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Discovery of Vixotrigine: A Novel Use-Dependent Sodium Channel

Blocker for the Treatment of Trigeminal Neuralgia
David R. Witty,* Giuseppe Alvaro, Dominique Derjean, Gerard M. P. Giblin, Kevin Gunn, Charles Large,
David T. Macpherson, Valerie Morisset, Davina Owen, Joanne Palmer, Francois Rugiero, Simon Tate,
Christopher A. Hinckley, and Himanshu Naik

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ABSTRACT: Drugs that block voltage-gated sodium channels (NaVs)

Downloaded via UTRECHT UNIV on October 8, 2020 at 20:54:50 (UTC).

have utility in treating conditions including pain, epilepsy, and cardiac

arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin.
Ther. Pat.201020755779). The identification of compounds with
improved efficacy and safety is a key aim for the discovery of improved
NaV blocking drugs (Comprehensive Medicinal Chemistry III; Elsevier,
2017; pp 131−175). We report the identification of a novel class of brain
penetrant and voltage-gated sodium channel blockers, leading to the
discovery of vixotrigine, a use-dependent sodium channel blocker with
activity in in vivo models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical
and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a
Phase II study for pain associated with trigeminal neuralgia.
KEYWORDS: Use-dependent, state-dependent, sodium channel blocker, NaV, trigeminal neuralgia, analgesic

■ INTRODUCTION
The mechanism of action of several drugs in current clinical
practice is, at least in part, due to nonselective blockade of
voltage-gated sodium channels.1−4 For example, lamotrigine5
for epilepsy and bipolar disorder and carbamazepine6 for
epilepsy and trigeminal neuralgia are characterized as non-
selective sodium channel blockers. However, the utility of these
drugs is limited by side effects and multiple drug−drug
interactions that require careful and prolonged titration to the
effective clinical dose. Hence there is a need for sodium channel
blockers with improved safety profiles.
Within the mammalian genome, nine subtypes of the voltage-
gated sodium channel (designated NaV1.1−NaV1.9) have been
identified and cloned.7 Physiological and human genome-wide
association studies have identified mutations of several NaV
subtypes in a range of diseases (“channelopathies”).8 For
example heteroallelic mutations in the SCN4A gene encoding
the α-subunit of NaV1.4 (the skeletal muscle sodium channel)
have been associated with a myasthenic (fatigue and weakness)
syndrome.9 Of particular focus, various NaV mutations have
been implicated in different types of pain; several mutations in
the human SCN9A gene, encoding the α-subunit of the NaV1.7
channel, have been found to be causative for primary
erythromelalgia,10 an autosomal dominant neurological disorder
characterized by severe burning pain and erythema. Further-
more, SCN9A and SCN10A (encoding NaV1.8) are both
genetically associated11 with painful small fiber neuropathy due
to dorsal root ganglion neuron hyperexcitability.
Trigeminal neuralgia12,13 is a rare disease associated with
intense, unilateral facial pain characterized by electric shock-like
episodes linked to entrapment of the trigeminal nerve. 150,000
cases are diagnosed in the United States each year. Treatment
options for this debilitating condition include microvascular
decompression surgery, which risks facial numbness and
paralysis, or drug treatment with carbamazepine or oxcarbaze-
pine. These agents are nonselective voltage-gated sodium
channel blockers but are poorly tolerated, and their use is
hampered by multiple clinically relevant drug−drug interactions
and the active pharmacology of their metabolites.14
Our goal was to identify a NaV blocker with potential utility in
the treatment of neuropathic pain, including trigeminal
neuralgia and other CNS disorders. Pain is associated with
high frequency nerve signaling and our hypothesis is that
preferential binding to the inactivated state of the sodium
channel should favor high frequency blockade and give
Received: May 17, 2020
Accepted: July 16, 2020
Published: July 16, 2020

© 2020 American Chemical Society https://dx.doi.org/10.1021/acsmedchemlett.0c00263

