ACS Medicinal Chemistry Letters
Letter
Encouraged by these results, we tested 3 in a complete
Freund’s adjuvant (CFA) induced cold allodynia assay in
mice.16 Following intraplantar injection of CFA in the left hind
paw, inflammation develops in the affected (ipsilateral) hind
paw. On day 2 after CFA administration, mice received an ip
dose of either test compound 3 (as Na-salt 3a) or the vehicle.
Cold sensitivity pain was induced by evaporation of acetone,
which was applied directly to the plantar surface of the
ipsilateral hind paw. Compound 3 displayed a dose-dependent
reduction of the pain response (Figure 2C). At the lowest dose
of 10 mpk, no change in pain behavior relative to vehicle was
observed. In comparison, the higher doses significantly reduced
nociceptive behavior, with 59% reduction at the 30 mpk dose
and reduction close to baseline at the 100 mpk dose (83%
compared to vehicle).
AUTHOR INFORMATION
Corresponding Author
■
Present Addresses
∥Hangzhou Yingchuang Pharma, Longtan Road No. 20,
Yuhang District, Hangzhou, Zhejiang, 31121, P. R. China.
§Department of Chemistry, Universite
́ ́
de Montreal, PO Box
6128, Station Downtown, Montreal, QC H3C 3J7, Canada.
⊥Sabila Biosciences LLC, 5 Overlook Road, New City, New
York 10956, United States.
#Inception Sciences Canada, 887 Great Northern Way, Suite
210, Vancouver, BC V5T 4T5, Canada.
Author Contributions
All authors have given approval to the final version of the
manuscript.
Combined, the data from our efficacy studies demonstrate
that NaV1.7 inhibitor 3 markedly attenuates pain sensation in
rodent models of acute and inflammatory pain and indicates in
vivo target engagement of sodium channels. Though compound
3 displayed high selectivity for hNaV1.7 over other human
isoforms, the selectivity profile in other species remains to be
investigated. Thus, we cannot rule out a contribution of other
sodium channel isoforms associated with sensation of pain,
such as NaV1.617 or NaV1.8,4,18 to the observed analgesic effect
in rodents. Existing data from animal studies with a NaV1.7-
selective monoclonal antibody however suggest that inhibition
of NaV1.7 alone is sufficient to produce an analgesic effect.19 In
addition, results from a formalin study with NaV1.7 DRG-null
mice (NaV1.7R−/−) showing a reduced pain response further
validate the major role of NaV1.7 in acute and inflammatory
pain.20,21
Notes
The authors declare the following competing financial
interest(s): Both Xenon Pharmaceuticals and Genentech are
actively developing NaV1.7 inhibitors as therapeutic agents.
ABBREVIATIONS
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ANOVA, analysis of variance; CFA, complete Freund’s
adjuvant; CLhep, predicated hepatic clearance; CLp, plasma
clearance; Cmax, maximum concentration; DRG, dorsal root
ganglion; HH, human hepatocytes; MDR1, multidrug resist-
ance protein 1; MH, mouse hepatocytes; mpk, milligram per
kilogram; h/m/r NaV, human/mouse/rat voltage-gated sodium
channel; Papp, apparent permeability; RH, rat hepatocytes; SD,
standard deviation; SEM, standard error of the mean; Tmax
time of maximum concentration; Vss, volume of distribution;
,
In summary, we have described the discovery and
optimization of a novel series of aryl sulfonamides as potent
and isoform-selective NaV1.7 inhibitors. Our compounds show
exquisite selectivity over the human sodium channel isoforms
NaV1.1, NaV1.3, NaV1.5, and NaV1.8 as determined by voltage-
clamp electrophysiology, but less selectivity against NaV1.2 and
NaV1.6. Compound 3 displayed significant analgesic effects in
rodent models of acute and inflammatory pain and
demonstrated that highly plasma protein bound aryl
sulfonamides can display meaningful target engagement in
vivo. In addition, we were able to validate that targeting the
VSD4 of NaV1.7 leads to an analgesic effect in vivo. Our findings
support the notion of NaV1.7 as an important mediator of the
pain response and should augment the current high interest in
developing isoform-selective NaV1.7 inhibitors as analgesics.
The observed isoform selectivity against myocardial NaV1.5
presents a highly desirable safety advantage. In addition, the low
CNS exposure may minimize adverse events putatively arising
from block of CNS sodium channels and thereby mitigate
potentially potent block of NaV1.6 and NaV1.2.2 Further
optimization of PK properties and CYP inhibition is desirable
and will focus on the heterocyclic A- and D/E-ring systems.
VSD, voltage sensor domain
REFERENCES
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(1) Dib-Hajj, S. D.; Yang, Y.; Black, J. A.; Waxman, S. G. The NaV1.7
Sodium Channel: From Molecule to Man. Nat. Rev. Neurosci. 2013, 14,
49−62.
(2) Eijkelkamp, N.; Linley, J. E.; Baker, M. D.; Minett, M. S.; Cregg,
R.; Werdehausen, R.; Rugiero, F.; Wood, J. N. Neurological
Perspectives on Voltage-Gated Sodium Channels. Brain 2012, 135,
2585−2612.
(3) England, S.; Rawson, D. Isoform-Selective Voltage-Gated Na+
Modulators as Next-Generation Analgesics. Future Med. Chem. 2010,
2, 775−790.
(4) de Lera Ruiz, M.; Kraus, R. L. Voltage-Gated Sodium Channels:
Structure, Function, Pharmacology, and Clinical Indications. J. Med.
Chem. 2015, 58, 7093−7118.
(5) Sun, S.; Cohen, C. J.; Dehnhardt, C. M. Inhibitors of Voltage-
Gated Sodium Channel NaV1.7: Patent Applications Since 2010.
Pharm. Pat. Anal. 2014, 3, 509−521.
(6) Bagal, S. K.; Chapman, M. L.; Marron, B. E.; Prime, R.; Storer, R.
I.; Swain, N. A. Recent Progress in Sodium Channel Modulators for
Pain. Bioorg. Med. Chem. Lett. 2014, 24, 3690−3699.
(7) Nardi, A.; Damann, N.; Hertrampf, T.; Kless, A. Advances in
Targeting Voltage Gated Sodium Channels with Small Molecules.
ChemMedChem 2012, 7, 1712−1740.
(8) McCormack, K.; Santos, S.; Chapman, M. L.; Krafte, D. S.;
Marron, B. E.; West, C. W.; Krambis, M. J.; Antonio, B. M.; Zellmer, S.
G.; Printzenhoff, D.; Padilla, K. M.; Lin, Z.; Wagoner, P. K.; Swain, N.
A.; Stupple, P. A.; de Groot, M.; Butt, R. P.; Castle, N. A. Voltage
Sensor Interaction Site for Selective Small Molecule Inhibitors of
Voltage-Gated Sodium Channels. Proc. Natl. Acad. Sci. U. S. A. 2013,
110, E2724−E2732.
(9) Ahuja, S.; Mukund, S.; Deng, L.; Khakh, K.; Chang, E.; Ho, H.;
Shriver, S.; Young, C.; Lin, S.; Johnson, J. P., Jr.; Wu, P.; Li, J.; Coons,
M.; Tam, C.; Brillantes, B.; Sampang, H.; Mortara, K.; Grimwood, M.;
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge on the
Synthetic procedures and NMR spectra of all final
compounds, and description of the in vitro assays and
E
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