Phenoxyphenyl pyridines as novel state-dependent, high-potency sodium channel inhibitors

Article abstract of DOI:10.1021/jm040048d

In the search for more efficacious drugs to treat neuropathic pain states, a series of phenoxyphenyl pyridines was designed based on 4-(4-flurophenoxy) benzaldehyde semicarbazone. Through variation of the substituents on the pyridine ring, several potent state-dependent sodium channel inhibitors were identified. From these compounds, 23 dose dependently reversed tactile allodynia in the Chung model of neuropathic pain. Administered orally at 10 mg/kg the level of reversal was ca. 50%, comparable to the effect of carbamazepine administered orally at 100 mg/kg.

Full text of DOI:10.1021/jm040048d

J . Med. Chem. 2004, 47, 4277-4285
4277
P h en oxyp h en yl P yr id in es a s Novel Sta te-Dep en d en t, High -P oten cy Sod iu m
Ch a n n el In h ibitor s
Bin Shao,* Sam Victory, Victor I. Ilyin, R. Richard Goehring, Qun Sun, Derk Hogenkamp,# Diane D. Hodges,†
Khondaker Islam, Deyou Sha, Chongwu Zhang, Phong Nguyen,† Silvia Robledo,† George Sakellaropoulos,§ and
Richard B. Carter‡
Purdue Pharma, L.P., Discovery Research, 6 Cedar Brook Drive, Cranbury, New J ersey 08512
Received February 28, 2004
In the search for more efficacious drugs to treat neuropathic pain states, a series of
phenoxyphenyl pyridines was designed based on 4-(4-flurophenoxy)benzaldehyde semicarba-
zone. Through variation of the substituents on the pyridine ring, several potent state-dependent
sodium channel inhibitors were identified. From these compounds, 23 dose dependently reversed
tactile allodynia in the Chung model of neuropathic pain. Administered orally at 10 mg/kg the
level of reversal was ca. 50%, comparable to the effect of carbamazepine administered orally
at 100 mg/kg.
In tr od u ction
Voltage-gated sodium channels play an important role
in the molecular pathophysiology of pain. They are
essential for the initiation and propagation of neuronal
impulses and are dynamically regulated in animal
models of neuropathic pain states.1 Sodium channels
can be distinguished pharmacologically according to
their sensitivity to tetrodotoxin (TTX) as either TTX-
sensitive (TTX-S), or TTX-resistant (TTX-R).2
F igu r e 1. Structures of carbamazepine and lamotrigine.
the channel. Thus, during episodes of hyperexcitability,
when sodium channels accumulate in inactivated states,
this class of inhibitors selectively blocks the pathological
state while leaving the remainder of the nervous system
to function normally.
Current evidence suggests that both TTX-S and
TTX-R channels expressed in primary afferent neurons
play roles in the pathological firing patterns that are
established following nerve injury.3 Thus, a potentially
powerful approach to control neuropathic pain is to
selectively suppress the repetitive firing that is common
in these states.4 Consistent with this idea, drugs that
block sodium channels, such as carbamazepine5 and
lamotrigine,6 have clinical utility in treating neuropathic
pain (Figure 1). However, these agents were developed
as anticonvulsants with no view to optimizing the
sodium channel activity for pain states. At present, due
to limited efficacy and problematic CNS side effects,
there are few available options for treating neuropathic
pain.
Sodium channels can be thought of as existing in
three states: a closed resting state, an open state, and
a closed inactivated state. Driven by membrane voltage,
the channel is able to cycle through these states within
a few milliseconds. It is thought that to achieve a
desirable side effect profile it is important to have a
state-dependent mechanism of inhibition. The most
desirable molecules should have higher affinity for the
inactivated state versus the resting or open states of
4-(4-Fluorophenoxy)benzaldehyde
semicarbazone
(Scheme 1) was originally identified as a compound with
anticonvulsant properties in animals.7 It was subse-
quently found to be a state-dependent sodium channel
blocker with submicromolar affinities (Ki) for inactivated
states for a variety of TTX-S sodium channels, including
recombinant rBIIa (0.37 µM) and hSkM1 (0.2 µM), and
wild-type sodium currents in acutely dissociated rat
hippocampal neurons (0.6 µM).8 It has a minimum
effective dose of 2.5 mg/kg in the rat Chung model of
neuropathic pain9 following oral administration.10 In
addition, 4-(4-fluorophenoxy)benzaldehyde semicarba-
zone does not have obvious CNS side effects. Despite
the attractive in vitro and in vivo properties, this
compound carries a number of concerns for development
including the possible formation of a reactive species
during metabolism (Scheme 1).11
Toward the discovery of a second-generation com-
pound, we embarked on a systematic structure-activity
investigation aiming to replace the labile semicarbazone
moiety with various heterocycles as bioisosteric replace-
ments.
It is conceivable that one such direct transformation
is to replace one nitrogen atom of the semicarbazone
with a carbon atom and incorporate the resulting moiety
into a pyridine ring (Figure 2). By doing so, the double
bond character between the carbon and nitrogen atom
would be kept intact. Most importantly, this would
retain the relative spatial relationship between the
* Corresponding author: Dr. Bin Shao, CCMC, Purdue Pharma,
L.P., 6 Cedar Brook Drive, Cranbury, NJ 08512. Tel: 609-409-5135;
fax: 609-409-6039; e-mail: bin.shao@pharma.com.
#
Current address: College of Medicine, Department of Pharmacol-
ogy, Medsurge 2, Room 355, University of California, Irvine, CA 92697.
† Current address: Allergan, 2525 Dupont Drive, Irvine, CA 92612.
§ Current address: University of Toronto, Department of Physiology,
Room 3336, King’s College Circle, Toronto, Ontario, Canada, M5S 1A8.
‡ Current address: Novartis Neuroscience, East Hanover, NJ 07936-
1080.
10.1021/jm040048d CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/16/2004

4278 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 17
Shao et al.
Sch em e 1
carboxamide and the phenoxyphenol moiety present in
4-(4-fluorophenoxy)benzaldehyde semicarbazone. With
this design, we significantly departed from the original
structure and entered into a new series of structures,
the phenoxyphenyl pyridines. During the progress of our
work, a report by Itoh et al.12 on a sodium/calcium
channel blocker NS-7 (Figure 3) triggered our curiosity
on the role of the carboxamide of phenoxyphenyl pyr-
idines in determining the potency of sodium inhibitors.
On the basis of the structure of NS-7 we designed
compound 22c, analogous to NS-7 (Figure 3), to probe
the importance of the carboxamide on activity of the new
series.
In this paper, we report our work toward the effective
replacement of the semicarbazone moiety with a pyri-
dine scaffold, which leads to the discovery of a new
potent and state-dependent sodium channel inhibitor,
compound 6. In addition, we will report a brief structure-
activity relationship study of the pyridine ring system,
carried out to maximize the potential of these scaffolds.
The structure-activity investigation started with the
synthesis of analogues designed to probe the importance
of the spatial relationship of the carboxamide group
relative to the phenoxyphenyl moiety. Several analogues
with substituents at either the 4-position of the pyridine
or at the carboxamide nitrogen atom were prepared in
attempt to improve the pharmaceutical profile of the
molecules while maintaining their potency and state
dependence.
14, and 17, which were easily obtained from com-
mercially available 10, 13, and 16.
