarboxamide sodium channel blockers as a potential treatment for chronic pain

Article abstract of DOI:10.1016/j.bmcl.2005.02.002

A series of new voltage-gated sodium channel blockers were prepared based on the screening lead succinic diamide BPBTS. Replacement of the succinimide linker with the more rigid cyclic 1,2-trans-diamide linker was well tolerated. N-Methylation on the biph

Full text of DOI:10.1016/j.bmcl.2005.02.002

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1901–1907
Novel cyclopentane dicarboxamide sodium channel blockers as
a potential treatment for chronic pain
a,
a
b
Pengchang P. Shao,a,* Dong Ok, Michael H. Fisher, Maria L. Garcia,
*
Gregory J. Kaczorowski,b Chunshi Li,a Kathryn A. Lyons,a William J. Martin,c
Peter T. Meinke,a Birgit T. Priest,b McHardy M. Smith,b Matthew J. Wyvratt,a
Feng Yea and William H. Parsonsa
aDepartment of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
bDepartment of Ion Channels, Merck Research Laboratories, Rahway, NJ 07065, USA
cDepartment of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, USA
Received 3 December 2004; revised 31 January 2005; accepted 1 February 2005
Abstract—A series of new voltage-gated sodium channel blockers were prepared based on the screening lead succinic diamide
BPBTS. Replacement of the succinimide linker with the more rigid cyclic 1,2-trans-diamide linker was well tolerated. N-Methylation
on the biphenylsulfonamide side of the amide moiety significantly reduced the clearance rate in rat pharmacokinetic studies.
Ó 2005 Elsevier Ltd. All rights reserved.
Voltage-gated sodium channels (VGSCs) are transmem-
brane proteins that selectively conduct Na+ ions. These
proteins belong to a multigene family; nine subtypes of
which have been cloned and functionally expressed.1
VGSCs are responsible for the rising phase of the action
potential in electrically excitable cells, such as those
present in the central and peripheral nervous system
and in cardiac tissue. A number of studies suggest that
VGSCs play a key role in chronic pain syndromes,
including nerve injury-induced neuropathic pain.2
Amongst the subtypes of VGSCs expressed in primary
sensory neurons that transmit pain signals, Nav1.3,3
Nav1.7,4 Nav1.8,5 and Nav1.96 have been most strongly
implicated in injury-induced hyperexcitability of periph-
eral nerves. Several therapeutic classes of drugs, includ-
ing local anesthetics (e.g., lidocaine), antiarrhythmics
(e.g., mexiletine), and anticonvulsants (e.g., carbamaze-
pine), share the common mechanism of blocking VGSCs
and have been shown to be effective in reducing neuro-
pathic pain behavior in animal models and in the treat-
ment of this condition in humans.7 VGSC blockers are
effective in treating neuropathic pain despite their rela-
tively weak in vitro potency against these channels.
Moreover, because the aforementioned VGSC blockers
were not developed for the purpose of treating neuro-
pathic pain, they possess a relatively narrow therapeutic
index, which limits their clinical utility.
Recently, Compound 1 (BPBTS),8 a succinamide deriv-
ative with biphenylsulfonamide and bithiophene side
arms, was identified as a potent sodium channel blocker
through screening of in-house sample collection in a
functional assay. BPBTS exhibits an IC50 = 0.15 lM in
a Nav1.7 voltage-ion-probe-reader (VIPR) assay and a
Ki of 0.15 lM in electrophysiology assays (EP).8 How-
ever, BPBTS has a poor rat pharmacokinetic profile
with an oral bioavailability of 2%. Structure–activity
relationship (SAR) studies, systematically replacing the
succinamide center linker and the side arms, were car-
ried out with the goal of improving the PK profile and
N
O
N
O
S
SO2NH2
S
Keywords: Sodium channel blocker; Chronic pain; Neuropathic pain.
*
1
Corresponding authors: Tel.: +1 732 594 2955; fax: +1 732 594
5350; e-mail: pengcheng_shao@merck.com
BPBTS
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.02.002

