Discovery of XEN907, a spirooxindole blocker of NaV1.7 for the treatment of pain

Article abstract of DOI:10.1016/j.bmcl.2011.04.088

Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of Na_V1.7 blockers were developed. Following the elimination of undesirable structural features, preliminary optimization of the oxindole C-3 and N-1 substituents afforded the simplified analogue 9b, which demonstrated a 10-fold increase in target potency versus the original HTS hit. A scaffold rigidification strategy then led to the discovery of XEN907, a novel spirooxindole Na_V1.7 blocker. This lead compound, which in turn showed a further 10-fold increase in potency, represents a promising structure for further optimization efforts.

Full text of DOI:10.1016/j.bmcl.2011.04.088

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3676–3681
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of XEN907, a spirooxindole blocker of NaV1.7 for the treatment of pain
Sultan Chowdhury a, Mikhail Chafeev a, Shifeng Liu a, Jianyu Sun a, Vandna Raina a, Ray Chui b,
Wendy Young b, Rainbow Kwan b, Jianmin Fu a, Jay A. Cadieux a,
⇑
a Department of Medicinal Chemistry, Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, British Columbia, Canada V5G 4W8
b Department of Biological Sciences, Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, British Columbia, Canada V5G 4W8
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of
NaV1.7 blockers were developed. Following the elimination of undesirable structural features, prelimin-
ary optimization of the oxindole C-3 and N-1 substituents afforded the simplified analogue 9b, which
demonstrated a 10-fold increase in target potency versus the original HTS hit. A scaffold rigidification
strategy then led to the discovery of XEN907, a novel spirooxindole NaV1.7 blocker. This lead compound,
which in turn showed a further 10-fold increase in potency, represents a promising structure for further
optimization efforts.
Received 17 March 2011
Revised 14 April 2011
Accepted 19 April 2011
Available online 24 April 2011
Keywords:
Sodium channel
SCN9A
Ó 2011 Elsevier Ltd. All rights reserved.
Pain
Spirooxindole
Oxindole
Voltage-gated sodium channels have been implicated in a num-
ber of neurological pathologies, including epilepsy, migraine, mul-
tiple sclerosis, neurodegenerative diseases and neuropathic pain.1
In particular, the NaV1.7 subtype (encoded by the SCN9A gene),
primarily expressed in the peripheral nervous system, has elicited
significant attention as a drug target for the treatment of chronic
pain. Loss-of-function mutations in SCN9A have been linked to a
condition known as congenital indifference to pain.2 Individuals
with such mutations are completely unable to experience pain
but otherwise display normal neurological function. On the other
hand, corresponding gain-of-function mutations correlate to two
distinct pain syndromes: paroxysmal extreme pain disorder and
hereditary erythromelalgia.3
In light of this genetic validation of NaV1.7 as a target for the
treatment of chronic pain, a high-throughput screening campaign,
predicated on a previously described [14C]guanidinium influx assay
adapted for use in HEK-293 cells expressing human NaV1.7, was
undertaken.4,5 From this effort, the 3-hydroxyoxindole analogue
2a (Scheme 1) was identified as a promising candidate for hit-to-
lead activities. The 3-hydroxy-2-oxindole framework is featured
in a number of natural products with a broad range of biological
activities.6 Initial efforts were focused on replacing the b-hydrox-
surrogate for the metabolically labile furyl moiety.7 Initial
substitution of the furyl moiety with a thienyl ring was tolerated
(Table 1). Geminal demethylation
a to the ketone moiety led to a
sharp reduction in potency observed in analogue 4, whereas trun-
cation of the methylene spacer to afford derivative 7 also led to re-
duced activity. However, upon further shortening of the spacer to
obtain the 3-aryl-3-hydroxyoxindole 3f (Table 2), modest potency
was restored.