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ACS Medicinal Chemistry Letters
Figure 1. NaV pharmacophore generation and selected published NaV blockers.
selectivity over normal physiological signaling at lower firing
frequencies. Achieving a sufficient degree of inactivated-state
block of sodium channels was targeted for optimal safety and
efficacy. This is measured by the use-dependence and voltage
dependence of the channel inhibition.15 Furthermore, based on
genetic association studies, by targeting state dependence we
were aiming for enhanced NaV blockade in neurons with
pathologically elevated activity, while sparing channels asso-
ciated with low frequency activities such as cardiac function.16
Importantly, we chose to optimize for CNS penetration on the
basis that nociceptors express a variety of NaV subtypes, and
blockade of brain sodium channels (NaV 1.1, 1.2, 1.3) is highly
precedented17 for efficacious NaV blockers. We thereby sought
to harness the proven mode of action of existing sodium channel
blockers while significantly improving the therapeutic index and
side effect profile.
In summary, we targeted compounds with preferential
binding to the inactivated state of relevant sodium channels;
selectivity over the hERG channel;18 and pharmacokinetic
properties suitable to support oral dosing and efficient brain
exposure with low potential for clinically relevant drug−drug
interactions.
■
DISCOVERY
A requirement for an improved safety profile, including avoiding
the need for dose titration,19 led us to look for starting points
structurally differentiated from currently marketed drugs. A high
throughput FLIPR screen was conducted using cells expressing
the brain sodium channel NaV1.2 to find general chemotypes
with sodium channel blocking activity. Hits were assessed for
their tonic and use-dependent block on an Ionworks platform
using the NaV1.3 channel as a surrogate for brain sodium
channels. Tonic block was assessed by measuring the effect of
test compounds on the peak current elicited by the first pulse in a
10 Hz pulse train at a range of concentrations, from which a
pIC50 was determined.20 The use-dependent block was assessed
on the final pulse, and data presented here show the negative log
of the concentration that caused a 15% inhibition of the sodium
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current (pUD15). The ratio of UD15 to IC50 is reported as the
Tonic Selectivity (TS).
A pharmacophore for use-dependent sodium channel block-
ers emerged in which a lipophilic aromatic group was linked to a
basic amine or polar heterocycle, which was in turn linked to an
amide or amide isostere (Figure 1). This was precedented in the
published literature with the compounds ralfinamide and
safinamide reported to be state dependent blockers by
Newron.21 In addition the Abbott compound A-803467 and
Merck’s rufinamide, mapping to this pharmacophore, are
reported as NaV1.8 and NaV1.7 blockers, though for rufinamide
no channel selectivity is claimed.22,23
Following this analysis, an N-benzyl glycinamide scaffold was
chosen as a minimum template with both tonic and use-
dependent block of NaV1.3 to examine for optimization through
substitution and derivatization. Compound 1, an unsubstituted
N-benzyl glycinamide, incorporating the precedented para 2-
fluorobenzyloxy group, was synthesized and showed modest
tonic and reasonable use-dependent block of NaV1.3 (Table 1).
We hypothesized that conformational restriction around the
benzyl-amino-amide feature could be associated with enhanced
state-dependency, improved tonic selectivity, and better
chemical developability properties. Our strategy was to induce
conformational restriction of this simple template (Figure 2) to
build the targeted profile. This starting point had the additional
advantage of good solubility and reasonable synthetic
accessibility, favoring a lead optimization campaign.
Conformationally constrained amides were selected by
introducing cyclization along the benzyl glycinamide backbone:
between the amide nitrogen and either the α-position or the
basic nitrogen (A), from the aromatic ring on to the glycinamide
backbone (B), and between positions α- to the amino nitrogen
(C) (Figure 2). In order to maintain developability properties
within a range suitable for a brain penetrant drug, we targeted
analogs with clogP values between 2 and 3.5 and with molecular
weight below 400. The 2-fluorobenzyl substituent was
maintained as a 2-fluoro benzyl or benzyl group.
A. Cyclization between the amide nitrogen and the basic
nitrogen gave analog 2, which showed no significant sodium
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Table 1. Selected Constrained Benzyl Glycinamides
channel blockade. Cyclization through the glycine α-carbon
resulted in compound 3, which retained some use-dependent
block, but at a significantly lower level than 1 and with very low
tonic block (Table 1).
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B. Constraint of the benzylic position was investigated by
cyclization onto the central aromatic ring, either through
nitrogen (4−10) or benzylic carbon (11−13), while retaining
an unsubstituted amide. Ring systems incorporating the amino
nitrogen and branching at nitrogen (4−8) gave markedly
reduced tonic block at NaV1.3. Similar compounds in which the
amide group was attached α to the nitrogen (9, 10) still showed
significantly reduced use-dependent block relative to benzyl
glycine 1. Exocyclic amines in which the benzylic position alone
was constrained (11, 12) were relatively potent tonic blockers of
NaV1.3 and showed significant use-dependent block. Interest-
ingly, however, an oxygen atom in the heterocyclic constraint,
forming a benzopyran system (13), led to a loss of sodium
channel blockade.
C. A further constraint incorporated the amino nitrogen into a
discrete pyrrolidine ring. Isomers of structure 14 maintained
blockade of NaV1.3 with good tonic selectivity. Isomers of
compound 15, incorporating a tertiary nitrogen, had higher use-
dependent block, while the proline derivative 16 gave the
highest use-dependent block in the series with a tonic selectivity
of 64.
Compounds 11, 12, and 14−16 were selected for further
profiling and series optimization. Individual isomers were
prepared, their ADME properties investigated, and hERG
inhibition profile examined to evaluate series properties and
liabilities. Specific indanes and tetrahydroquinoline isomers
related to 11 and 12 had a low potential for hERG blockade and
showed low microsomal clearance; however, they proved to be
inhibitors of cytochrome P450 isoforms. Modification with
additional alkyl substituents typically led to much higher hERG
inhibition or increased rat microsomal clearance. Analogs of 15
or 16 possessing a tertiary pyrrolidine ring were associated with
high clearance in rat microsomes. Attempts to block
metabolically vulnerable positions adjacent to the basic nitrogen
by alkyl substitution typically gave rise to higher hERG
