Bioorganic & Medicinal Chemistry Letters 24 (2014) 3690–3699
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
BMCL Digest
Recent progress in sodium channel modulators for pain
Sharan K. Bagal a,⇑, Mark L. Chapman b, Brian E. Marron c, Rebecca Prime d, R. Ian Storer a, Nigel A. Swain a
a
Worldwide Medicinal Chemistry, Pfizer Neusentis, The Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, UK
Electrophysiology, Pfizer Neusentis, 4222 Emperor Blvd., Durham, NC, USA
Chemistry, Pfizer Neusentis, 4222 Emperor Blvd., Durham, NC, USA
d
Electrophysiology, Pfizer Neusentis, The Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, UK
b
c
a r t i c l e
i n f o
Article history:
Received 29 April 2014
Revised 11 June 2014
Accepted 12 June 2014
Available online 21 June 2014
Keywords:
Voltage-gated sodium channels
Electrophysiology screening
Sodium channel toxins
Sodium channel structure
Sodium channel drugs
a b s t r a c t
Voltage-gated sodium channels (Navs) are an important family of transmembrane ion channel proteins
and Nav drug discovery is an exciting field. Pharmaceutical investment in Navs for pain therapeutics
has expanded exponentially due to genetic data such as SCN10A mutations and an improved ability to
establish an effective screen sequence for example IonWorks BarracudaÒ, SynchropatchÒ and QubeÒ.
Moreover, emerging clinical data (AZD-3161, XEN402, CNV1014802, PF-05089771, PF-04531083)
combined with recent breakthroughs in Nav structural biology pave the way for a future of fruitful
prospective Nav drug discovery.
Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
Voltage-gated sodium channels (Nav) are a family of transmembrane ion channel proteins. Structurally, they are members of the
6-TM ion channel family and are composed of a transmembrane
a-subunit of approximately 260 kDa and several associated transmembrane b-subunits of lower molecular weight. The family comprises nine members Nav1.1-Nav1.9 and related NaX. Navs are
involved in Na+ ion conduction across cell membranes during cell
membrane depolarization. If cell membrane depolarization reaches
a threshold value Nav channels open to allow Na+ ions to flow into
cells. This movement creates action potentials and nerve impulses
in electrically excitable cells, for example neurons, and affects
many functions for example the peripheral and central nervous
system, cardiac and skeletal muscle etc. Blockade of Navs has been
successfully accomplished in the clinic to enable control of pathological firing patterns that occur in a diverse range of conditions
such as chronic pain, epilepsy, and cardiac arrhythmias. In this
review we will discuss recent advances in the field of Nav drug discovery for the treatment of pain. In particular progress in biology,
structural biology, assay technology, inhibitor development and
clinical success will be discussed.
Sodium channel topology and structure: Structural studies of
6TM-topology ion channels date back to the late 1980s, when
Numa et al. successfully cloned a-subunits of sodium channels.1,2
According to sequence analysis, Nav a-subunits are composed of
⇑ Corresponding author. Tel.: +44 7817653523.
E-mail address: sharan.bagal@pfizer.com (S.K. Bagal).
approximately 2000 amino acids which assemble into four distinct
domains (D1–D4), each of which consists of 6TM a-helices (S1–S6)
(Fig. 1). Two helices (S5–S6) from each domain contribute towards
formation of the channel pore which is responsible for Na ion conduction. The S1–S4 helices from each domain form a voltage sensor
which works as a sensor of change in voltage across the cell membrane. Consequently, the pore is formed from eight helices and
there are four voltage sensors surrounding the pore. Between the
pore-forming helices (S5–S6) from each domain there is an
extended P-loop which acts to form the Na ion selectivity filter.
Other voltage-gated channels, Kv and Cav, share common topology
and mechanism of activation with the Nav class.3
Recently, structural understanding of this class of ion channels
has been drastically improved due to the publication of site directed mutagenesis work and several crystal structures; a KV1.2/2.1
chimera crystal structure by MacKinnon4 and multiple NavAb bacterial sodium channel apo crystal structures from Catterall.5,6
Interestingly, these structures complement each other by appearing to sample several states of the NavAb channel. By comparison
of the structural differences these structures provide valuable
insight into gating mechanisms and conformational changes which
occur to open the channel pore to ion flux.5 These studies also
highlight fenestration regions within the channel pore that may
constitute potential binding sites for small molecule modulators.
However, to date there have been no reported co-crystal structures
of any sodium channel proteins with small molecule or toxin molecules bound.
http://dx.doi.org/10.1016/j.bmcl.2014.06.038
0960-894X/Ó 2014 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
S. K. Bagal et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3690–3699
3691
Figure 1. (a) NaV channel structural topology. Domains D1–D4 are represented in different colors while b subunits are shown in gray. Transmembrane segments (S1–S6)
labelled together with graphical representation of P-loops. (b) Side view; (c) Top view of voltage-gated sodium channel from the bacterium Arcobacter butzleri (NavAb–PDB
code 3RVY)5,6 with highlighted postulated toxin binding sites (1–6), local anesthetic binding site and significant structural features.