The SAR around the 3-aryl substituent was then explored
(Table 2). Addition of aryl Grignard reagents or aryllithium spe-
cies to the N-substituted isatin 1 allowed for the rapid generation
of a series of analogues. The 3,4-methylenedioxyphenyl analogue
3a showed the greatest target potency (equipotent with the origi-
nal HTS hit 2a). The corresponding 3,4-ethylenedioxyphenyl and
3,4-propylenedioxyphenyl analogues 3c and 3f demonstrated a
decrease in potency with increasing ring size. The methoxypyri-
dine analogue 3b and 3-methoxyphenyl derivative 3d were both
potent, suggesting a preference for a H-bond acceptor at the aryl
ring’s 3-position. In contrast, both the 2-methoxyphenyl and the
4-methoxyphenyl analogues 3h and 3j were significantly less
potent. The replacement of the 3,4-methylenedioxyphenyl moiety
in 3a with the corresponding monocyclic 3,4-dimethoxyphenyl
ring in 3i was poorly tolerated. Geminal difluorination of the
dioxolane carbon in 3a also led to a reduction in potency (3k).
The next phase of optimization involved variation of the
oxindole N-substituent while preserving the 3-(3,4-methylenedi-
oxyphenyl) moiety present in 3a (Scheme 2, Table 3). While the
N-unsubstituted compound 9r was poorly active, a wide variety
yketone motif present in 2a in order to obviate potential a,b-unsat-
urated ketone formation as well as on identifying a suitable
⇑
Corresponding author. Tel.: +1 604 484 3300x157; fax: +1 604 484 3321.
E-mail address: jcadieux@xenon-pharma.com (J.A. Cadieux).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.088

S. Chowdhury et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3676–3681
3677
O
O
HO
N
X
X
O
O
O
O
a
O
O
N
b
N
H
Cl
Cl
c
1
2a (X = O)
2b (X = S)
HO
Ar
HO
N
N
S
O
O
O
Cl
3a-q
d
S
1 +
Cl
4
S
S
S
HO
HO
N
O
S
S
S
H
O
S
O
g
f
S
e
O
H
N
5
Cl
Cl
6
7
Scheme 1. Reagents and conditions: (a) p-chlorobenzyl chloride, NaH, DMF, 1 h; (b) iPr2NH (cat.), EtOH, reflux, 1 h; (c) ArMgX, 0 °C to rt or ArLi, ꢀ78 °C to rt, THF, 2–16 h; (d)
(i) N-methylaniline, EtMgBr, PhH, rt, 1 h; (ii) 1, THF, ꢀ15 °C to rt, 3 h; (e) HS(CH2)3SH, BF3ꢁEt2O (cat.), CH2Cl2, rt, 24 h; (f) nBuLi, THF, ꢀ78 °C then 1, ꢀ78 °C to rt, 16 h; (g)
PhI(OCOCF3)2, MeCN/H2O, 0 °C to rt, 2.5 h.
O
O
Table 1
O
O
Guanidinium influx assay potencies of initial 3-hydroxyoxindole analogues and
reference compounds
HO
a
b
O
O
O
Compound
hNaV1.7 IC50
(l
M)
c log P
N
R
N
N
R
H
2a
2b
4
7
0.30
0.20
6.08
>10
0.006
7.51
2.50
3.87
5.14
3.92
<ꢀ1
0.41
8a-r
9a-r
Scheme 2. Reagents and conditions: (a) RX, NaH, DMF, rt, 1–16 h; (b) 3,4-
methylenedioxyphenylmagnesium bromide, THF, 0 °C to rt, 16 h.
Tetrodotoxin
Tetracaine
14, which was subsequently elaborated to the carboxamide deriv-
atives 15 and 16 with loss of target potency. However, conversion
of the ester 14 to the corresponding acyl hydrazide, followed by
oxidation and Curtius rearrangement, provided the highly potent
3-amino-3-aryloxindole 17.10 Finally, alkylation of intermediate
10 with either methyl 3-bromopropionate or methyl bromoacetate
led to a series of inactive homologated esters, acid and amides (18–
23).