1902
P. P. Shao et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1901–1907
in vivo efficacy. In this letter we report the progress gen-
erated from this lead structure.
CHO
Li
S
S
S
g
S
S
S
S
NHMe
OH
86%
3c
d
4c
3a
70%
S
Two synthetic approaches were used to assemble these
diamido compounds. To obtain small quantities of
material for in vitro assays, a rapid, one-pot amide-cou-
pling reaction was used, taking advantage of the large
polarity difference between the biphenylsulfonamide
and bithiophene moieties. In general, these one-pot
amide-coupling reactions gave a statistical mixture
(1:2:1) of three diamido products I, II, and III, which
were separated on a reverse phase HPLC column
(Scheme 1). The symmetrical diamido compounds I
and III are typically much less active, thus only the
mixed diamido compounds II were assayed. When a lar-
ger amount of material is required, monoamides IV are
prepared first (Scheme 2). After dicarboxylic acids were
activated with a stoichiometric amount of CDI, the
reaction mixture was treated with 1.2 equiv of an amine
to give the desired monoacid IV as the major product.
Symmetrical diamido compounds and most of the unre-
acted dicarboxylic acid starting materials were washed
away during an acid and base workup. Monoacid IV
was then reacted with a second amine by a standard
EDC coupling procedure to give the desired diamido
compounds II.
S
S
a
b
76%
79%
2
c
e,f
65%
S
S
S
S
NH2
OH
e,f
4a
3b
S
S
53%
NH2
4b
Scheme 3. Reagents and conditions: (a) nBuLi, THF, À78 °C; (b)
(CHO)n; (c) CH3CHO; (d) DMF; (e) DPPA, DBU, Zn(N3)2ÆPy,
0.1 equiv, CH2Cl2, rt; (f) PPh3, THF/H2O; (g) MeNH2, NaB(OAc)3H,
CH2Cl2.
acid/base work up. Bithienyllithium can be also trapped
with acetaldehyde to give alcohol 3b, which was then
converted to amine 4b. In order to synthesize methyl
amine 4c, bithienyllithium was trapped with DMF to
give aldehyde 3c. It was converted to amine 4c by reduc-
tive amination reaction.
The syntheses of bithiophenemethylamine and related
derivatives are illustrated in Scheme 3. Bithiophene in
THF was treated with 1 equiv of n-BuLi at À78 °C to
generate bithienyllithium 2, which was trapped with
paraformaldehyde to give alcohol 3a. Alcohol 3a was
converted to the azide intermediate by reacting with
DPPA and DBU. A catalytic amount of Zn(N3)ÆPy ap-
pears to accelerate the desired reaction and suppress
formation of the bis(bithienylmethyl)ether by-product.
Amine 4a was cleanly obtained after the azide interme-
diate was treated with PPh3 and water and subsequent
The synthesis of amine 6a was reported,9 however, the
route outlined in Scheme 4 is more versatile. Suzuki cou-
pling reaction between 2-bromobenzenesulfonamide and
boronic acids was initially investigated. This reaction
failed under common Suzuki coupling reaction condi-
tions most likely due to the strong chelating ability of
the sulfonamide group. Fortunately, Suzuki coupling
proceeded smoothly after the sulfonamide group was
protected as its tert-butylsulfonamide. Thus amine 7a,
b, and c can all be prepared from a common starting
material.
The syntheses of 10, 11, and 12 are outlined in Scheme 5.
2-Iodothioanisole was coupled with propargylamine
with a catalytic amount of Pd(dppf)Cl2 and CuI. For
this Sonogashira reaction,10 it was found that pyrroli-
dine is a more effective base than TEA.11 The amount
of CuI was critical. Lower loading (0.02 equiv) gave
the best results. Amine 8 was then coupled with mono-
acid intermediates by standard EDC coupling. Thioe-
ther 9 was oxidized to methylsulfone 10 with m-CPBA.
Compound 10 was hydrogenated either with Lindlar
catalyst to give cis olefin product 11, or with Pd/C as
a catalyst to give alkyl compound 12.
Ar1
Ar1
HO2C
S
CO2H
N
N
O O
S
I
NH2
a
Ar1
Ar2
Ar2
Ar2
Ar1CH2NH2
N
N
N
O O
O O
II
NH2
SO2NH2
Ar2CH2NH2
N
III
The synthesis of biaryl derivatives is illustrated in
Scheme 6. 4-Bromobenzylamine or 4-bromobenzylmeth-
ylamine was coupled with monoacids IV under standard
EDC coupling reaction conditions. The resulting bromo
intermediates V can be coupled with various boronic
acids in a standard Suzuki coupling protocol to give
the desired diamido products VI.
Scheme 1. Reagents: (a) EDC, HOBt, DIEA, THF.
b
a
Ar1
Ar1
Ar2
N
CO2H
IV
N
N
HO2C
CO2H
O
O O
II
To define the SAR of these compounds, a fluorescence-
based functional assay, using a voltage sensitive dye pair
and the VIPR instrument (Aurora Biosciences), was
Scheme 2. Reagents: (a) (1) CDI, THF, (2) Ar1CH2NH2; (b) EDC,
HOBt, DIEA, Ar1CH2NH2, THF.