To further complement these recent advances in X-ray crystal
structures, the field is also benefiting from advances in computational modeling and molecular dynamics to understand the opening/closing mechanism of voltage-gated channels. For example, a
publication from Jensen et al., which describes micro second order
molecular dynamics for the related KV1.2/2.1 channels, suggests
that these channels close with a hydrophobic collapse of a pore
residue, which is followed by movement of the voltage-sensor
domain towards the pore.7,8 Conversely, in the opening process,
the voltage sensor moves outward first, which pulls the pore
domain to open.
Overall, the combination of structural, mutagenesis and computational studies have been used to build an understanding of Nav
channel conformational gating and function. At a simplistic level,
Nav channels are believed to exist in three states characterized
by conduction behavior at different voltage potentials: open,
closed (resting) and inactivated. At a resting trans-membrane
potential, the channels are in a non-conducting closed state. When
membrane potential is decreased (depolarization) the voltage sensors (S1–S4) move outward in a rotational movement, pulling the
pore open for a short period (<1 ms). Subsequently the channel
then moves via a combination of fast- or slow-inactivation processes into a non-conductive inactivated state. It is currently
believed that a specific loop between D3 and D4 termed the inactivation gate is responsible for fast inactivation. Finally, an increase
in membrane potential (hyperpolarization) causes the Nav channels to return to the resting state.
Nav channel genetics and biology: Nav channels as pain targets
gained traction with the recognition that some Nav subtypes
showed preferential or exclusive expression in peripheral sensory
neurons.9 While peripheral sensory neurons express nearly all
Nav subtypes at some level, there are three subtypes, Nav1.7,
Nav1.8, and Nav1.9 which are enriched in peripheral neurons of
the trigeminal and dorsal root ganglia (DRG). Of these, Nav1.7 is
the most broadly expressed in DRG neurons, while expression of
Nav1.8 and Nav1.9 is largely restricted to the subset of small and
medium neurons which are thought to represent the majority of
nociceptors. The role of Nav1.7, Nav1.8, and Nav1.9 in pain signaling
has been well established in pharmacological, molecular and
genetic studies with preclinical species.10 Human validation of
these targets had lagged behind the animal studies until the discovery that inherited erythromelalgia (IEM) is causally linked to
missense mutations in Nav1.7.11 Since this discovery, the family
of Nav channelopathies has expanded in two important areas. First,
the link between Nav1.7 variants and clinical pain syndromes now
includes a subset of idiopathic small fiber neuropathies, a disorder
which affects millions of patients. Second, additional Nav related
channelopathies have been discovered which are causally linked
to Nav1.8 and Nav1.9. These studies provide evidence for the contribution of each subtype of peripherally expressed Nav channel
to pain signaling.
Nav1.7: The first Nav channelopathy linked to pain to be identified was inherited erythromelalgia (IEM). IEM is characterized by
extreme burning pain, typically in the distal extremities, which is
triggered by moderate increases in temperature. Electrophysiological characterization of the mutant channels revealed a gainof-function phenotype in channel activation, consistent with the
pathological sensitivity to heating. To date, twenty SCN9A variants
have been linked to IEM and have consistently shown a gain of
function phenotype and demonstrated the ability to produce
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hyperexcitability in dorsal root ganglion (DRG) neurons.12 A second rare genetic disease, paroxysmal extreme pain disorder
(PEPD), has also been linked to SCN9A gene mutations.13 PEPD also
produces a burning pain accompanied by flushing of the skin but is
considered clinically distinct from IEM. Electrophysiological
characterization of PEPD mutations similarly revealed a gainof-function phenotype but they disrupt fast-inactivation of
Nav1.7, preventing the channel from closing properly, and produce
prolonged flow of sodium current and resurgent currents upon
repolarization.14
Following the discovery of a causal link between Nav1.7 function and disorders of enhanced or aberrant pain, another rare disorder, congenital insensitivity to pain (CIP), was linked to
mutations of SCN9A.15 These recessive mutations result in a complete loss of functional Nav1.7 channels and an apparent complete
loss of ability to sense painful stimuli. Affected individuals report
no sensation of pain which can often lead to a significant negative
impact on overall health. The most recent pain related disorder to
be linked to SCN9A is idiopathic small fiber neuropathy (I-SFN), a
common adult-onset pain disorder. The family of small-fiber neuropathies is extensive, potentially affecting upwards of 40 million
Americans, with nearly 50% of cases classified as idiopathic.16
Nav1.7 variants have been found in 28% of a group of patients diagnosed with idiopathic small fiber neuropathy.17 Electrophysiological characterization of these mutant channels also showed a gain of
function affecting either activation or inactivation, resulting in
increased excitability of DRG neurons.