inhibition, and compounds of this class were reported to have
other off-target activities.24,28
In contrast, the individual isomers of 14, compounds 17−20,
while showing broadly similar use-dependent block of NaV1.3,
possessed differential effects in their other properties (Table 2).
Syn-isomers 17 and 20 showed a trend toward lower blockade of
hERG while, interestingly, there was a clear diastereomeric
preference for the 2-(S)-stereochemistry alpha to the carbonyl
(19, 20) giving the lowest rat microsomal clearance. Of these
analogs 2-(S)-5-(R) isomer 20 had the most attractive overall
profile exhibiting a tonic selectivity of 31, and an analog program
was initiated around 20 while maintaining clogP values between
2.5 and 3.5. In addition to measuring rat clearance and hERG
inhibition, in a number of cases, the potential for brain exposure
was assessed by measuring the fraction unbound in rat plasma
and brain tissue (Table 3).
Changing the ring from a pyrrolidine to a piperidine (21, 22
absolute stereochemistry unassigned) led to a significant
increase in NaV1.3 tonic block, but reduced tonic selectivity
(21) or increased hERG inhibition (22). Thiomorpholine 23, in
contrast, showed poorer use-dependent block. Analogs of 20 in
which the fluorine atom was removed (25), or moved to a meta-
substituted (24) or para-position (26), maintained good use-
dependent NaV block but with a trend for increased hERG
inhibition. More generally, increased hERG inhibition was
observed for the more lipophilic compounds, but an attempt to
reduce lipophilicity by introducing a cyano group as a terminal
benzyl substituent had little impact at any positional isomers
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Figure 2. Targeted contraints of benzyl glycinamides.
Table 2. Isomers of Phenyl Prolineamide 14
(27−29) although the ortho example 29 possessed the best
overall profile. Substitution on the benzylic methylene increased
hERG affinity in compound 30, but fluoro analog 31 maintained
a good state-dependent profile, although tonic block was
marginal. Alkylation of the pyrrolidine nitrogen (32) markedly
reduced state-dependent activity.
Substitution in the 3-position of the central aromatic ring was
also examined in order to modulate hERG inhibition; however,
both methoxy analog 34 and cyano analog 35 gave reduced use-
dependent block relative to the unsubstituted 20. A central ring
pyridyl analog 36 was also detrimental to use-dependent NaV
blockade. Replacement of the terminal benzyl ether with a
phenyl ether was tolerated in analog 37 and a range of
substituted analogs (38−40) was prepared; however, the
unsubstituted ether 37 had the best overall profile. Finally,
repositioning the terminal aromatic-containing group meta led
to reduced sodium channel block, for both phenyl ether 41 and
benzyl ether 42.
Compound 31 was not progressed as some tonic block was
believed to be important to modulate overall physiological
channel tone. Four compounds with high brain tissue binding,
meeting the criteria of tonic block greater than 4, tonic selectivity
greater than 10-fold, rat microsomal clearance less than 2.0 mL/
min/g, and hERG pIC50 less than 5.0, were progressed into rat in
vivo exposure studies, to determine clearance and bioavailability
and measure tissue distribution in in vitro studies (Table 4).
Three compounds showed oral bioavailability greater than
30% and were analyzed for brain penetrance. The more polar
analog 29 showed a brain:blood ratio of less than 1 but 2-
fluorobenzyloxy- and 4-fluorobenzyloxy analogs 20 and 26
achieved high brain penetration. Isomer 26 was highly cleared in
vivo, but compound 20 had good oral bioavailability and
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moderate clearance. This compound was therefore selected for
further studies
The interaction of 20 with binding sites on 130 receptors, ion
channels, transporters, and enzymes was examined in a
radioligand binding cross screening panel. The pan-sodium
channel inhibition profile of this compound is reported
separately.25 The most significant off-target interaction was
inhibition of MAO-B. This activity was confirmed in human liver
microsomes where 20 inhibited MAO-B enzyme activity with a
pIC50 of 8.4. In contrast 20 had no measurable inhibitory effect
on MAO-A enzyme activity (pKi < 5).
■ SYNTHESIS
Compounds in these studies were prepared by a variety of
general routes typified by A−E shown in Scheme 1. Where
nonstereoselective syntheses were performed, compounds were
separated by chiral reverse phase HPLC. The absolute
stereochemistry of compound 20 was confirmed by single
crystal X-ray crystallography.26
Benzyl glycinamides were synthesized by adapting a number
of published methodologies (Scheme 1). Two main strategies
were employed. Reductive amination of an appropriate aldehyde
A1 or ketone A2 with a glycine amide27 or prolinamide24
(Route A) was used for 1−3, 11, and 16. Alternatively (Route
B) alkylation of a benzylic amine such as B128 with an
appropriate acetic ester bearing a leaving group alpha to the
carbonyl, followed by amidation of the ester provided a route to
4−8. The right-hand side benzyl ether could be introduced by
alkylation of the corresponding hydroxyaromatic, undertaken
either prior to introducing the glycine component or with a
suitably protected glycine in place (Route C). Thus, amines of
structure C1 (for 12 and 13) could be prepared from parent
heterocycles by ether formation then reduction. Likewise
compounds of generic structure D1, in which the glycine
nitrogen is in a ring fused to the central aromatic group (e.g., 9,
10), are accessible by alkylation and amidation of corresponding
heterocycles (Route D).29 Compounds in which the benzylgly-
cinamide nitrogen was also linked to the benzylic position by a
pyrrolidine ring (e.g., 15) were accessible (Route E) by
reductive cyclizations onto carbonyl precursors.30
For certain analogs, enantiomeric mixtures were separated by
reverse phase chiral chromatography; however, an enantiose-
lective route to the isomers of compound 14 (compounds 20
and its analogs) was developed, illustrated in Scheme 2.31 Chiral
Boc-protected (S)-pyroglutamate 43 was treated with the
organolithium reagent formed from 4-benzyloxy-1-bromoben-
zene 44 at low temperature to furnish the ketone adduct 45.
Deprotection under acidic conditions formed the cyclic 2H-
pyrrolidine 46. Stereoselective reduction of the double bond
over a platinum catalyst installed predominantly the 2(S)-
stereogenic center in 47. Hydrolysis and reprotection with Boc
gave acid 49 which could be amidated to give 50 and the benzyl
group removed by a second hydrogenation, this time over
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Table 3. Analogs of Phenyl Prolinamide 20 Table 4. Rat Clearance, Tissue Penetration, and Oral
Bioavailability
Entry Blood Clb (mL/min/kg) Brain:Blood ratioa % F(po)
20 39 6.8 43
26 91 3.5 31
29 37 0.8 39
37 40 4.8 25
a
Total by equilibrium dialysis.