P. P. Shao et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1901–1907
1903
NH2
d
NH2
SO2NHtBu
92%
SO2NH2
7a
6a
b,c
82%
CHO
CHO
SO2NHtBu
Br
NHMe
e,d
B(OH)2
77%
a
SO2NHtBu
5a
SO2NH2
95%
7b
O
a
B(OH)2
90%
NH2
NH2
b,c
d
89%
O
90%
SO2NHtBu
6c
SO2NHtBu
SO2NH2
7c
5a
Scheme 4. Reagents and conditions: (a) Pd(dppf)Cl2, Na2CO3, toluene, 85 °C; (b) NH2OH, Na2CO3, EtOH; (c) H2, 50 psi, Pd–C, EtOH; (d) TFA,
50 °C; (e) MeNH2, NaB(OAc)3H, CH2Cl2.
SMe
SMe
NH2
c
b
a
R
O
I
SMe
N
71%
92%
8
9
R
O
d
N
R
O
SO2Me
MeO2S
75%
N
10
11
96%
e
MeO2S
S
R
O
S
H
N
R :
N
O
1 2
Scheme 5. Reagents and conditions: (a) Pd(dppf)Cl2 0.03 equiv, CuI 0.02 equiv, pyrrolidine 2 equiv, THF, Na2CO3 2 M, 70 °C, 1.5 h; (b) EDC,
HOBt, DIEA, RCO2H, THF; (c) m-CPBA 2 equiv; (d) H2, Lindlar catalyst, EtOH; (e) H2, Pd–C, EtOH.
Br
b
a
Ar1
Ar1
N
CO2H
N
N
HO2C
CO2H
O
O
O
R
IV
V
c
R1
R: H or Me
Ar1
N
N
O
O
R
VI
Scheme 6. Reagents and conditions: (a) (1) CDI, THF, (2) Ar1CH2NH2; (b) EDC, HOBt, DIEA, 4-bromobenzylamine or (4-bromobenzyl)methyl-
amine or (6-bromopyridin-3-yl)methyl]methylamine, THF; (c) boronic acid, Pd(dppf)Cl2, EtOH, Na2CO3 2 M, 80 °C.