Nav1.8: The tetrodotoxin resistant Nav1.8 channel has been
shown to be the primary contributor of sodium flux during the
upstroke of the action potential of DRG neurons.18 In follow-up
studies of I-SFN, a group of patients negative for mutations of the
SCN9A gene were subjected to exome sequencing of the SCN10A
gene which encodes the Nav1.8 channel.19 Three mutations were
identified which had a high likelihood of altering Nav1.8 function.
Two of these mutations, L554P and A1304T, were shown to
enhance recovery from fast inactivation and hyperpolarize the
voltage dependence of activation, respectively. As with Nav1.7,
these biophysical changes were predicted to be pro-excitatory
and both channels were subsequently demonstrated to produce
hyperexcitability of DRG neurons.
Nav1.9: The three most recently discovered Nav channelopathies
are associated with mutations of the Nav1.9 channel. Nav1.9 is biophysically distinct from other Nav channels, displaying slow activation and inactivation properties. Consequently, Nav1.9 does not
directly contribute to the action potential waveform, but is thought
to provide a variable background Na conductance that is important
for determination of resting membrane potential and membrane
excitability.20
Two large Chinese families with episodic pain, primarily of the
distal extremities, were found to harbor missense mutations within
the SCN11A gene.21 Electrophysiological studies of the mutant
channels showed no significant alteration of activation or inactivation properties but did reveal enhanced current amplitude when
compared to the wild type Nav1.9 channel. A different, novel
Nav1.9 missense mutation results in gain of channel function but
gives a seemingly confounding clinical phenotype of complete
insensitivity to pain.22 Despite the Nav1.9 gain of function, the loss
of pain sensitivity phenotype is presumed to arise from inactivation
of Nav channels responsible for action potential propagation resulting in an inability to sustain firing and conduction block. A recent
study involving three hundred and forty five patients with peripheral neuropathy but without mutations in SCN9A and SCN10A identified missense mutations of Nav1.9 as a cause of painful peripheral
neuropathy. Eight variants of SCN11A were identified in twelve
patients. Functional profiling by electrophysiological recordings
showed that these Nav1.9 mutations confer gain-of-function
attributes to the channel, depolarize resting membrane potential
of DRG neurons, enhance spontaneous firing, and increase evoked
firing of these neurons.23
Sodium channel toxin-derived modulators: Numerous natural
toxins and synthetic derivatives are known to modulate sodium
channels. These include both polar small molecule toxins and a
variety of peptide-based venom toxins. Interestingly these toxins
cover a wide range of structural classes and have been isolated
from many different animal sources including fish, shellfish, spider,
snail, scorpion and centipede venoms.24 All known sodium
channels modulators are believed to act via binding to sites on
the a-subunits. Currently there are at least six different binding
sites known for toxins, classified as Neurotoxin receptor site 1–6
(Fig. 1).
Site 1 binds non-peptidic neurotoxins tetrodotoxin (TTX), saxitoxin and also several peptide toxins such as cone snail l-conotoxins (Fig. 2). The binding site for these toxins is formed by amino
acids on the pore and selectivity filter loops on the extracellular
end of the pore. As a result, site 1 toxins bind to directly block
the pore to Na+ access. Interestingly, the sensitivity of the nine
sodium channels to TTX blockade has been used to divide the family into two classes TTX-S sensitive IC50 <30 nM (Navs 1.1, 1.2, 1.3,
1.4, 1.6, 1.7) and TTX-R resistant IC50 >30 nM (Navs 1.5, 1.8). This
TTX affinity difference between the Navs is believed to be
explained by the presence or absence of a key cysteine residue in
the TTX-binding site.25
Site 2 binds a group of lipid-soluble toxins, including batrachotoxin, veratridine, aconotine, antillatoxin, hoiamides and grayanotoxin all of which increase activation of Nav channels by binding to
the open conformation of the channels leading to persistent activation (Fig. 2). A combination of mutagenesis and photoaffinity labeling experiments suggest that transmembrane segments S6 from
D1 and D4 play a role in the binding site of batrachotoxin.24
Site 3 binds peptidic a-scorpion and sea anemone anthopleurin
toxins which work to slow the rate that the sodium channel moves
from open to inactive states. These peptides are believed to bind to
a site that is formed from the S3 to S4 loop at the extracellular end
of the D4 voltage sensor as demonstrated by site-directed
mutagenesis.24
Site 4 is known to bind b-scorpion toxins at the S3–S4 loop on
the extracellular side of the D2 voltage sensor. These toxins act as
gating modifiers that shift the activation threshold to more negative membrane potentials. Conversely, several spider toxins (e.g.,