diastereomers 17 and 18 was accessed by using the (R)

enantiomer of 43 in the procedure.
Using the methodology of Scheme 2, the different aromatic
right-hand groups of 21−30 could be introduced by alkylating
intermediate 51 with the corresponding substituted benzyl
bromide. Analogs 21−23 could also be prepared using this route
by employing piperidine or thiomorpholine analogs of Boc-
pyroglutamic acid. Analogs 31 and 34−36 could be prepared by
using a corresponding bromoaromatic in place of 4-benzylox-
ybromobenzene 44 in the lithiation step. Reductive alkylation of
20 with formaldehyde gave 32. Amidation of ester 47 with
ammonia gave 42 and with methylamine gave compound 33.
A more efficient and scalable route to 20 was subsequently
developed (Scheme 3) in which a Grignard formed from 4-(2-
fluorobenzyoxy)-4-bromobenzene 53 was reacted with pyro-
glutamate 43. Hydrolysis of the resulting Boc-protected ketone
54 gave an imine 55 which could be stereoselectively
hydrogenated to ester 56. Aminolysis of this ester and
precipitation of the resulting amide as a hydrochloride salt
furnished 20. Analogs of 20 containing phenyl ethers (37−41)
can be accessed by using an appropriate bromophenyl ether in
place of benzyl ether 53. The details and yields for Scheme 3 and
the further development of efficient routes to 20 are described
elsewhere.32