In light of the results obtained with the 3-methyl derivative 13,
which suggested that substitution of the oxindole 3-position with
an aliphatic moiety allowed for some target potency to be retained,
a rigidification strategy involving the preparation of a number of
spirooxindole derivatives was then explored (Scheme 4). Addition
of the Grignard reagent obtained from treating sesamol (3,4-meth-
ylenedioxyphenol) with isopropylmagnesium chloride to the
substituted isatin 8b afforded the diol 24.11 Triethylsilane-medi-
ated dehydroxylation to the phenol derivative 25, followed by
aldol condensation and intramolecular cyclization under
Mitsunobu conditions afforded spiroether 29 (XEN907).12,13 This
analogue was 10-fold more active than the most potent acyclic
oxindole analogue 9b (Table 5). The estimated lipophilicity of
XEN907 (c log P 3.97) is comparable to or less than those of some
reported sodium channel blockers under investigation for the
of substituted alkyl and benzyl moieties were well tolerated at that
position. Of note, potency was invariant with respect to the elec-
tronic nature of the benzyl substituent (c.f. compounds 9d, 9e
and 9o). Amongst the N-alkyl derivatives, branching (e.g., 9c and
9i) as well as the inclusion of saturated carbocycles (e.g., 9a, 9j,
9m, and 9n) were also tolerated. When compared to the starting
p-chlorobenzyl compound 3a, several analogues demonstrated im-
proved activity along with reduced lipophilicity. The simple n-pen-
tyl derivative 9b was selected over the equipotent but somewhat
less soluble and permeable (2-cyclopropyl)ethyl analogue 9a as
the starting point for investigations aimed at further improve-
ments by replacement of the potentially labile tertiary alcohol.
Derivatization of the tertiary alcohol in 9b to the corresponding
methyl ether 12 was not tolerated (Scheme 3, Table 4). Triethylsi-
lane-mediated dehydroxylation of 9b afforded the key intermedi-
ate 10.8 Treatment of 10 with sodium hydride, followed by
alkylation with iodomethane furnished the modestly active 3-
methyl analogue 13. A lanthanide triflate-catalyzed aldol conden-
sation between p-formaldehyde and oxindole 10 yielded the
hydroxymethylene compound 11, which was ca. 20-fold less po-
tent than 9b.9 Deprotonation of the intermediate 10, followed by
treatment with methyl cyanoformate led to the carboxylic ester

3678
S. Chowdhury et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3676–3681
Table 2
SAR of 1-(4’-Chlorobenzyl)-3-aryl-3-hydroxyoxindoles
HO
Ar
O
N
Cl
3a-q
Compound
Ar
hNaV1.7 IC50
(lM)
c log P
Solubilitya
(l
g/mL)
Permeabilityb (ꢂ10ꢀ6 cm/s)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3,4-Methylenedioxyphenyl
(2-Methoxypyridin)-5-yl
3,4-Ethylenedioxphenyl
3-Methoxyphenyl
Phenyl
3,4-Propylenedioxyphenyl
3-Furyl
0.20
0.27
0.48
1.19
1.58
3.21
4.17
6.08
6.14
7.37
>5
4.19
4.08
3.91
4.28
4.41
4.02
3.02
4.28
4.15
4.28
5.59
4.02
<5
<5
9
6
5
<5
11
<5
26
<5
<5
<5
9.0/10.9
NDc
1.9/3.5
ND
13.1/12.5
ND
ND
ND
ND
ND
ND
ND
2-Methoxyphenyl
3,4-Dimethoxyphenyl
4-Methoxyphenyl
2,20-Difluoromethylenedioxyphenyl
(Benzo[b]furan)-6-yl
3j
3k
3l
>5
a
b
c
Solubility at pH 7.4 in phosphate-buffered saline.
Permeability (a?b/b?a) determined in CaCo-2 cells.
ND = not determined.