ProTx-II, HwTx-IV) and a centipede toxin have been recently
described to bind to this site and inhibit sodium channels by modifying the voltage dependence of channel activation towards more
positive values.24,26,27
Site 5 binds the complex lipophilic polyether marine toxins
brevetoxin and ciguatoxins that have been implicated in a number
of effects including inhibition of channel opening and shift of activation towards hyperpolarized potentials. Pore helices S5 from D1
and S6 from D4 have been implicated in the binding of brevetoxin
as highlighted by photoaffinity labeling studies.24
Site 6 binds d-conotoxins which are known to slow the rate of
inactivation in a similar manner to the a-scorpion toxins. The location of this binding site is not well understood but is believed to be
the extracellular part of the D4 voltage sensor, adjacent to site 3.24
Recently there has been increased activity in the arena of synthetic toxins with the objective of generating toxin-based tools
and therapeutics. Most notably, site 1 toxin tetrodotoxin (TTX)
has been advanced into clinical trials by Wex Pharmaceuticals
and is currently progressing in Phase III trials for cancer and chemotherapy-related pain. In addition, there have been several
papers and patents outlining synthetic analogues of site 4 toxin
inhibitors, most notably the synthesis of potent Nav1.7 selective
HwTx-IV analogs.28–30
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O
OH
O
O
HO
OH
H 2N
OH
NH
OH
HO
N
H
N
H
Tetrodotoxin (TTX) (1)
O
O
HN
HO
H
N
O
HN
N
N
NH 2
OH
OH
O
HO
Saxitoxin (2)
NH
N
O
H
Batrachotoxin (3)
Figure 2. Selected toxin modulators.
Screening capabilities: HTS electrophysiology has been largely
developed to enable sodium and calcium channel drug discovery.
In fact, the investigation of ion channels has always been challenging, with data being limited to non-functional information, such as
binding and FRET based data or functional electrophysiology data
where screening throughput is often at the expense of quality.
Although developments in the field of automated electrophysiology now allow for its use in higher throughput screening cascades
through to more in depth biophysical characterization of channel
interactions, the biggest limitation remains with how to interpret
this electrophysiology data. The range of platforms available and
subtle differences in the protocol designs are so varied that comparing information across screening platforms is an additional significant challenge.
Current technologies: The conventional patch clamp approach
using a glass pipette to patch a single cell is considered the gold
standard in electrophysiological measurements and is relied upon
for in depth biophysical characterization. However, planar patch
clamp technologies are generally the first choice as a screening
platform as they allow for electrophysiological recordings to be
made from multiple cells simultaneously, with varying levels of
quality and throughput.31 Giga seal platforms such as 16 well
PatchXpressÒ and 48 well QpatchÒ offer high quality, low throughput data whilst the 384 well IonWorksÒ system deliver high
throughput, lower quality data. By combining these screening
technologies they allow for a comprehensive screening cascade.32
Recent advances with the IonWorksÒ BarracudaÒ, SynchropatchÒ
and QubeÒ provide giga seal quality data in a 384 well format, continuous voltage control and faster fluid exchanges. This permits a
functional measure of compound activity at a much earlier stage
in the drug discovery cascade.
Non-functional assays: One of the first methodologies employed
for ion channel investigation was radioligand binding. Whilst this
screen has been used for many years to triage ion channel ligands,
it has some limitations, for example, the need for highly specific and
selective ligands along with difficulty in functional interpretation of
binding data unless there is confidence in the functional importance of the binding site.33 Moreover, for targets where generating
stable cell lines is difficult, fluorescence based assays are sometimes
the only option available for high throughout assessment.34
Aims for the future: There are still many technical limitations
around the quality of automated patch clamp techniques, such as
access resistance and compensation, which require much improvement before automated patch clamp techniques will be able to
replace conventional patch electrophysiology.35 Despite this, the
future of screening technologies for ion channel drug discovery
promises to be an exciting one.36 The real breakthrough will come
as more clinical data becomes available to interpret which in-vitro
assays or protocols are the most predictive of clinical outcomes.
Recent advances in current clamp technology on the automated
platforms should help with this in-vitro to clinical in-vivo translation by allowing measurement of effects on excitability.