The reaction sequence shown in Scheme 3 was
utilized to prepare several 4-substituted pyridine ana-
logues (22-25).13 2,4-Pentanedione (19) was converted
to a keto-enamine intermediate through its reaction
with aniline in the presence of p-toluenesulfonic acid
as catalyst. Treatment of this intermediate with lithium
2,2,6,6-tetramethylpiperidide (LTMTP) at low temper-
ature resulted in the generation of a dianion that was
subsequently reacted with 4-(4-fluorophenoxy) benzoni-
trile to obtain hydroxypyridine 20. Brief treatment of
20 with POCl3 at elevated temperature yielded chloro-
pyridine 21. Serving as a key intermediate, compound
21 was reacted with several nucleophiles including
dimethylamine, morpholine, 2-piperidinyl ethanol, and
methanol in the presence of NaH at elevated tempera-
tures to produce 22a -22d . Oxidation of 22a with SeO2
in refluxing pyridine failed to provide the corresponding
carboxylic acid; only starting material 22a was recov-
ered. Extended reaction time and excess SeO2 did not
change the outcome. In contrast, the oxidation of 22b
with SeO2 in refluxing pyridine provided the corre-
sponding acid in good yield, which was then converted
to the desired amide 23. This process involved the
conversion of the acid to the corresponding methyl ester,
followed by the treatment with NH3 in methanol to
complete the synthesis of the primary amide. In a
similar reaction sequence, 22d was converted to meth-
oxy-substituted pyridines 24 and 25 with NH3 and N,N-
dimethylethylenediamine, respectively.
Ch em istr y
Pyridine carboxamides 6-9 were prepared in a one-
step Suzuki coupling reaction between the correspond-
ing halopyridine carboxamides 2-5 and 4-(4-fluorophe-
noxy)benzene boronic acid (Scheme 2). In a similar
fashion, compounds 12, 15, and 18 were synthesized
with the corresponding halopyridine carboxamides 11,
Resu lts a n d Discu ssion
The extent of sodium channel inhibition was mea-
sured with the rat brain NaIIa (rNav1.2) -B2 cell line
hosted in HEK-293 cells. In addition, the activity of
selected compounds was confirmed by assaying for the
F igu r e 2. Replacement of semicarbazone with pyridine-2-carboxylic acid amide.
F igu r e 3. Analogue of NS-7.

Phenoxyphenyl Pyridines as Na Channel Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 17 4279
Sch em e 2. Synthesis of 6-(4-Fluorophenoxy)phenyl Pyridine Carboxamidesa
a
Reagents: (a) Pd(PPh3)4, boronic acid 1, DME, H2O (6: 18%; 7: 40%; 8: 55%; 9: 31%); (b) HOBT, DIC, DMF, 1-(2-aminoethyl)piperidine,
H2O (12: 42% from 10; 15: 52% from 13; 18: 75% from 16).
inhibition of native TTX-R and TTX-S sodium currents
in acutely dissociated rat dorsal root ganglion (DRG)
neurons14 using a conventional whole-cell patch clamp
technique. As discussed earlier, the first modification
of the semicarbazone moiety in 4-(4-fluorophenoxy)-
benzaldehyde semicarbazone involved the replacement
of one nitrogen atom with a carbon atom and incorpora-
tion of the remaining moieties into a pyridine ring such
as 6 (Figure 2).
Evaluation of compound 6, the direct analogue of 4-(4-
fluorophenoxy)benzaldehyde semicarbazone, led to the
discovery of a potent sodium channel inhibitor (Table
1), with an apparent dissociation constant for the
inactivated state of sodium channels (Ki) below 100 nM.
Furthermore, its actions appear to be state-dependent,
similar to 4-(4-fluorophenoxy)benzaldehyde semicarba-
zone as evidenced by its large Kr/Ki ratio.
With 6 as a potent lead, we embarked on a systematic
investigation of the SAR within this series. Compounds
7-9 were prepared by varying the point of attachment
of the primary carboxamide to the pyridine ring. It was
observed that when the amide was moved away from
the 2-position, all analogues lost potency at the inacti-
vated state of sodium channel, compound 9 showing this
most dramatically.
tially increasing water solubility. With such anticipa-
tion, compounds 12 and 15 were prepared (Scheme 2).
When evaluated, 12 and 15 showed increased potency
toward the sodium channel compared with their pri-
mary amide analogues (6 and 7, respectively). In addi-
tion, both 12 and 15 retained their favorable state
dependence.
In compound 12, the carboxamide and phenoxyphenyl
substituents are in the same spatial orientation (meta-)
as in compound 6. While holding the position of these
two substituents constant, we relocated the nitrogen in
the pyridine ring, resulting in compound 18. Both
potency and state dependency of 18 are reduced, com-
pared to 12 but not abolished. Thus, it would seem that
as long as the relative orientation of the two substitu-
ents on the pyridine ring is maintained, the potency
could be retained to a fair degree.
With the relative orientation of substituents on the
pyridine ring established, we returned to the 2,6-
relationship present in compounds 6 and 12 to assess
the effect of additional substituents on the pyridine ring.
4-Substituted pyridines were investigated because of
their ease of synthesis and the potential electronic effect
of the substituent on the pyridine ring. Compounds 23-
25 were prepared with amino and methoxy groups at
the 4-position of the pyridine ring (Scheme 3). While
the substituents are tolerated, there is a reduction in
both potency and state dependency compared to 6. When
an additional basic center is attached to the amide
On the basis of previous work,15 we knew that amides
substituted on nitrogen with a piperidinyl ethyl moiety
showed increased potency toward the sodium channel.
In addition, the incorporation of an additional basic
center makes it possible to form a salt thereby poten-

4280 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 17
Sch em e 3. Synthesis of 4-Substituted Pyridine Analoguesa
Shao et al.
a
Reagents: (a) aniline, TsOH, toluene (100%); (b) LTMP, 4-(4-fluorophenoxy)benzonitrile, THF, -78 °C (60%); (c) POCl3, CH2Cl2 (33%
from 19); (d) 22a : NaH, dimethylamine, sealed tube, room temp, 48 h (10%); 22b: NaH, morpholine, sealed tube, 135 °C, 2 h (100%);
22c: NaH, 2-piperidinyl ethanol, DMF, 80 °C, 16 h (42%); 22d : NaOMe, MeOH, sealed tube, 85 °C, 4 h (100%); (e) (i) SeO2, pyridine,
reflux, 3 days; (ii) thionyl chloride, MeOH, reflux, 12 h; (iii) 2 N NH3 in MeOH, room temp, 12 h (23: 32%; 24: 48%); (f) (i) SeO2, pyridine,
reflux, 3 days; (ii) thionyl chloride, MeOH, reflux, 12 h; (iii) excess N,N-dimethylethylenediamine, MeOH, room temp, 4 days (94%).
nitrogen, the state dependency is partially restored
(compare 25 vs 24).
tactile allodynia when administered orally, was selected
for studies on this aspect. The corresponding values for
6 are MEDChung ) 3 mg/kg and MAD ) 30 mg/kg, giving
an estimated therapeutic index (TI) of 10. The corre-
sponding values for carbamazepine are MEDChung ) 100
mg/kg and MAD ) 100 mg/kg, giving an estimated TI
of 1, i.e., efficacy in the Chung model was only seen at
doses that produced ataxia. Clearly, compound 6 has
an improved TI in rat compared to carbamazepine.