■ PHARMACOLOGY
Compound 20 was evaluated in the chronic constriction injury
(CCI) model of neuropathic pain by oral administration at 0.5
or 5 mg/kg, BID. It significantly reversed mechanical allodynia
after 6 and 8 days of dosing (Figure 3) starting during day 22.
Mean free plasma concentrations of 20 achieved on Day 8 at 0.5
h postdose were 1.9 ng/mL and 23.4 ng/mL at 0.5 and 5 mg/kg,
respectively. In the same study, gabapentin (30 mg/kg orally
BID) was dosed as a positive control and significantly inhibited
CCI induced mechanical allodynia on days 1, 6, and 8 of dosing.
Compound 20 was also evaluated in the Complete Freund’s
Adjuvant (CFA) in vivo model of inflammatory pain. After single
oral doses, it produced a dose-related reversal of the established

palladium, to give a versatile phenolic intermediate 51.

Alkylation of this material to 52 followed by removal of the
Boc protection afforded carboxamide 20 as the crystalline
hydrochloride salt. The benzylic epimer 19 could be prepared by
taking the minor isomer from the imine reduction (48) through Figure 3. Compound 20 CCI induced static allodynia (0.5 h post
the later stages of this sequence. The corresponding pair of dose).

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Scheme 1. Synthetic Routes to Benzyl Glycinamidesa

a
Typical reagents and conditions: (a) R1-benzyl-bromide, K2CO3, MeCN; (b) NaH3CN, MeOH, AcOH, substituted glycinamide; (c) LAH, THF;
(d) DIPEA, THF, TfO−CH(R3)CO2Et; (e) NH3, MeOH; (f) NH2OMe, EtOH then LiBH4, ZrCl4, THF; (g) Boc2O, THF; (h) TBTU, HMDS,
DIPEA, DMF; (i) TFA, DCM.