treatment of pain, such as PPPA14 (c log P 4.25) or BZP15 (c log P
5.95). The corresponding five- and six-membered carbocyclic
derivatives were prepared from the 3-aryloxindole derivative 10
by treatment with an excess of sodium hydride, followed by alkyl-
ation with a suitable bromoester. Following saponification and acyl
halide formation, the poorly active ketones 27 and 28 were ob-
tained via tin (IV) chloride-promoted internal Friedel–Crafts acyla-
tion.16 Reduction of the benzylic ketone with triethylsilane
Table 3
SAR of 1-substituted-3-(3,4-methylenedioxyphenyl)-3-hydroxyoxindoles
O
O
HO
O
N
R
3a, 9a-r
Compound
R
hNaV1.7 IC50
(lM)
c log P
Solubilitya
(lg/mL)
Permeabilityb (a?b/b?a) (ꢂ10ꢀ6 cm/s)
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
3a
9p
9q
9r
(2-Cyclopropyl)ethyl
n-Pentyl
3-Methylpentyl
4-Methoxybenzyl
Benzyl
(5-Chloro-2-thienyl)methyl
3,4-Methylenedioxybenzyl
4,4,4-Trifluorobutyl
Isopentyl
(Cyclopropyl)methyl
n-Hexyl
4-Fluorobenzyl
(Cyclohexyl)methyl
(Cyclobutyl)methyl
3,4-Difluorobenzyl
4-Chlorobenzyl
4-(Trifluoromethyl)benzyl
(1-Napthyl)methyl
H
0.02
0.03
0.04
0.04
0.06
0.06
0.06
0.07
0.07
0.08
0.09
0.09
0.11
0.13
0.14
0.20
0.22
2.14
>5
2.97
3.56
3.89
3.50
3.63
3.98
3.41
3.43
3.47
2.62
3.97
3.79
3.87
3.04
3.95
4.19
4.55
4.63
1.66
11
37
14
6
<5
<5
14
9
<5
22
10
<5
<5
38
<5
<5
<5
<5
56
19.9/19.8
28.9/25.4
10.5/11.5
6.5/11.9
9.3/13.6
NDc
7.7/12.1
ND
ND
ND
ND
ND
ND
21.7/21.1
ND
9.0/10.9
5.4/7.9
ND
ND
a
b
c
Solubility at pH 7.4 in phosphate-buffered saline.
Permeability (a?b/b?a) determined in CaCo-2 cells.
ND = not determined.

S. Chowdhury et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3676–3681
3679
O
O
O
O
O
HO
HO
a
b
O
O
O
O
N
N
N
nPent
nPent
nPent
10
11
9b
e
c
d
O
O
MeO2C
O
O
O
O
MeO
O
N
O
O
nPent
14
N
N
nPent
12
nPent
13
f
g, h, i
O
O
RHNOC
H2N
O
O
O
O
N
N
nPent
nPent
17
15 (R = Me)
16 (R = Bn)
O
O
O
O
O
MeO2C
HO2C
R'RHNOC
n
n
O
j
k
l
10
O
O
O
N
N
nPent
N
nPent
nPent
22 (R = R' = H)
18 (n = 0)
20 (n = 0)
21 (n = 1)
19 (n = 1)
23 (R = Me, R' = H)
24 (R = R' = Me)
Scheme 3. Reagents and conditions: (a) Et3SiH, TFA, DCM, rt, 6 h; (b) (i) TMSCl, NEt3, CH2Cl2, 0 °C, 2 h; (ii) (CH2O)n, Yb(OTf)3 (cat.), THF, rt, 48 h; (c) MeI, NaOMe, THF, 0 °C to
rt, 16 h; (d) MeI, NaH, THF, 0 °C, 1 h; (e) NaH, NCCO2Me, THF, 0 °C to rt, 2 h; (f) MeNH2 or BnNH2, MeOH, sealed tube, 70–100 °C, 16 h; (g) hydrazine monohydrate, n-PrOH,
100 °C, 2 h; (h) NaNO2, AcOH, 10 °C, 1 h; (i) t-BuOH, PhMe, reflux, 1 h then HBr, HOAc, rt, 1 h; (j) (c) NaH, THF, 0 °C, 0.5 h, then methyl 3-bromoproionate or methyl
bromoacetate, rt; (k) LiOH, THF/H2O, rt, 16 h; (l) (i) (COCl)2, DMF (cat.), PhMe, rt, 4 h; (ii) amine, NaHCO3, CH2Cl2, rt, 16 h.
Table 4
Table 4 (continued)
SAR of 1-pentyl-3-(3,4-methylenedioxyphenyl)-3-substituted oxindoles
Compound
R
hNaV1.7
IC50
(lM)
c log P Solubilitya Permeabilityb
(l
g/mL)
(ꢂ10ꢀ6 cm/s)
O
O
R
21
22
23
24
(CH2)2CO2H
CH2CONH2
CH2CONMe
CH2CONMe2
>5
>5
>5
>5
4.32
3.25
3.48
3.72
35
35
31
<5
ND
ND
ND
ND
O
N
nPent
a
b
c
Solubility at pH 7.4 in phosphate-buffered saline.