In summary, we have demonstrated that within the
phenoxyphenyl pyridine series, compounds significantly
more potent than lamotrigine or carbamazepine can be
prepared, with improved state dependency. In addition,
compounds 6 and 23 have shown oral efficacy in the rat
Chung model. This demonstrates that state-dependent
sodium channel inhibitors incorporating a pyridine
scaffold have potential in the treatment of neuropathic
pain.
Finally, the importance of the carboxamide was
investigated in compounds 22a and 22c. Neither com-
pound contains the amide moiety, yet they are potent
and state-dependent sodium channel inhibitors, 22c
being the most state dependent. The fact that they are
active at the sodium channel is not completely unex-
pected, especially for 22c, in light of NS-7 (Figure 3).12
However, the high degree of state dependency is sur-
prising. NS-7 was reported to preferentially block
sodium channels in the activated state rather than the
inactivated state or the resting state, while 22c blocks
the channels of inactivated state preferentially.
Within this series of compounds, we proceeded to
select compounds for further in vivo evaluation in the
rat Chung model of painful neuropathy. On the basis
of results from a battery of screening assays including
potency, pharmacokinetics, and pharmacodynamics,
several compounds were evaluated in the Chung para-
digm. At 3 and 10 mg/kg (oral administration), 23
reversed tactile allodynia in a dose-dependent manner
(Figure 4). At 10 mg/kg the level of reversal was ca. 50%,
comparable to the effect of carbamazepine at 100 mg/
kg (oral administration). We further estimated the
potential CNS side-effect by comparing the minimum
effective dose (MED) in Chung model and minimum
ataxic dose (MAD) in accelerated rotarod experiment.
Compound 6, which has a relatively large Kr/Ki value
of 252 (Table 1) and also dose dependently reverses
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise indicated, reactions
were run under an atmosphere of N2. Solvents and reagents
were purchased from commercial sources and used without
further purification unless otherwise noted. Flash chromatog-
raphy was routinely performed on silica gel. Yields for reac-
tions are not typically optimized. Proton NMR spectra were
recorded on a Bruker Avance 400 spectrometer and were
referenced to TMS. LCMS was performed on an Agilent 1100
Series LC/MSD. HRMS were performed on a Bruker Apex II
4.7T FTMS. Analytical HPLC was carried out at room tem-
perature with two diverse conditions. Robertson Microlit Labs,

Phenoxyphenyl Pyridines as Na Channel Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 17 4281
Ta ble 1. Apparent Dissociation Constants for Binding to Resting (Kr) and Inactivated (Ki) States of rNav1.2 Channels Stably
Expressed in HEK-293 Cells and to Native Na+ Channels in Rat DRG Neuronsa
a
b
d
Three determinations unless otherwise noted. Two determinations. c Single determination. Not determined. e More than four
determinations. The data are mean ( SEM.

4282 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 17
Shao et al.
C18H13N2O2F, 308.09611; found, 308.09621. Anal. (C18H13N2O2F)
C, H, N.
2-[4-(4-F lu or op h en oxy)p h en yl]n icotin a m id e (9). This
compound was prepared as white solid in a manner similar to
that described for 6 using 5 and 4-(4-fluorophenoxy)phenyl
boronic acid (31%). mp 149-150 °C. 1H NMR (400 MHz,
CD3OD): δ 8.68 (d, J ) 4.9 Hz, 1H), 8.45 (d, J ) 4.9 Hz, 1H),
8.02-7.97 (m, 2H), 7.65 (d, J ) 8.8 Hz, 2H), 7.42-7.02 (m,
5H). MS (ES+): 309 (MH+). HRMS: calcd for C18H13N2O2F,
308.09611; found, 308.09597.
6-Br om o-p yr id in e-2-ca r boxylic a cid (2-p ip er id in -1-yl-
eth yl)a m id e (11). To a solution of 6-bromopicolinic acid (10,
5.0 g, 24.8 mmol) and 1-(2-aminoethyl)piperidine (3.3 g, 26.0
mmol) in DMF (100 mL) was added HOBT (3.4 g, 24.8 mmol)
and DIC (3.1 g, 24.8 mmol). The reaction was allowed to stir
24 h at ambient temperature. The reaction was diluted with
methylene chloride, and water was then added. The phases
were separated, and the aqueous phase was extracted twice
with methylene chloride. The combined organic phases were
dried over sodium sulfate. The solution was filtered and then
concentrated to give 11 as a pale-yellow oil. Purification by
flash chromatography (silica gel, 40% ethyl acetate/methylene
F igu r e 4. Reversal of tactile allodynia by compound 23 in
the Chung model.
Madison, NJ , performed combustion analysis. 4-(4-Fluorophe-
noxy) benzene boronic acid was purchased from Magellan
Laboratories, P.O Box 13341, Research Triangle Park, NC
27709. Melting points were obtained on Electrothermal IA9000
series digital melting point apparatus.
1
chloride) gave 7.3 g (94%) of 11. H NMR (400 MHz, CDCl3):
δ 8.23 (bs, 1H), 8.14 (d, J ) 7.6 Hz, 1H), 7.71 (t, J ) 7.6 Hz,
1H), 7.61 (d, J ) 7.6 Hz, 1H), 3.55 (m, 2H), 2.57 (t, J ) 6.4
Hz, 2H), 2.46 (bs, 4H), 1.62 (m, 4H), 1.46 (m, 2H). MS (ES+):
313 (MH+).
6-Br om op yr id in e-2-ca r boxylic Acid Am id e (2). To a
solution of 6-bromopicolinic acid (1 g, 5 mmol) in methanol
(10 mL) was added slowly thionyl chloride (1.2 g, 10 mmol) at
room temperature. The resulting mixture was refluxed for 8
h. The reaction mixture was then concentrated under reduced
pressure to give pure methyl ester, which was treated with
excess NH3 in methanol (50 mL, 7 N, 350 mmol) for 12 h at
room temperature. The solvent was removed under reduced
6-[4-(4-Flu r oph en oxy)ph en yl]pyr idin e-2-car boxylic acid
(2-p ip er id in -1-yl-eth yl)a m id e (12). This compound was
prepared as white solid in a manner similar to that described
for 6 using 11 and 4-(4-fluorophenoxy)phenyl boronic acid
(45%). mp 216-217 °C. 1H NMR (400 MHz, CDCl3): δ 8.80
(bs, 1H), 7.91-7.81 (m, 5H), 7.71-7.64 (m, 1H), 7.07-7.05 (m,
5H), 2.59 (t, J ) 6.3 Hz, 2H), 2.48 (bs, 2H), 1.67-1.61 (m, 4H),
1.48 (bs, 2H). MS (ES+): 420 (MH+). HRMS: calcd for
1
pressure to give 955 mg 2 as white solid. mp 122-124 °C. H
NMR (400 MHz, CDCl3): δ 8.00 (s, 1H); 7.79 (d, J ) 7.2 Hz,
1H); 7.24 (t, J ) 8.4 Hz, 1H); 7.08 (m, 1H); 6.90 (d, J ) 8.4
Hz, 1H). MS (ES+): 201(M+).
C
25H26N3O2F, 419.20090; found 419.20127. 12 was converted
to an HCl salt for analysis. Anal. (C25H26N3O2F.HCl) C, H, N.