1904
P. P. Shao et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1901–1907
used as the primary in vitro assay.12 Potent Nav1.7
channel blockers were further evaluated in a whole cell
voltage clamp (EP) assay designed to determine affinity
for the resting and inactivated states of the channel.13 It
should be noted that most compounds reported here are
state-dependent sodium channel blockers. Thus, po-
tency for blocking the inactivated state was much higher
(>100-fold) than for blocking the resting state. This
state-dependence is also seen with clinically used sodium
channel blockers and is believed to be critical for achiev-
ing a suitable therapeutic window.14
or pentanediamide as center linkers are at least 5-fold
less potent (14, 15). Substitution on the succinamide
fragment also led to less potent compounds (16, 17).
Results with cyclic dicarboxamides varied (18–24).
Compounds with trans-cyclopentanedicarboxamide and
trans-cyclobutanedicarboxamide moieties were the most
potent (19 and 20). In the EP assay, compound 20
was threefold more potent than BPBTS. The cis-analog
was less potent (21). It is interesting that the phthal-
amide derivative showed good potency, especially in
the EP assay (23), while the isophthalamide analog
was clearly less potent (24).
Data in Table 1 indicate that replacement of the succin-
amide moiety with the maleamide group was tolerated,
although the resulting compound was about threefold
less potent than the parent (13). The two-carbon linker
appeared to be optimal since analogs with malonamide
From this SAR study, the trans-cyclopentanedicarbox
amide design emerged as an interesting conformation-
ally restricted replacement for the succinimide moiety.
Compound 20 was chosen for rat pharmacokinetics
studies but no significant improvement over BPBTS
was observed, other than a modest reduction of clear-
ance rate (Table 5). It was hypothesized that amide
hydrolysis could be one of the metabolic liabilities.
Increasing steric bulk around the amide group might
prevent the hydrolysis. To test this hypothesis, analogs
of 20 with methyl groups on amide nitrogens or at ben-
zylic positions were synthesized. Sodium channel block-
ing activity of these compounds is summarized in Table
2. Substitution on the bithienyl side was not tolerated
(25, 26, 29, and 30). However, methyl substitution was
tolerated on the biphenylsulfonamide side (27, 28), espe-
cially on the amide nitrogen. Thus, 28 has similar po-
tency to 20. In rat PK studies, 28 showed an improved
clearance rate and half life relative to 20, but its bio-
availability remained low (Table 5).
Table 1. Inhibition of Nav1.7 by diamido compounds
N
N
O
O
S
S
SO2NH2
Compound
Center linker
Nav1.7 VIPR
IC50(lM)
Nav1.7 EP
Ki (lM)
*
BPBTS
0.15
0.15
0.41
*
13
14
15
0.52
0.86
3.2
*
*
*
*
*
Attention turned to modification of the side arms.
Biphenylsulfonamide modification was first explored to
determine the contribution of this moiety to biological
activity and to PK profile. The results are summarized
in Table 3. Removing the distal phenyl ring resulted in
significant loss of potency (31–34), suggesting an impor-
tant interaction with the channel. The next step was to
assess whether the vicinal phenyl ring contributed
directly to binding or acted as a spacer. For synthetic
convenience, a methyl sulfonyl group was used as a sul-
fonamide surrogate since the two groups are inter-
changeable (20 and 37). As demonstrated by 10, 11,
and 12, replacing the phenyl ring with alkynyl, alkenyl
*
*
*
16
17
1.4
2.3
*
*
rac-18
0.84
5.7
*
*
*
*
*
*
rac-19
rac-20
0.21
0.37
*
*
*
0.06
0.67
2.1
Table 2. Inhibition of Nav1.7 by diamido compounds
R1
R3
rac-21
rac-22
1.6
1.4
N
N
O
O
S
R4
S
R2
SO2NH2
Compound R1 R2 R3 R4 Nav1.7 VIPR Nav1.7 EP
*
IC50 (lM)
Ki (lM)
rac-25
rac-26
rac-27
rac-28
rac-29
rac-30
H
H
H
Me
H
10
5.3
23
24
2.2
2.9
0.14
6.2
H
H
Me
H
*
*
*
H
Me
H
H
1.4
0.76
10
0.05
Me
Me
Me
H
H
H
H
Me
Me
H
*
H
>10