Small molecule modulators: Small molecule binding sites:
Although sodium channels have six known binding sites for neurotoxins, extensive evidence suggests most small molecule inhibitors
of Nav channels bind within the pore region for example local anesthetic, antiepileptic and antiarrhythmic agents (Fig. 1).37 Elegant
site directed mutagenesis experiments suggested that these agents
interact with amino acid residues within the inner cavity of the
channel pore (S6 in D4), and this binding site has been named
the local anesthetic (LA) binding site.38 The LA binding site is
highly conserved across Nav channels and most likely accounts
for the lack of subtype selectivity for most clinically used sodium
channel blockers. Clinically, non-selective modulation of sodium
channels can be associated with undesirable side effects for
example cardiac toxicity due to inhibition of Nav1.5 channels.39
Strategies to identify inhibitors with improved sodium channel
subtype selectivity and side effect profile include developing binding assays and site directed mutagenesis studies to elucidate and
exploit novel binding sites. Several radioactively labeled toxin
binding assays have been developed offering new tools in the
search for novel sodium channel blockers (Fig. 2). Historically, a
[3H]batrachotoxin (3H-BTX 3) binding assay has been utilized to
discover novel sodium channel inhibitors due to the perceived
binding overlap of this toxin site with the ‘druggable’ LA site.40
However, the realization that inhibitors binding to alternative sites
may offer greater selectivity has driven more recent binding assay
development towards radiolabelling alternative peptides. For
example, radiolabelled spider venom peptides 125I-Pro-Tx-II41
and 125I-HwTx-IV28 may provide the necessary assays to identify
and design novel peptides and potentially small molecules with
improved potency and/or subtype selectivity.
Merck have described a small molecule binding assay based on
a high affinity 1-benzazepin-2-ones series with the belief that
enhanced channel interactions could pave the way for seeking
novel chemotypes with improved subtype selectivity ([3H]BNZA,
Fig. 3).42 However, most clinical LA site binders compete for
[3H]BNZA (4) binding to Nav channels consistent with overlapping
binding sites and the benzazepine series itself only displays modest levels of Nav1.5 selectivity. Interestingly, Amgen have demonstrated that a representative compound from a triazene series
does not displace 3H-BTX (3) but does displace tritiated triazene
structural analog 5 (Fig. 3).43 Furthermore, the local anesthetic tetracaine inhibits 3H-BTX (3) binding but does not affect 3H-triazene
5 binding consistent with separate interaction sites for this novel
series compared with the local anesthetics. Examples from this series also demonstrate good levels of selectivity for Nav1.7 over the
cardiac Nav1.5 and hERG channels. In contrast, A-803467 (6), a
small molecule inhibitor from Icagen/Abbott, displays excellent
levels of Nav1.8 selectivity over other Nav channel subtypes yet
its binding site appears to overlap with that of local anesthetic tetracaine.44 More recently, a unique interaction region on the D4
voltage sensor that is structurally distinct from the channel pore,
has been described.45 Using both chimeras and single point
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S. K. Bagal et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3690–3699
F
O
N
N
NH
O
O
HN
NH
O
N
N
O
O
O
O
O
HN
O
O
N
H
5
3H-BNZA (4)
O O S
S
N
N
H
Cl
N
A-803467 (6)
N
N
N
PF-04856264 (7)
Figure 3. Probes utilized for small molecule binding site elucidation.
mutations new classes of potent, highly selective acidic chemotypes have been reported. These compounds interact with ‘extracellular’ facing regions of the channel which appear to be the
major determinants of Nav subtype selectivity (e.g., PF-04856264
(7), Nav1.7 IC50 28 nM, Nav1.5 IC50 >10000 nM).
Small molecule patent literature: Over the past two years, there
have been few new disclosures of Nav1.8 inhibitors in the literature
since previous reviews and no new disclosures for selective Nav1.3
or Nav1.9 inhibitors. A greater number of patent applications for
compounds claiming Nav1.7 inhibition or mixed Nav1.7 activity
with other sodium channels for treating pain have been published.
There have also been several disclosures of compounds as sodium
channel inhibitors for treating pain that do not provide a description of the sodium channel tested. Representative examples from
patent applications publishing over the past two years are compiled in Figures 4–14 along with biological activity, subtype selectivity and screening platform data if available. It is prudent to note
that screening technologies and protocols vary significantly across
the pharmaceutical industry.
Pfizer has recently disclosed two new series of potent Nav1.8
inhibitors, an arylimidazole and a benzimidazole series (Fig. 4).
No selectivity data was presented in these patent applications.