6-[4-(4-F lu r op h en oxy)p h en yl]p yr id in e-2-ca r b oxylic
Acid Am id e (6). To a solution of compound 2 (201 mg, 1.0
mmol) in 1,2-dimethoxyethane (10 mL) was added 4-(4-
fluorophenoxy)phenyl boronic acid (278 mg, 1.2 mmol), fol-
lowed by water (2 mL) and potassium carbonate (27.6 mg, 0.1
mmol). To this mixture was added Pd(PPh3)4 (23.1 mg, 0.02
mmol), and the reaction was heated at 85 °C for 16 h. The
reaction was allowed to return to ambient temperature, and
the phases were separated. The aqueous phase was extracted
three times with ethyl acetate, and the combined organic
phases were dried over sodium sulfate. The solution was
filtered, concentrated, and then filtered through a bed of
Florisil to give crude compound 6. Purification was then
carried out by flash chromatography (silica gel, 40% ethyl
acetate/methylene chloride) to yield 56 mg of 6 as white solid
(18%). mp 150-151 °C. 1H NMR (400 MHz, DMSO-d6): δ 8.32
(d, J ) 9.0 Hz, 2H), 8.31 (bs, 1H), 8.12 (d, J ) 8.1 Hz, 1H),
8.03 (dd, J ) 8.1, 7.2 Hz, 1H), 7.94 (d, J ) 7.2 Hz, 1H), 7.69
(bs, 1H), 7.27 (t, J ) 9.0 Hz, 2H), 7.18-7.13 (m, 2H), 7.07 (d,
J ) 9.0 Hz, 2H). MS (ES+): 309 (MH+). HRMS: calcd for
C18H14N2O2F (MH+), 309.10338; found 309.10301. Anal.
(C18H13N2O2F) C, H, N.
6-Ch lor o-N-(2-p ip er id in -1-yl-eth yl) n icotin a m id e (14).
This compound was prepared and isolated as yellow solid in a
manner similar to that described for 11 using 13 and 1-(2-
aminoethyl)piperidine. mp 83-86 °C. 1H NMR (400 MHz,
CDCl3): δ 8.76 (d, J ) 2.0 Hz, 1H), 8.10 (dd, J ) 2.4, 8.3 Hz,
1H), 7.42 (d, J ) 8.3 Hz, 1H), 7.11 (bs, 1H), 3.52 (m, 2H), 2.56
(t, J ) 6.0 Hz, 2H), 2.44 (bs, 4H), 1.59 (m, 4H), 1.47 (m, 2H).
MS (ES+): 268.1 (MH+).
6-[4-(4-Flu or op h en oxy)ph en yl]-N-(2-p ip er id in -1-yl-eth -
yl)n icotin a m id e (15). This compound was prepared as white
solid in a manner similar to that described for 6 using 14 and
4-(4-fluorophenoxy)phenyl boronic acid (52% from 13). mp
1
156-157 °C. H NMR (400 MHz, CDCl3): δ 9.04 (s, 1H), 8.22
(d, J ) 8.3 Hz, 1H), 8.03 (d, J ) 8.8 Hz, 2H), 7.78 (d, J ) 8.3
Hz, 1H), 7.21 (bs, 1H), 7.11-7.04 (m, 6H), 3.58 (t, J ) 5.8 Hz,
2H), 2.61 (t, J ) 6.0 Hz, 2H), 2.48 (bs, 4H), 1.66-1.50 (m, 4H),
1.27 (bs, 2H). MS (ES+): 420.1 (MH+). HRMS: calcd for
C25H26N3O2F, 419.20090; found, 419.20133. Anal, (C25H26N3O2F)
H, N; C: calcd. 71.58; found 70.90.
5-Br om o-N-(2-p ip er id in -1-yl-eth yl)n icotin a m id e (17).
This compound was prepared and isolated as white solid in a
manner similar to that described for 11 using acid 16 and 1-(2-
aminoethyl)piperidine. mp 97-99 °C. 1H NMR (400 MHz,
CD3OD): δ 8.96 (d, J ) 2.0 Hz, 1H), 8.82 (d, J ) 2.0 Hz, 1H),
8.45 (t, J ) 2.0 Hz, 1H), 3.58 (t, J ) 6.8 Hz, 2H), 2.63 (t, J )
6.8 Hz, 2H), 2.56 (bs, 4H), 1.66 (m, 4H), 1.52 (m, 2H). MS
(ES+): 312 (M).
6-[4-(4-F lu or op h en oxy)p h en yl]n icotin a m id e (7). This
compound was prepared as white solid in a manner similar to
that described for 6 using 3 and 4-(4-fluorophenoxy)phenyl
boronic acid (55%). mp 250-251 °C. 1H NMR (400 MHz,
DMSO-d6): δ 9.08 (d, J ) 2.0 Hz, 1H), 8.26 (dd, J ) 2.4, 8.4
Hz, 1H), 8.17 (m, 3H, including one amide NH), 8.03 (d, J )
8.0 Hz, 1H), 7.60 (bs, 1H, amide NH), 7.28 (m, 2H), 7.17 (m,
2H), 7.08 (m, 2H). MS (ES+): 309 (MH+). Anal. (C18H13N2O2F)
C, H, N.
5-[4-(4-Flu or op h en oxy)ph en yl]-N-(2-p ip er id in -1-yl-eth -
yl)n icotin a m id e (18). This compound was prepared as yellow
oil in a manner similar to that described for 8 using 17 and
4-(4-fluorophenoxy)phenyl boronic acid (75% from 16). 1H NMR
(400 MHz, CDCl3): δ 8.92 (d, J ) 2.1 Hz, 2H), 8.35 (t, J ) 2.2
Hz, 1H), 7.59 (d, J ) 8.6 Hz, 2H), 7.32 (bs, 1H), 7.11-7.03 (m,
6H), 3.58 (t, J ) 5.7 Hz, 2H), 2.60 (t, J ) 6.1 Hz, 2H), 2.47 (bs,
4H), 1.64-1.59 (m, 4H), 1.48 (bs, 2H). MS (ES+): 420 (MH+).
HRMS: calcd for C25H26N3O2F, 419.20090; found, 419.20133.
2-[4-(4-Flu or oph en oxy)ph en yl]ison icotin am ide (8). Com-
pound 8 was prepared as white solid in a manner similar to
that described for 6. (55%). mp 172-173 °C. 1H NMR (400
MHz, CDCl3): δ 8.81 (d, J ) 5.2 Hz, 1H), 8.10 (m, 1H), 8.03
(m, 2H), 7.51 (dd, J ) 1.6, 4.8 Hz, 1H), 7.10 (m, 6H), 6.31 (bs,
1H), 6.06 (bs, 1H). MS (ES+): 309 (MH+). HRMS: calcd for

Phenoxyphenyl Pyridines as Na Channel Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 17 4283
18 was converted to an HCl salt for analysis. Anal. (C25H26
N3O2F.HCl‚H2O) C, N; H: calcd, 6.35; found 5.64.
-
chromatography (silica gel, 10% methanol/methylene chloride
with 1% concentrated aqueous ammonium hydroxide) to obtain
3.2 g (100%) of 22b as brown solid. mp 126-128 °C. H NMR
(400 MHz, CDCl3): δ 7.87 (d, J ) 8.7 Hz, 2H), 7.00 (m, 6H),
6.86 (d, J ) 2.2 Hz, 1H), 6.52 (d, J ) 2.2 Hz, 1H), 3.85 (t, J )
4.9 Hz, 4H), 3.33 (t, J ) 4.9 Hz, 4H), 2.52 (s, 3H). MS (ES+):
365 (MH+). HRMS: calcd for C22H21N2O2F, 364.15871; found,
364.15890.