Permeability (a?b/b?a) determined in CaCo-2 cells.
ND = not determined.
9b-24
Compound
R
hNaV1.7
IC50
(lM)
c log P Solubilitya Permeabilityb
(
lg/mL)
(ꢂ10ꢀ6 cm/s)
afforded the carbocycles 30 and 31, which themselves were mod-
estly active against NaV1.7. Finally, the regioisomeric tetrahydrofu-
ran spirocycle 35 was prepared from the bromoaldehyde 32 by
means of a reduction/metal-halogen exchange/carbonyl addition
sequence, followed by Mitsunobu cyclization. Notably, this ana-
logue was ca. 400-fold less potent than its regioisomer XEN907.
9b
10
11
12
13
14
15
16
17
18
19
20
OH
H
CH2OH
OMe
Me
CO2Me
CONHMe
CONHBn
NH2
CH2CO2Me
(CH2)2CO2Me >5
CH2CO2H >5
0.03
1.74
0.63
>5
1.63
1.90
>5
1.10
0.03
>5
3.17
4.18
3.82
3.92
4.89
4.22
3.54
5.27
3.56
4.16
4.58
3.90
37
6
28.9/25.4
NDc
ND
ND
2.4/3.6
ND
ND
ND
22.0/22.3
ND
ND
<5
<5
<5
<5
10
<5
34
<5
<5
73
XEN907 showed no significant activity at 10 lM against a broad
panel of 63 receptors and transporters. Determination of the ADME
properties of XEN907 (Table 6) revealed that the compound was
not cytotoxic and had favourable hepatocyte metabolic stability
for both human and dog, although inhibition of CYP3A4 was ob-
served in a recombinant human enzyme assay.
ND

3680
S. Chowdhury et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3676–3681
HO
HO
HO
O
O
O
O
O
a
b
O
O
O
N
N
N
nPent
nPent
nPent
8b
25
26
d, e
O
n
O
O
HO2C
O
O
O
n
c
O
O
nPent
O
O
O
N
N
N
nPent
nPent
20 (n = 0)
29 (XEN907)
21 (n = 1)
27 (n = 0)
28 (n = 1)
f
O
n
O
O
N
nPent
30 (n = 0)
31 (n = 1)
HO
O
O
O
OH
HO
O
O
N
OHC
Br
O
O
O
O
e
h
g
O
O
N
Br
nPent
nPent
32
33
34
35
Scheme 4. Reagents and conditions: (a) sesamol, iPrMgCl, THF, 0 °C to rt, 16 h; (b) Et3SiH, TFA, CH2Cl2, rt, 6 h; (c) (i) (COCl)2, DMF (cat.), PhMe, rt, 4 h; (ii) SnCl4, CH2Cl2, 0 °C to
rt, 16 h; (d) (i) TMSCl, NEt3, CH2Cl2, 0 °C, 2 h; (ii) (CH2O)n, Yb(OTf)3 (cat.), THF, rt, 48 h; (e) PPh3, DEAD, THF, ꢀ10 °C to rt, 16 h; (f) Et3SiH, TFA, rt, 16 h; (g) NaBH4, THF, 0 °C to rt,
10 h; (h) nBuLi, THF, ꢀ78 °C, 0.5 h then isatin 8b, ꢀ78 °C to rt, 16 h.