In terms of Nav1.7 selective inhibition, Pfizer and Pfizer/Icagen
have published patents with compounds containing aryloxysulfonamides and sulfonylated amides.46–48 Pfizer has since made
additional disclosures of aryloxysulfonylated amides and acylsulfonyl ureas and arylindazole sulfonylated amides (Fig. 5). Selectivity data is not disclosed in these patents, however it is reported
that the lipophilic acid PF-04856264 (7) is highly Nav1.7 selective
over Nav1.5 (Fig. 3).45 A number of other companies have recently
filed patent applications for compounds occupying similar physiochemical space as the compounds described by Pfizer. These companies include Amgen, Daiichi Sankyo, Merck, Xenon, DaeWoong
and joint filings between Xenon and Genetech. Amgen have disclosed several series of compounds with bicyclic core sulfonamides
(Fig. 6). These compounds are potent Nav1.7 inhibitors with selectivity against Nav1.5. Xenon has disclosed potent zwitterionic
substituted piperazine and piperizine methyleneoxy arylsulfonamides, and a series of aryloxysulfonamides (Fig. 7). Nav1.5 data
for multiple examples indicate that these compounds are Nav1.7
selective. In joint applications between Xenon and Genetech aryloxysulfonylated amides and acylsulfonyl ureas have been reported
N
N
H
F3CO
NH 2
WO2013114250
Nav1.8 EIC50 0.127 µM
N
NH 2
NH
O
WO2013061205
Nav1.8 EIC 50 0.190 µM
Figure 4. Nav1.8 modulators developed by Pfizer; EIC50 = estimated IC50.47,61
(Fig. 8). In these applications Nav1.7 membrane binding data is
provided in addition to the Nav1.7 and Nav1.5 PatchXpressÒ (PX)
data that demonstrates selectivity for many of these compounds.
Merck has claimed benzo-oxazolone core sulfonamides that are
potent Nav1.7 inhibitors with good selectivity against Nav1.5
(Fig. 9). Many of the compounds are zwitterionic. The compounds
from Daiichi Sankyo employ a cycloalkyloxyaryl-sulfonamide to
deliver potent Nav1.7 inhibitors as determined by testing on the
IonWorksÒ Quattro™ (IWQ) platform (Fig. 9).
Purdue has continued to patent extensively on the aryloxybiarylmotifs with multiple filings over the past two years
(Fig. 10). Nav1.7 activity is reported but no subtype selectivity data
is provided. They employ a range of polar groups on the distal ring
of the biaryl, and it will be interesting to see what effect these substitutions have on selectivity, central nervous system (CNS) penetration and solubility. Other companies reporting compounds
with Nav1.7 activity (with no subtype selectivity data provided)
are shown in Figure 11. The representative examples from Zalicus,
Schering and Shionogi appear to be moderate Nav1.7 modulators.
RaQualia have filed a number of applications with substituted heteroaryl cores that are claimed as TTX-S inhibitors. Nav1.3, Nav1.5
and Nav1.7 data were also reported (Fig. 12). The biaryl spiropyrrolidine-lactams reported by Convergence are moderately
potent against Nav1.7 as tested on the QPatchÒ platform at the
half-maximal voltage for steady state inactivation protocol. Moreover, pIC50 values at 90 mV are also provided. Two examples
shown in Figure 13 are claimed in multiple filings by Convergence.
The spiro-piperidine compounds published by Vertex claim activity towards ‘a sodium channel’ and appear to be related to previous
applications (Fig. 14).49
Compounds in clinical development: A number of orally administered sodium channel modulators have been reported to enter clinical trials for the treatment of pain (Table 1). CNV1014802 (8) is a
novel oral state-dependent sodium channel blocker being developed by Convergence (Fig. 15). CNV1014802 has completed Phase
II trials for lumbosacral radiculopathy and is in Phase II trials for
trigeminal neuralgia. Furthermore, CNV1014802 was granted
orphan drug designation in 2013 by the US Food and Drug Administration (FDA) for the treatment of trigeminal neuralgia.50 Pfizer
have advanced several Nav1.7 and Nav1.8 selective compounds into
Phase I/II clinical trials. PF-05089771 has completed Phase II clinical trials of third molar extraction and primary inherited erythromelalgia.51,52 Pfizer has also reported advancing selective Nav1.8
blockers including PF-04531083.53 Dainippon Sumitomo recently