1
2-[4-(4-F lu or op h en oxy)p h en yl]-6-m eth yl-1H-p yr id in e-
4-on e (20). A solution of 2,4-pentanedione (19, 10 g, 100
mmol), aniline (11.2 g, 120 mmol), and a catalytic amount of
p-toluenesulfonic acid monohydrate in toluene (100 mL) was
refluxed for 12 h in a round-bottom flask equipped with an
azeotropic apparatus and condenser. The solution was con-
centrated to dryness, and the enamine was used without
purification (17.5 g, 100%). 1H NMR (400 MHz, CDCl3): δ 7.35
(t, J ) 5.69 Hz, 2H), 7.19 (t, J ) 6.4 Hz, 1H), 7.10 (d, J ) 7.5
Hz, 2H), 5.19 (s, 1H), 2.10 (s, 3H), 1.99 (s, 3H).
To a solution of 2,2,6,6-tetramethylpiperidine (7.21 g, 51
mmol) in THF (80 mL) at -78 °C was added dropwise 1.6 M
n-BuLi (31 mL, 50 mmol) under an inert atmosphere. After
the addition the reaction mixture was stirred for 30 min. To
this solution was added dropwise a solution of the enamine (3
g, 17 mmol), prepared in the previous procedure, in THF (10
mL) at -78 °C. After addition, the reaction was stirred for 30
min. To the resulting dark red solution was added dropwise a
solution of 4-(4-fluorophenoxyl)benzonitrile (2.7 g, 17 mmol)
in THF (13 mL) at -78 °C. After addition the mixture was
slowly warmed to -50 °C and stirred for 1 h. The reaction
mixture was poured into a cold, saturated NH4Cl aqueous
solution, and extracted twice with ethyl acetate. The organic
phase was washed with brine and dried over magnesium
sulfate. After filtration, the filtrate was concentrated to
dryness to give 5 g of crude 20, which contains the unreacted
4-(4-fluorophenoxyl)benzonitrile (40% based on integration
from proton NMR). This crude 20 was used in the next step
without purification.1H NMR (400 MHz, CDCl3): δ 7.54 (d, J
) 3.8 Hz, 2H), 7.31 (m, 2H), 7.10-6.90 (m, 4H), 5.23 (s, 1H),
5.08 (s, 1H), 2.03 (s, 3H).
4-Ch lor o-2-[4-(4-flu or op h en oxy)p h en yl]-6-m eth ylp yr i-
d in e (21). To a flask containing POCl3 (20 mL) heated to 120
°C using an oil bath was carefully added a mixture of crude
compound 20 (5 g, 17 mmol) and DBU (2.6 mL, 17 mmol) in
methylene chloride (20 mL). After addition, the reaction
mixture was refluxed for 1 h. The resulting mixture was
concentrated to dryness and diluted with ethyl acetate. To the
solution was carefully added saturated aqueous sodium bicar-
bonate to pH 5-6. The organic phase was separated, and the
aqueous was extracted with the same volume of ethyl acetate.
The combined organics were then washed with brine, dried
over magnesium sulfate, filtered, and concentrated to dryness.
The residue was purified by flash chromatography (silica gel,
5% ethyl acetate/hexane) to obtain 1.8 g (34%) of compound
21 as brown oil. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J )
6.7 Hz, 2H), 7.48 (d, J ) 1.36 Hz, 1H), 7.09 (d, J ) 1.5 Hz,
1H), 7.00 (m, 6H), 2.59 (s, 3H). MS (ES+): 314 (MH+).
2-[4-(4-F lu or op h en oxy)p h en yl]-6-m eth yl-4-[(2-p ip er i-
d in -1-yl)eth oxy]p yr id in e (22c). A solution of compound 21
(157 mg, 0.5 mmol), 2-(piperidinyl)ethanol (97 mg, 0.75 mmol),
and NaH (60%, 40 mg, 1 mmol) in DMF (2.5 mL) was stirred
at 80 °C for 16 h. After being partitioned between ethyl acetate
and brine, the organic phase was dried over magnesium
sulfate, filtered, and concentrated. The crude product was
purified by flash chromatography (silica gel, 10% methanol/
ethyl acetate) to give 87 mg (42%) of 22c as tan oil.1H NMR
(400 MHz, CDCl3): δ 7.92 (d, J ) 8.8 Hz, 2H), 7.03 (m, 7H),
6.63 (d, J ) 2.1 Hz, 1H), 4.19 (t, J ) 6.0 Hz, 2H), 2.81 (t, J )
6.0 Hz, 2H), 2.57 (s, 3H), 2.51 (m, 4H), 1.61 (m, 4H), 1.42 (m,
2H). MS (ES+): 407 (MH+). HRMS: calcd for C25H27N2O2F,
406.20566; found, 406.20568. 22c was converted to an HCl salt
for analysis. Anal. (C25H27N2O2F.2HCl‚H2O) H, N; C: calcd,
60.36; found, 60.89
2-[4-(4-F lu or op h en oxy)p h en yl]-4-m et h oxy-6-m et h yl-
p yr id in e (22d ). A sealed tube containing compound 21 (1.8
g, 4.8 mmol) in 10 mL of 25 wt % NaOMe in methanol was
heated at 85 °C for 4 h. The reaction mixture was allowed to
cool, concentrated to dryness, and diluted with ethyl acetate.
The mixture was washed with saturated aqueous ammonium
chloride, then brine. The organic phase was dried over
magnesium sulfate, filtered, and concentrated to dryness to
give 1.5 g (100%) of compound 22d as white solid. mp 179-
180 °C. 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J ) 6.8 Hz,
2H), 7.00 (m, 7H), 6.62 (d, J ) 2.1 Hz, 1H), 3.88 (s, 3H), 2.57
(s, 3H). MS (ES+): 310 (MH+).
6-[4-(4-F lu or op h en oxy)p h en yl]-4-m or p h olin -4-yl-p yr i-
d in e-2-ca r boxylic a cid a m id e (23). To a solution of com-
pound 22b (3.2 g, 8.7 mmol) in pyridine (90 mL) was added
SeO2 (2 g, 18 mmol), and the resulting solution was refluxed
for 2 days. The cooled reaction mixture was concentrated to
dryness and dissolved in methanol. It was then filtered
through Celite and again concentrated to dryness. The residue
was redissolved in methanol (100 mL), and to this solution of
the crude acid was slowly added thionyl chloride (32 mL, 43.5
mmol). After addition, the resulting solution was refluxed for
12 h. The cooled reaction mixture was filtered and concen-
1
trated to dryness. H NMR (400 MHz, CDCl3): δ 7.95 (d, J )
8.8 Hz, 2H), 7.55 (d, J ) 2.2 Hz, 1H), 7.15 (d, J ) 2.2 Hz, 1H),
7.04 (m, 6H), 4.12 (s, 3H), 3.89 (t, J ) 4.8 Hz, 4H), 3.44 (t, J
) 4.8 Hz, 4H). MS (ES+): 408 (M).