Table 5
Table 7
SAR of spirocyclic analogues
Mean pharmacokinetic parameters of 29 (XEN907) after administration to male lewis
rats (n = 3/group)
Compound
hNaV1.7
c log P
Solubilitya
g/mL)
Permeabilityb (a?b/
b?a) (ꢂ10ꢀ6 cm/s)
IC50
(l
M)
(l
Parameter
po (10 mg/kg)
iv (3 mg/kg)
27
28
3.34
1.81
3.52
3.94
3.97
4.87
5.29
3.62
<5
<5
7.3
<5
<5
<5
NDc
Cmax (ng/mL)
AUClast (h ng/mL)
t1/2 (h)
35 26
143 61
—
0.33
—
953 96
320 52
2.6 0.1
—
35.0 4.5
9.4 1.7
—
ND
29 (XEN907)
0.003
0.44
1.48
1.18
5.9/7.2
1.1/1.6
ND
30
31
35
Tmax (h)
Vss (L/kg)
Cl (L/h/kg)
F (%)
ND
—
13
a
b
c
Solubility at pH 7.4 in phosphate-buffered saline.
Permeability (a?b/b?a) determined in CaCo-2 cells.
ND = not determined.
the compound was modestly bioavailable. Following an initial ra-
pid absorption phase (oral Tmax = 20 min), XEN907 was extensively
distributed (Vss ꢃ600-fold higher than the plasma volume in rats)
and rapidly cleared.
In summary, progressive elaboration of the HTS hit 2a via struc-
tural simplification to the 3-aryl-3-hydroxyoxindole 9b, prelimin-
ary optimization of the N1- and C3-substituents and
rigidification to a spirooxindole framework led to the identification
of the highly potent (IC50 = 3 nM) lead XEN907. Further optimiza-
tion efforts in this structural class aimed at defining analogues
with improved physico-chemical and ADME properties will be de-
scribed in due course.
Table 6
Selected ADME properties of 29 (XEN907)
Property
Value for 29
Plasma protein binding (rat)
Cytotoxicity (HepG2, % viable after 16 h)
Hepatocyte stability, % remaining after 2 h (rat/human/dog)
97%
>99%
21%/34%/46%
Pharmacokinetic analysis in rats of XEN907 (Table 7) demon-
strated that, consistent with the compound’s ADME parameters,

S. Chowdhury et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3676–3681
3681
4. Reddy, N. L.; Fan, W.; Magar, S. S.; Perlman, M. E.; Yost, E.; Zhang, L.; Berlove, D.;
Fischer, J. B.; Burke-Howie, K.; Wolcott, T.; Durant, G. J. J. Med. Chem. 1998, 41,
3298.
5. All IC50 data reported herein are means of no fewer than two replicate
experiments.
6. For a review, see: Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20.
7. (a) Peterson, L. A.; Cummings, M. E.; Vu, C. C.; Matter, B. A. Drug Metab. Dispos.
2005, 33, 1453; (b) Peterson, L. A. Drug Metab. Rev. 2006, 38, 615.
8. (a) Melch, W. M.; Williams, M. T. J. Labelled Compd. Radiopharm. 1993, 33, 119;
(b) Brueckner, C.; Holzinger, H.; Reissig, H.-U. J. Org. Chem. 1988, 52, 2450.
9. (a) Kobayashi, S.; Hachiya, I. Tetrahedron Lett. 1992, 33, 1625; (b) Kobayashi, S.;
Hamada, T.; Nagayama, S.; Manabe, K. Org. Lett. 2001, 3, 165.
10. Koza, G.; Oezcan, S.; Sahin, E.; Balci, M. Tetrahedron 2009, 65, 5973.
11. Kunihiro, M.; Yokomizo, K.; Uyeda, M. Chem. Pharm. Bull. 2002, 50, 298.
12. (a) Krohn, K.; Ahmed, I.; Markus, J. Synthesis 2009, 779; (b) Wilkinson, M. C.;
Bell, R.; Landon, R.; Nikiforov, P. O. Synlett 2006, 2151.
Acknowledgments
The authors are grateful to Audrey Wang, Xing Cheng, Jing
Zhong and Ivana Rajlic (for technical assistance) as well as Henry
Verschoof (for helpful discussions during the preparation of this
Letter).
References and notes
1. (a) Mantegazza, M.; Curia, G.; Ragsdale, D. S.; Avoli, M. Lancet Neurol. 2010, 9,
413; (b) Termin, A.; Martinborough, E.; Wilson, D. Ann. Rept. Med. Chem. 2008,
43, 43; (c) Catterall, W. A.; Goldin, A. L.; Waxman, S. G. Pharmacol. Rev. 2005,
57, 397; (d) England, S. Expert Opin. Invest. Drugs 2008, 17, 1849; (e) Dib-Hajj,
S. D.; Cummins, T. R.; Black, J. A.; Waxman, S. G. Ann. Rev. Neurosci. 2010, 33,
325.