progressed a Nav1.7/Nav1.8 compound DSP-2230 into Phase I for
neuropathic pain.54 NKTR-171 is a sodium channel blocker in
Phase I by Nektar Therapeutics for the treatment of peripheral neuropathic pain. NKTR-171 is sodium channel unselective although it
exhibits peripheral restriction together with state and use dependence leading to functional selectivity.55
Some therapeutic agents have been reported to enter clinical
trials for the treatment of pain that proceed via a non-oral administration route. AstraZeneca has reported the effects of intradermal
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S. K. Bagal et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3690–3699
O
O O
S
N
H
Cl
F3C
F
O
O
N
O
O O O
S
N
N
H
F
O
N
Cl
WO2013093688
Na v1.7 EIC 50 0.035 µM
WO2013088315
Na v1.7 EIC 50 0.24 µM
O
N
N
O O
S
N
H
WO2012095781
Nav1.7 EIC50 0.13 µM
N
O
Figure 5. Nav1.7 modulators developed by Pfizer; EIC50 = estimated IC50.62–64
HN
N
N
N
O O S N
S
N
N
H
O
O
S
HN
N
O
S N
N
Cl
F3 C
WO2013025883
Nav1.7 IC50 0.038 µM
Nav1.5 IWQ IC 50 >10 µM
N
O O S
S
N
N
H
O
WO2013086229
Nav1.7 PX IC 50 0.019 µM
Nav1.5 IWQ IC 50 4.75 µM
F
O O S N
S
N
N
N
H
F3C
N
Cl
N
H
CF3
WO2013134518
Nav1.7 PX IC50 0.03 µM
Nav1.5 IWQ IC50 >10 µM
WO2013122897
Nav1.7 PX IC 50 0.0386 µM
Nav1.5 IWQ IC 50 >10 µM
Figure 6. Nav1.7 modulators developed by Amgen; PX = PatchXpressÒ; IWQ = IonWorksÒ.65–71
F
Cl
Cl
F O
O
S
HN
O
F
N
O
N
H
S N
F
WO2013064983
Nav1.7 IC 50 0.0033 µM
Nav1.5 IC 50 >10 µM
N
O O S
S
N
N
H
NH2
O N
WO2013064984
Nav1.7 PX IC 50 0.0006 µM
Nav1.5 IC 50 >1 µM
Figure 7. Nav1.7 modulators developed by Xenon; PX = PatchXpressÒ.72,73
administration of AZD3161 (10) in a Phase I UVIH burn study.56
Tetrodotoxin (TTX, Fig. 2), an injectable non-narcotic marine
neurotoxin, is being advanced in Phase II/III clinical trials for the
treatment of cancer related pain. TTX was originally developed at
Wex Pharmaceuticals followed by a collaboration with Esteve.29,57
XEN402 (9) is a novel topical Nav1.7 sodium channel blocker in
3696
S. K. Bagal et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3690–3699
F
O
O O O
S
N
N
H
N
Cl
F
O
O O O
S
N
H
O
Cl
WO2014008458
Nav1.7 PX IC50 0.0021 µM
Nav1.5 PX IC50 1.2 µM
WO2013177224
Nav1.7 PX IC 50 0.0038 µM
Nav1.5 PX IC 50 1.07 µM
Figure 8. Nav1.7 modulators developed by Xenon and Genentech PX = PatchXpressÒ.74,75
F
F
O O S
S
N
N
H
F
H
N
N
O O
S
N
H
N
O
N
O
N
N
O
Daiichi Sankyo
WO2013118854
Nav1.7 IWQ IC 50 0.0026 µM
Merck
WO2013063459
Nav1.7 PX IC 50 4 nM
Nav1.5/1.7 ratio 5541
Figure 9. Nav1.7 modulators developed by Merck; PX = PatchXpressÒ; IWQ = IonWorksÒ.76,77
Cl
O
O
OH
N
O
N
F
F
OH
OH
WO2013136170
FLIPR Nav1.7 IC50 0.133 µM
OH
N
NH2
O
WO2013072758
FLIPR Nav1.7 IC50 0.067 µM
EP Ki 0.027 µM
O
O
OH
N
F
O
N
F3C
NH 2
OH
N
N+
O
N
H
WO2013064884
FLIPR Nav1.7 IC50 0.872 µM
EP Ki 6.03 µM
WO2013064883
FLIPR Nav1.7 IC50 0.244 µM
EP Ki 0.347 µM
F
O
HN
O
N
Cl
N
HN
NH2
F
O
NH2
WO2013030665
FLIPR Nav1.7 IC50 0.18 µM
EP Ki 0.016 µM
N
O
N
H
N
O
N
H
O O
S
WO2012085650
FLIPR Nav1.7 IC50 0.14 µM
EP Ki 0.019 µM
Figure 10. Nav1.7 modulators developed by Purdue; FLIPR = fluorescence based assay; EP = Electrophysiology (platform unknown).78–83
Phase II clinical evaluation at Xenon Pharmaceuticals. Xenon has
reported positive Phase II readouts where topical application of
XEN402 reduced pain in patients suffering from primary erythromelalgia and in patients suffering from postherpetic neuralgia.58,59
Results from an oral Phase II study with XEN402 suggested positive
effects in the dental model of acute inflammatory pain. XEN402
has been granted orphan drug designation by the FDA for the treatment of erythromelalgia. Moreover, the product was licensed to
Teva by Xenon Pharmaceuticals in 2012 on a worldwide basis for
the treatment of pain and is now called TV-45070. XEN403 has
been presented as a backup candidate of XEN402/TV-45070 for
the potential oral treatment of pain, although there have been no
recent updates.60
The accurate isoform selectivity and biophysical characteristics
of many of the clinical compounds described above that are
advancing through clinical efficacy trials have not been disclosed.