{2-[4-(4-F lu or op h en oxy)p h en yl]-6-m eth yl-p yr id in e-4-
yl}d im eth yla m in e (22a ). In a three-neck round-bottom flask
cooled to -78 °C, dimethylamine (20 mL) was condensed and
then transferred to a sealed vessel containing compound 21
(50 mg, 0.16 mmol) at -78 °C. The sealed vessel was slowly
allowed to warm to room temperature, and the solution was
stirred for 48 h. The vessel was then cooled to -20 °C and
opened. The remaining dimethylamine was evaporated at room
temperature. The residue was purified by flash chromatogra-
phy (silica gel, 5-10% methanol/methylene chloride) to give
5 mg (10%) of compound 22a as brown oil. 1H NMR (400 MHz,
CDCl3): δ 7.89 (d, J ) 6.7 Hz, 2H), 7.00 (m, 6H), 6.69 (d, J )
2.3 Hz, 1H), 6.35 (d, J ) 2.3 Hz, 1H), 3.03 (s, 6H), 2.51 (s,
3H). MS (ES+): 323 (MH+). HRMS: calcd for C20H19N2OF,
322.14814; found 322.14829. 22a was converted to an HCl salt
for analysis. Anal. (C20H19N2OF.HCl‚H2O) H, N; C: calcd,
63.74; found, 64.19.
4-{2-[4-(4-F lu or op h en oxy)p h en yl]-6-m eth yl-p yr id in e-
4-yl}m or p h olin e (22b). A mixture of compound 21 (2.6 g, 8.8
mmol) and NaH (60%, 704 mg, 17.6 mmol) in morpholine (8
mL) was heated in a sealed tube at 135 °C for 2 h using an oil
bath. Methanol was carefully added to the cooled reaction
mixture to quench the NaH. The resulting mixture was
concentrated to dryness, and the residue was purified by flash
To a solution of NH3 (2 M, 50 mL) in methanol was added
the crude methyl ester, and the resulting solution was stirred
for 12 h at room temperature. The mixture was then concen-
trated to dryness, and the resulting solid was recrystallized
from methanol to give 1.1 g (32% from 22b) of 23 as white
solid. mp 225-226 °C.1H NMR (400 MHz, DMSO-d6): δ 8.05
(bs, 1H), 7.93 (d, J ) 8.8 Hz, 2H), 7.62 (d, J ) 2.5 Hz, 1H),
7.14 (d, J ) 2.5 Hz, 1H), 7.08 (m, 6H), 5.56 (bs, 1H), 4.15 (t, J
) 5.1 Hz, 4H), 3.47 (t, J ) 5.1 Hz, 4H). MS (ES+): 394 (MH+).
HRMS: calcd for C22H20N3O3F, 393.14887; found, 393.14929.
Anal. (C22H20N3O3F‚H2O) H, N; C: calcd, 64.23, found, 64.73.
6-[4-(4-F lu or op h en oxy)p h en yl]-4-m eth oxyp yr id in e-2-
ca r boxylic a cid a m id e (24). To a solution of 1.5 g (4.8 mmol)
of compound 22d in pyridine (36 mL) was added SeO2 (2.1 g,
19 mmol), and the resulting solution was refluxed for 3 days.
The cooled reaction mixture was concentrated to dryness and
diluted with methanol. It was then filtered through Celite and
concentrated to give 1.5 g (100%) of acid.1H NMR (400 MHz,
CDCl3): δ 7.92 (d, J ) 8.8 Hz, 2H), 7.69 (s, 1H), 7.38 (m, 3H),
7.07 (m, 4H), 3.97 (s, 3H). MS (ES+): 321(MH+).
The residue was dissolved in methanol (50 mL), and to this
solution of crude acid was carefully added thionyl chloride (7
mL, 9.6 mmol). After addition, the resulting solution was

4284 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 17
Shao et al.
refluxed for 12 h. The cooled reaction mixture was filtered and
concentrated to dryness. The residue was then filtered through
a plug of silica gel, eluting with 10% triethylamine in ethyl
acetate. The filtrate was concentrated to dryness to yield 1.6
g (94%) of the methyl ester as brown solid. mp 86 °C. 1H NMR
(CDCl3): δ 7.98 (d, J ) 8.7 Hz, 2H), 7.61 (d, J ) 2.2 Hz, 1H),
7.33 (d, J ) 2.2 Hz, 1H), 7.00 (m, 6H), 4.05 (s, 3H), 4.00 (s,
3H). MS (ES+): 354 (MH+).
To a solution of NH3 (2 M, 10 mL) in methanol was added
crude methyl ester (140 mg, 0.39 mmol), and the resulting
solution was stirred for 12 h. The mixture was then concen-
trated to dryness, and the resulting solid was recrystallized
from methanol to give 67 mg (50%) of 24 as white solid. mp
202-203 °C. 1H NMR (400 MHz, DMSO-d6): δ 8.31 (d, J )
8.9 Hz, 2H), 8.27 (bs, 1H), 7.70 (bs, 1H), 7.61 (d, J ) 2.3 Hz,
1H), 7.47 (d, J ) 2.3 Hz, 1H), 7.26 (t, J ) 8.7 Hz, 2H), 7.13
(m, 2H), 7.03 (d, J ) 9.0 Hz, 2H), 3.94 (s, 3H). MS (ES+): 339
(MH+). HRMS: calcd for C19H15N2O3F, 338.10667; found,
338.10668. Anal. (C19H15N2O3F‚H2O) C, N; H: calcd, 4.81,
found, 4.00.
6-[4-(4-F lu or op h en oxy)p h en yl]-4-m eth oxy-p yr id in e-2-
ca r boxy a cid (2-(d im eth yla m in o)-eth yl)-a m id e (25). Com-
pound 25 was prepared as light brown oil in a manner similar
to that described for 24 using 22d and N,N-dimethylethyl-
enediamine (94%). 1H NMR (400 MHz, CDCl3): δ 8.97 (bs, 1H),
8.10 (d, J ) 8.8 Hz, 2H), 7.61 (d, J ) 2.2 Hz, 1H), 7.32 (d, J )
2.2 Hz, 1H), 7.05 (m, 6H), 4.00 (m, 1H), 3.96 (s, 3H), 3.78 (m,
1H), 3.63 (m, 1H), 3.45 (s, 3H), 3.27 (bs, 1H), 2.85 (s, 3H). MS
(ES+): 410 (MH+). HRMS: calcd for C23H24N3O3F, 409.18017;
found, 409.18035. 25 was converted to an HCl salt for analysis.
Anal. (C23H24N3O3F.2HCl‚H2O) C, H, N.
In vitr o p h a r m a cology. HEK-293 cell culture. The rat
brain NaIIA-B2 cell line (hosted in HEK-293 cells) was
established in house using standard techniques. It was found
to expresses tetrodotoxin-sensitive (TTX-S) currents with an
average INa amplitude of ∼2.5 nA and with fast activation and
inactivation properties characteristic of Na+ channels observed
in CHO cells expressing the rat brain IIa channel.16 HEK-293
cells were cultured using standard techniques. For electro-
physiology, cells were plated onto 35-mm Petri dishes (pre-
coated with poly-D-lysine) at a density of ∼104 cells/dish on
the day of reseeding from confluent cultures. HEK-293 cells
were suitable for recordings for 3-4 days after plating.
inactivated channels even for the slowest compounds. This step
was followed by a short (3 ms) hyperpolarizing gap back to
-110 mV, which was sufficient to permit about 80% recovery
from inactivation in control. Then a 5 ms test pulse to 0 mV
was applied to measure the proportion of channels available
for activation. In the presence of a drug only unbound channels
have a chance to recover from inactivation at a normal pace
since repriming from inactivation is significantly retarded by
drug binding. Thus, the current caused by the test pulse
reported the proportion of liganded (and blocked) channels.