13. All compounds described herein were characterized by 1H NMR, 13C NMR and
ESI-MS and had purities P98% a/a by HPLC. Characterization data for 29
(XEN907): mp 89–90 °C; 1H NMR (300 MHz, CDCl3) d 7.34–7.29 (m, 1H), 7.19–
7.15 (m, 1H), 7.07–7.01 (m, 1H), 6.92–6.87 (m, 1H), 6.51 (s, 1H), 6.12 (s, 1H),
5.88–5.84 (m, 2H), 4.91, 4.66 (ABq, JAB = 8.9 Hz, 2H), 3.87–3.64 (m, 2H), 1.77–
1.65 (m, 2H), 1.41–1.32 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 177.4, 156.0, 148.9, 142.5, 142.4, 132.6, 129.0, 124.0, 132.2, 119.7,
108.7, 103.1, 101.6, 93.7, 80.6, 58.3, 40.5, 29.1, 27.2, 22.5, 14.1; MS (ESI+) m/z
352.3 (M+1); purity (HPLC, UV at 254 nm) 99.2% a/a.
14. Ilyin, V. I.; Pomonis, J. D.; Whiteside, G. T.; Harrison, J. E.; Pearson, M. S.; Mark,
L.; Turchin, P. I.; Gottshall, S.; Carter, R. B.; Nguyen, P.; Hogenkamp, D. J.;
Olanrewaju, S.; Benjamin, E.; Woodward, R. M. J. Pharmacol. Exp. Ther. 2006,
318, 1083.
2. (a) Goldberg, Y. P.; MacFarlane, J.; MacDonald, M. L.; Thompson, J.; Dube, M. P.;
Mattice, M.; Fraser, R.; Young, C.; Hossain, S.; Pape, T.; Payne, B.; Radomski, C.;
Donaldson, G.; Ives, E.; Cox, J.; Younghusband, H. B.; Green, R.; Duff, A.;
Boltshauser, E.; Grinspan, G. A.; Dimon, J. H.; Sibley, B. G.; Andria, G.; Toscano,
E.; Kerdraon, J.; Bowsher, D.; Pimstone, S. N.; Samuels, M. E.; Sherrington, R.;
Hayden, M. R. Clin. Genet. 2007, 71, 311; (b) Cox, J. J.; Reimann, F.; Nicholas, A.
K.; Thornton, G.; Roberts, E.; Springell, K.; Karbani, G.; Jafri, H.; Mannan, J.;
Raashid, Y.; Al-Gazali, L.; Hamamy, H.; Valente, E. M.; Gorman, S.; Williams, R.;
McHale, D. P.; Wood, J. N.; Gribble, F. M.; Woods, C. G. Nature 2006, 444, 894.
3. (a) Yang, Y.; Wang, Y.; Li, S.; Xu, Z.; Li, H.; Ma, L.; Fan, J.; Bu, D.; Lui, B.; Fan, Z.;
Wu, G.; Jin, J.; Ding, B.; Zhu, X.; Shen, Y. J. Med. Genet. 2004, 41, 171; (b)
Cummins, T. R.; Dib-Hajj, S. D.; Waxman, S. G. J. Neurosci. 2004, 24, 8232; (c)
Fertleman, C. R.; Baker, M. D.; Parker, K. A.; Moffat, S.; Elmslie, F. V.;
Abrahamsen, B.; Ostman, J.; Klugbauer, N.; Wood, J. N.; Gardiner, R. M.; Rees,
M. Neuron 2006, 52, 767.
15. McGowan, E.; Hoyt, S. B.; Li, X.; Lyons, K. A.; Abbadie, C. Anesth. Analg. 2009,
109, 951.
16. (a) Starflinger, W.; Kresze, G.; Huss, K. J. Org. Chem. 1986, 51, 37; (b) Han, D. I.;
Oh, D. Y. Synth. Commun. 1989, 19, 2213.