3697
S. K. Bagal et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3690–3699
O
H
N
O
CF 3
N
H
N
N
H
N
O
CF3
Schering
WO2012047703
FLIPR Nav1.7 IC 50 0.237 µM
Zalicus
WO2013131018
Nav1.7 PX IC50 1.150 µM
Cl
O
F3CO
N
N
O
O
Cl
N N
N
Shionogi
WO2013161929
FLIPR Nav1.7 IC50 0.77 µM
Shionogi
WO2013161928
FLIPR Nav1.7 IC 50 0.62 µM
N
H
Figure 11. Other Nav1.7 directed compounds; FLIPR = fluorescence based assay.84–87
O
H
N
N
N
H
N
O
N
O
O
CF3
N
WO2012053186
F3 C
O
O
N
H
N
N
H
F3C
N
O
N
N
HN
WO2013161312
O
O
WO2013161308
Figure 12. Compounds reported by RaQualia as TTX-S Nav inhibitors.88–90
O
N
N
N
N
H
O
F3C
WO2013179049
Qpatch v1/2 Nav1.7 pIC50 6.4
H
N
N
O
WO2013175206
WO2013175205
Qpatch v1/2 Nav1.7 pIC50 5.7
N
WO2013093496
WO2013093497
Qpatch v1/2 Nav1.7 pIC50 5.5
HN
OCF3
O
N
Figure 13. Nav1.7 modulators developed by Convergence.91–95
The hope is that new agents with greater subtype or functional
selectivity will achieve therapeutic utility with decreased cardiovascular and CNS risks.
Outlook and summary: Sodium channel drug discovery is an
exciting and developing field of science. It appears that pharmaceutical investment in this target class in the search for pain therapeutics is driven by two major parameters: genetic data linking
Nav mutations to pain phenotypes for target validation and the
ability to express stable cell lines and establish effective screen
sequences. For example, recent Nav1.9 genetic data may be
expected to lead to an explosive pharmaceutical effort in the same
vein as Nav1.7. However, this work will be significantly hindered
until stable Nav1.9 expressing cell lines are available for adequate
screening. Screening methods vary greatly across the pharmaceutical sector and it is often unclear which protocol is the most predictive for efficacy in a clinical disease setting. Hopefully, as clinical
data emerge this screening effort can be condensed to identify
the most relevant approach for preclinical in-vitro to clinical invivo translation. Finally, prospective Nav drug design is complicated by the variety of available Nav binding sites across multiple
3698
S. K. Bagal et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3690–3699
O
O
F3 C
N
N
N
O
O
N
O
N
O
N
O
F2 C
WO2012125613
WO2014022639
WO2012106499
O
N
N
O
S
O
O
WO2013109521
Figure 14. Compounds developed by Vertex with reported IC50 <2 lM inhibition against a sodium channel.49,96–98
Table 1
Nav channel modulators that have reached clinical development for the treatment of pain
Compound
Company
Pharmacology
Phase
Therapeutic indication
Refs.
AZD3161
CNV1014802
AstraZeneca
Convergence
Nav1.7
Nav1.7
I
II
56
50
DSP-2230
NKTR-171
PF-04531083
PF-05089771
TTX
XEN402
XEN403
Dainippon Sumitomo
Nektar
Pfizer
Pfizer
WEX
Xenon/Teva
Xenon
Nav1.7/1.8
Broad Nav
Nav1.8
Nav1.7
TTX-S Nav
Nav1.7
Nav1.7
I
I
I
II
III
II
I
Neuropathic/Inflammatory pain (IV, intradermal)
Neuropathic pain
Trigeminal neuralgia (oral)
Neuropathic pain (oral)
Neuropathic pain (oral)
Neuropathic/Inflammatory pain (oral)
Neuropathic/Inflammatory pain erythromelalgia (oral)
Neuropathic/Inflammatory cancer pain (IV)
Neuropathic/Inflammatory pain erythromelalgia (topical)
Neuropathic/Inflammatory pain erythromelalgia (oral)
O
F
N
H
O
O
O
O
F3C
O
N
H
N
O
Convergence
CNV1014802 (8)
O
O
NH2
N
N
Xenon
XEN402 (9)
54
55
53
52
57
58–59
60
O
CF3
N
O
Astrazeneca
AZD3161 (10)
Figure 15. Nav channel modulators in clinical development for the treatment of pain.
ion channel states. Perhaps the recent significant advances made in
Nav structural biology coupled with the improved high quality
screening capabilities can address this challenge to ultimately
enhance the discovery of pharmaceutically relevant Nav based
painkillers.
Acknowledgments
The authors would like to acknowledge the contribution of
Kiyoyuki Omoto in the preparation of this article.
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