Reduction in the size of the current to test pulses in the
presence of a compound was used to calculate the fractional
response. For most compounds, a concentration was empiri-
cally chosen that caused about 50% inhibition. From the
fractional response (FR) at this concentration the estimate for
Ki was obtained using the equation: Ki ) {FR/(1 - FR)}
*[antagonist], where [antagonist] is concentration of antago-
nist. Data are presented as mean ( standard error.
Acu tely d issocia ted r a t DRG n eu r on s. Acutely dissoci-
ated neurons were prepared from newborn Sprague Dawley
rat pups by the technique described by Wilding and Huett-
ner.11 Liberated cells were plated on poly-D-lysine coated 35
mm plastic Petri dishes and were suitable for electrophysi-
ological recordings for up to two weeks. Recordings were done
with Axopatch 200A amplifier and analyzed with pClamp 6
software (Axon Instruments, Inc.). Tetrodotoxin (TTX), 0.4 µM,
was used to dissect TTX-R component of the current. TTX-S
currents were collected in a subset of neurons, which did not
contain TTX-R component as justified by application of TTX.
External solution was (in mM): 65 NaCl, 5 KCl, 50 choline
chloride, 1.8 CaCl2, 1 MgCl2, 5 D-glucose, 5 HEPES, 5 HEPES
Na+ salt, 20 TEA chloride; pH 7.4 (NaOH). The internal
solution contained (in mM): 130 CsF, 20 NaCl, 1 CaCl2, 2
MgCl2, 10 EGTA, 10 HEPES, pH 7.4 (CsOH). Osmolality was
set ∼5 mmol/kg lower than that of the bathing solution.
Protocol to measure fractional responses was essentially same
as for HEK-293 cell culture with exception that depolarizing
prepulse was 1 s long and the hyperpolarizing gap was set at
5 ms. Fractional responses were collected at least for three
concentrations for each drug to get partial concentration-
inhibition curves. Logistic fit to these curves returned Ki
values.
In Vivo P h a r m a cology. Ch u n g Mod el. Male Sprague
Dawley rats weighing between 150 and 200 g (Harlan Spra-
gue-Dawley, Inc., San Diego) were anesthetized with hal-
othane. The left branches of L5 and L6 spinal nerves were
surgically exposed and tightly ligated with 6.0 silk sutures as
previously described.9 Rats were evaluated prior to surgery
and 7 to 28 days post-surgery for the development of tactile
allodynia. Manual measurements of tactile sensitivity were
performed using Von Frey filaments (North Coast Medical),
ranging from 3.64 to 5.46/0.6 to 26 g of pressure. Starting with
the largest filament, filaments were applied to the plantar
surface of the left hind paw with enough force to cause the
filament to bend. This force was either maintained until the
rat withdrew the limb, or for a maximum of 4 s. A positive or
“allodynic” response was characterized by a sharp withdrawal
of the hind limb that may be followed by flicking or licking of
the paw. In the event of a positive response, a thinner filament
was applied to the left hind paw as described. A negative
response, as characterized by lack of reaction to the filament,
resulted in cessation of testing. This cycle was repeated three
times on each rat and values expressed as the log gram of force.
The mean value of the three measurements was determined
for each rat and the data expressed as the mean ( standard
error (SEM) for each time point. Allodynic rats were defined
as those animals with post-surgical baseline withdrawal
thresholds below 0.30 log gram units. Rats were fasted for a
minimum of 6 h prior to drug administration. A minimum 48-
hour washout was allowed for each rat prior to subsequent
experimental repetitions. Animals in the vehicle group were
administered 1% DMSO, 10% TWEEN-80 PO. Drugs were
administered orally at a volume of 10 mL/kg bodyweight.
Dr u g a p p lica tion . Drug solutions and intervening inter-
vals of wash were applied through a linear array of flow pipes
(Drummond Microcaps, 2-µL, 64-mm length). Drugs were
dissolved in dimethyl sulfoxide (DMSO) to make 1-30 mM
stock solutions. The stock solutions were diluted into external
solution to generate final concentrations of 0.003-10 µM. The
concentration of DMSO was 0.1%. At this level DMSO itself
had only marginal inhibitory effects on the peak Na+ current.
For HEK-293 cells external solution contained (in mM): 150
NaCl, 5.4 KCl, 1.8 CaCl2, 1 MgCl2, 10 D-glucose, 5 HEPES;
pH 7.4 (NaOH). The internal solution contained (in mM): 130
CsF, 20 NaCl, 1 CaCl2, 2 MgCl2, 10 EGTA, 10 HEPES, pH 7.4
(CsOH); osmolality was set at ∼10 mmol/kg lower than that
for external solution.
Exp er im en ta l d esign a n d d a ta a n a lysis. To quantify the
affinity toward resting state cells were held at -110 mV and
pulsed to 0 mV every 2 s to cause maximal Na+ current. At
such a negative voltage there was virtually no resting inacti-
vation (e1%, data not shown). Steady-state currents were
measured after at least 1 min in control or drug-containing
solutions. The magnitude of inhibition was measured at high
drug concentration, usually 3 µM. From the fractional response
(FR) at this concentration the estimate for the apparent
dissociation constants for resting state, Kr, was obtained using
the equation: Kr ) {FR/(1 - FR)} *[antagonist], where
[antagonist] is concentration of antagonist.
To measure the affinity toward inactivated state a double-
pulse protocol was used.17 From a holding voltage of -110 mV
cells were depolarized by a conditioning step to -20 mV for 3
s. This step caused complete inactivation of sodium channels
and was long enough to ensure the steady-state for binding to

Phenoxyphenyl Pyridines as Na Channel Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 17 4285
(6) (a) Sandner-Kiesling, A.; Rumpold Seitlinger, G.; Dorn, C.; Koch,
H.; Schwarz, G. Lamotrigine Monotherapy for Control of Neu-
ralgia after Nerve Section. Acta Anaesth. Scand. 2002, 46, 1261-
1264. (b) Eisenberg, E.; Lurie, Y.; Braker, C.; Daoud, D.; Ishay,
A. Lamotrigine Reduces Painful Diabetic Neuropathy: A Ran-
domized, Controlled Study. Neurology 2001, 57, 505-509.
(7) (a) Dimmock, J . R.; Sidhu, K. K.; Thayer, R. S.; Mack, P.; Duffy,
M. J .; Reid, R. S.; Quail, J . W.; Pugazhenthi, U.; Ong, A.; Bikker,
J . A.; Weaver, D. F. Anticonvulsant Activities of Some Arylsemi-
carbazones Displaying Potent Oral Activity in the Maximal
Electroshock Screen in Rats Accompanied by High Protection
Indices. J . Med. Chem. 1993, 36, 2243-2252. (b) Dimmock, J .
R.; Puthucode, R. N.; Smith, J . M.; Hetherington, M.; Quail, J .
W.; Pugazhenthi, U.; Lechler, T.; Stables, J . P. (Aryloxy)aryl
Semicarbazones and Related Compounds: A Novel Class of
Anticonvulsant Agents Possessing High Activity in the Maximal
Electroshock Screen. J . Med. Chem. 1996, 39, 3984-3997.