P. P. Shao et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1901–1907
1905
or alkyl groups resulted in complete loss of activity. This
phenyl ring appears to be critical for binding or rigid
spacing. Next, the role of the sulfonamide group was
investigated. Initial data suggest the sulfonamide group
is important since des-sulfonamide compound 35 was
significantly less potent. However, further data revealed
that the sulfonamide group can be replaced with a vari-
ety of groups regardless of hydrogen bonding capability
(36–39). However, when the substitution was placed in a
meta or para position, the resulting compounds were not
active (40–41). Ortho substitution forces the two phenyl
rings to be orthogonal to each other, which may be crit-
ical for binding to sodium channels. Compound 42 with
the sulfonamide group replaced by a CF3 group was
tested in rat PK studies. It showed a lower clearance rate
than 28. However, bioavailability was still low (Table 5).
Table 3. Inhibition of Nav1.7 by diamido compounds
Focus was shifted to replacement of the bithiophene
group. It is known that thiophenes are prone to oxida-
tion by cytochrome P-450 enzymes to form epoxides
or sulfoxide reactive intermediates, which may cause
toxicity.15 As indicated in Table 4, bithiophene can be
replaced with various biphenyl groups without signifi-
cant loss of activity (43–46), and more interestingly, it
can be replaced with various phenyl derivatives (47–
56). The electronic nature of the substituents seems to
have little effect on activity (49 and 51). However, more
lipophilic substituents are favored (49–56). The triflu-
oromethoxy group at the para position appears to be
optimal (53 and 54).
N
R1N
S
S
O
R1N
Compound
Nav1.7 VIPR Nav1.7 EP
Ki (lM)
IC50 (lM)
H
N
F
rac-31
rac-32
10
H
Br
10
10
N
H
N
MeO
F3C
rac-33
rac-34
H
2.9
>10
Table 4. Inhibition of Nav1.7 by diamido compounds
N
R1
H
N
NR2
N
rac-10
rac-11
rac-12
O
O
SO2Me
SO2NH2
NR2
H
Compound R1
Nav1.7 VIPR Nav1.7 EP
IC50 (lM)
N
>10
Ki (lM)
SO2Me
H
N
rac-43
rac-44
H
H
0.66
0.03
>10
N
H
SO2Me
H
N
2.1
0.37
0.69
H
N
rac-35
rac-36
>10
2.1
2.5
H
N
rac-45
rac-46
H
H
0.66
H
N
MeO
F3C
0.13
H
N
0.37
0.51
H
N
rac-37
rac-38
rac-39
rac-40
rac-41
rac-42
0.26
2.3
0.14
0.16
0.11
SO2Me
OMe
H
N
rac-47
rac-48
H
Me
5
>10
H
N
H
N
rac-49
rac-50
H
Me
5
10
1.2
2.1
OMe
H
N
1.3
H
N
NO2
CF3
rac-51
rac-52
H
2.8
2.5
2.0
CF3
H
H
N
>10
>10
5
N
Me
0.28
F3C
F3C
H
N
H
rac-53
rac-54
H
Me
0.30
0.83
0.36
0.21
OCF3
OCF3
N
H
N
rac-55
rac-56
H
Me
1.1
1.3
N
0.33
0.53
CF3

1906
P. P. Shao et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1901–1907
Table 5. Rat pharmacokinetic profiles of selected compounds
sodium channel blocker that has shown efficacy in the
treatment of neuropathic pain in clinical studies.16 In
the spinal nerve ligation pain model of neuropathic pain
(SNL),1754 was more potent than mexiletine. When
dosed orally in rats at 10 mg/kg, 54 significantly reversed
mechanical allodynia by 35% (p < 0.05, plasma level at
2 h past dosing: 0.70 0.15 lM), while mexiletine pro-
duced 34% reversal at 100 mg/kg oral dose (p > 0.05).
Compound
Clp
(mL/min/kg)
t1/2 (h)
AUC (Norm)
lM h kg/mg
%F
1
68
39
0.5
0.3
1.2
1.7
0.98
0.5
0.009
0.009
0.07
0.1
1.9
rac-20
rac-28
rac-42
rac-54
57
1.2
3.3
1.5
13
5.0
14
0.90
0.06
44
27
141
In conclusion, SAR studies were performed to improve
the PK profile of BPBTS. By rigidifying the center linker
and replacing the bithienyl group, compound 54 was
identified. It has comparable in vitro potency to BPBTS
and a significantly improved PK profile. Further, it dis-
plays favorable in vivo efficacy compared to mexiletine
in an SNL pain model.
OCF3
N
N
57:
O
O
SO2NH2
The rat PK profile of compound 54 was assessed. It
showed significant improvement over compound 28 with
bioavailability of 44% (Table 5). AUC was more than
10-fold higher. Apparently, the bithiophene moiety
was a liability causing poor PK profiles. To assess affect
of the center linker, compound 57 with succinamide as
the center linker was tested. Its PK profile was much
worse than that of 54 with a 10-fold higher clearance
rate.
Acknowledgments
We thank Richard M. Brochu, Charles J. Cohen, Ivy E.
Dick, John P. Felix, Dorothy A. Levorse, Brita S. Reis-
eter, Robert S. Slaughter, Jason W. Tarpley, Dineen
White, and Brande S. Williams for their outstanding
technical contributions and Dr. Ying-Duo Gao for
modeling work.
Since 54 displayed good in vitro potency and an excel-
lent PK profile, it was selected for further evaluation.
In the rat formalin paw model,8 54 reduced pain behav-
ior by 29% at 10 mg/kg, p.o., which was comparable to
the inhibition (33%) produced by a 100 mg/kg, p.o. dose
of mexiletine (Fig. 1, A), an oral congener of lidocaine, a
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