(8) (a) Ilyin, V. I.; Whittemore, E. R.; Puthucode, R. N.; Dimmock,
J . R.; Woodward, R. M. Co 102862, a Novel Anticonvulsant, is a
Potent, Voltage-Dependent Blocker of Voltage-Gated Na+ Chan-
nels in Rat Hippocampal Neurons. Soc. Neurosci. Abstr. 1997,
23, 2163. (b) Ilyin, V. I.; Woodward, R. M. Kinetic and Steady-
Sate Parameters for Inhibition of hSkM1 Sodium Channels by
Co 102862, Phenytoin, Carbamazepine and Lamotrigine. Soc.
Neurosci. Abstr. 1998, 24, 1939.
(9) Kim, S. H.; Chung, J . M. An Experimental Model for Peripherial
Neuropathy Produced by Segmental Spinal Nerve Ligation in
the Rat. Pain 1992, 50, 355-363.
(10) Carter, R. B.; Vanover, K. E.; Wilent, W.; Xu, Z.; Woodward, R.
M.; Ilyin, V. I. Anti-allodynic and Anti-Hyperalgesic Effects of
the Novel Voltage-Dependent Sodium Channel Blocker Co
102862 in a Rat Model of Peripheral Neuropathy. Proceedings
of the International Symposium “Ion Channels in Pain and
Neuroprotection”, San Francisco, CA, 1999, p 19.
(11) (a) Ramu, K.; Lam, G N.; Hughes, H. In Vivo Metabolism and
Mass Balance of 4-[4-Fluorophenoxy]benzaldehyde Semicarba-
zone in Rats. Drug Metab. Dispos. 2000, 28, 1153-1161. (b)
Dimmock, R.; Semple, A.; J ohn, S.; Beazely, A.; Abrams, G.
Isolation and Identification of the Major Urinary Metabolite of
4-(4-Fluorophenoxy)benzaldehyde Semicarbazone After Oral
Dosing to Rats. Pharmazie 1999, 54, 260-262.
(12) Itoh, Y.; Oka, M.; Ukai, Y.; Kimura, K. A Novel Na+/Ca2+
Channel Blocker NS-7 Inhibits Evoked but not Spontaneous
Dopamine Release from Rat Striatum, as Measured by Intrac-
erebral Microdialysis. Neurosci. Lett. 1998, 252, 203-206.
(13) Bartoli, G.; Bosco, M.; Cimarelli, C.; Dalpozzo, R.; De Munno,
G.; Guercio, G.; Palmieri, G. Reaction of Dianions of Acyclic
â-enamino Ketones with Electrophiles. 3. Nitriles: Synthesis of
Pyridine and Pyrimidine Derivatives. J . Org. Chem. 1992, 57,
6020-6025.
Tactile allodynia measurements were recorded at 1, 2, 4, and
24 h postdrug administration.
Ack n ow led gm en t. We thank Dr. L. Zhou, Dr. F.
Cheng, Ms. E. Dharmgrongartama for analytical sup-
port, and Mr. M. Suruki for technical assistance on the
rotarod assay. We thank Dr. R. Woodward for fruitful
discussions and help in the preparation of this manu-
script.
Su p p or tin g In for m a tion Ava ila ble: Proton NMR spec-
tra, HRMS, LCMS spectra, and reverse-phase HPLC chro-
matograms of compounds in Table 1. This material is available
free of charge via Internet at http://pubs.acs.org.
Refer en ces
(1) (a) Bock, G.; Goode, J . A. Sodium Channels and Neuronal
Hyperexcitability. Proceedings of the 241st Novartis Foundation
Symposium, London, November 14-16, 2000. (b) Black, J . A.;
Dib-Haji, S.; Cummins, T. R.; Okuse, K.; Baker, M.; Wood, J .
N.; Waxman, S. G. Neuropathic Pain: Pathophysiology and
Treatment. Prog. Pain Res. Manage. 2001, 21, 19-36.
(2) (a) Elliott, A. A.; Elliott, J . R. Characterization of TTX-Sensitive
and TTX-Resistant Sodium Currents in Small Cells From Adult
Rat Dorsal Root Ganglia. J . Physiol. 1993, 463, 39-56. (b) Roy,
M. L.; Narahashi, T. Differential Properties of Tetrodotoxin-
Sensitive and Tetrodotoxin-Resistant Sodium Channels in Rat
Dorsal Root Ganglion Neurons. J . Neurosci. 1992, 12, 2104-
2111.
(3) (a) Lai, J .; Gold, M. S.; Kim, C.; Bian, D.; Ossipov, M. H.; Hunter,
J . C.; Porreca, F. Inhibition of Neuropathic Pain by Decreased
Expression of the Tetrodotoxin-Resistant Sodium Channel,
NaV1.8. Pain 2002, 95, 143-152. (b) Dib-Hajj, S.; Black, J . A.;
Cummins, T. R.; Waxman, S. G. NaN/NaV1.9:
a Sodium
Channel with Unique Properties. Trends Neurosci. 2002, 25,
253-259. (c) Kim, C.; Oh, Y.; Chung, J .; Chung, K. The Changes
in Expression of Three Subtypes of TTX-Sensitive Channels in
Sensory Neurons after Spinal Nerve Ligation. Mol. Brain Res.
2001, 95, 153-161. (d) Coward, K.; Aitken, A.; Powell, A.;
Plumpton, C.; Birch, R.; Tate, S.; Bountra, C.; Anand, P.
Plasticity of TTX-sensitive Sodium Channels PN1 and Brain III
in Injured Human Nerves. NeuroReport 2001, 12, 495-500.
(4) (a) Strichartz G. R.; Zhou, Z.; Sinnott, C.; Khodorova, A.
Therapeutic Concentrations of Local Anaesthetics Unveil the
Potential Role of Sodium Channels in Neuropathic Pain. Pro-
ceedings of the 241st Novartis Foundation Symposium, London,
November 14-16, 2000. (b) Khodorova, A.; Meissner, K.; Leeson,
S.; Strichartz, G. Lidocain Selectively Blocks Abnormal Impulses
Arising from Noninactivating Na Channels. Muscle Nerve 2001,
24, 634-647.
(14) Wilding, T. J .; Huettner, J . E. Differential Antagonism of
R-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic-Acid-Prefer-
ring and Kainate-Preferring Receptors by 2,3-Benzodiazepines.
Mol. Pharmacol. 1995, 47, 582-588.
(15) Sun, Q.; Tafesse, L.; Limberis, J .; Islam, K.; Kyle, D. Parallel
Synthesis of a Biased Library of Thiazolidinones as Novel
Sodium Channel Antagonists. Comb. Chem. High Throughput
Screen. 2003, 6, 481-488.
(16) West, W.; Scheuer, T.; Maechler, L.; Caterall, A. Efficient
Expression of Rat Brain Type IIA Sodium Chennel R Subunits
in a Somatic Cell Line. Neuron 1992, 8, 59-70.
(17) Kuo, C.; Bean, P. Slow Binding of Phenytoin to Inactivated
Sodium Channels in Rat Hippocampal Neurons. Mol. Pharma-
col. 1994, 46, 716-725.
(5) Harke, H.; Gretenkort, P.; Ladleif, H. U.; Rahman, S.; Harke,
O. The Response of Neuropathic Pain and Pain in Complex
Regional Pain Syndrome I to Carbamazepine and Sustained-
release Morphine in Patients Pretreated with Spinal Cord
Stimulation: A Double-blinded Randomized Study. Anesth.
Analg. 2001, 92, 488-495.
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