CFA-induced hypersensitivity to pain, as measured by weight
bearing. The ED50 for this effect was 0.91 mg/kg. A dose of 1
mg/kg po was associated with a mean free plasma concentration
of 7.8 ng/mL at 1 h postdose. A second experiment was
conducted in the CFA-induced knee joint model of subchronic
inflammation. At an oral dose of 1 mg/kg BID, 20 showed a
reversal of hypersensitivity that was equipotent to the effect
produced by the nonsteroidal anti-inflammatory drug celecoxib
over the 5 day dosing period.
In order to assess the centrally mediated side-effects such as
sedation or ataxia, 20 was tested in a model of spontaneous
locomotor activity (sLMA) of male rats. It was administered
orally at doses of 60, 100, or 300 mg/kg, 30 min before the test
session. No significant reduction in sLMA was observed with a
dose of 60 mg/kg. The mean plasma concentration of 20 60 min
postdose was 13.1 μg/mL. Higher doses of 100 or 300 mg/kg of
20 significantly reduced locomotor activity, a typical CNS side
1683
effect associated with NaV channel blockers. We concluded that
20 has a substantial therapeutic index (TI) between plasma
exposures associated with central side effects and exposures
required to demonstrate efficacy in the in vivo pain models.
The pharmacokinetics of 20 following a single intravenous
and an oral dose were investigated in the rat, dog, marmoset, and
monkey. A summary of the derived pharmacokinetic data is
provided in Table 5. Blood clearance of 20 was moderate in rat
and dog (46% and 39% of liver blood flow, respectively) and low
(11% of liver blood flow) in monkey. The volume of distribution
at steady state (Vss) was in excess of total body water in all
species, suggesting moderate to extensive tissue distribution and
resulting in half-lives of 0.8, 2.2, and 5 h in rat, dog, and monkey,
respectively.
The physicochemical properties of 20 lie within CNS drug-
like space (MW 314.4 Da; cLogP 1.6 and pKa 7.6). These
properties confer excellent aqueous solubility (solubility of HCl
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Scheme 2. Enantioselective Synthesis of Compound 20a

a
Reagents and conditions: (a) nBuLi, THF, −78 °C; (b) 43 −40 °C; (c) TFA, DCM; (d) H2, Pt/C, MeOH; (e) (i) LiOH aq THF; (f) Boc2O,
THF; (g) TBTU, DIPEA, DMF, HMDS; (h) H2 Pd/C MeOH; (i) (2-F)-benzyl bromide, K2CO3, MeCN; (j) AcCl, MeOH, EtOAc.

Scheme 3. Scalable Route to 20a

a
Reagents and conditions: (a) Mg, I2, THF, −60 °C, BrCH2CH2Br; (b) 43, THF; (c) NH4Cl/brine/IPA; (d) TFA, DCM (e) KHCO3, H2O, n-
heptane; (f) H2, 5%Pt/C, EtOAc/TFA; (g) NaHCO3, H2O, MeOH; (h) NH3 in MeOH, (i) toluene, n-heptane; (j) HCl, EtOAc.

salt: water 16.3 mg/mL; FeSSIF 6.9 mg/mL) and high
membrane permeability (Papps = 386 nm/s at pH 7.4) in the
MDCK cell assay. 20 has been assigned BCS Class I (high
solubility, high permeability).
Compound 20 has a low potential for clinically relevant drug−
drug interactions. Against a panel of CYP450 enzymes, it
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showed low levels of inhibition (pIC50: 1A2, 13 μM; 2A6, >100
μM; 2B6, 31 μM; 2C8, >100 μM; 2C9, >100 μM; 2C19, 79 μM;
2D6, >100 μM; 3A4, >100 μM vs atorvastatin, mizazolam, and
nifedipine). Furthermore in the same panel of CYP450 enzymes
it showed no time/mechanism dependent inhibition. Up to
concentrations of 100 μM, 20 is not an inhibitor of P-
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Table 5. Exposure of Compound 20 across Species (n = 3)
Species Route Dose(mg/kg) Tmax (h) Cmax (ng/mL)
Rat IV 0.5
Oral 3 0.5 226
Dog IV 0.5
Oral 3 0.75 705
Monkey IV 0.5
Oral 3 2 730
Figure 4. Plasma concentration−time profile for 20.
glycoprotein and is not an inhibitor of OATP1B1, BCRP,
OATP1B3, OAT1, or OCT2.
After successful first-time-in-human enabling studies (genetic
toxicology, safety pharmacology, and 28-day repeat dose
toxicology in rat and dog) 20 was progressed into clinical
Phase I studies in healthy volunteers. A single ascending dose
study demonstrated that 20 had a good tolerability profile and
was well absorbed with a dose related increase in exposure
(Figure 4).33 In a repeat dose study, steady state blood levels
were achieved rapidly and 20 exhibited a 12 h half-life consistent
with twice-daily dosing.34
■
CONCLUSION
In summary, we report the discovery of 20, now vixotrigine,35 a
novel use-dependent voltage-gated sodium channel blocker with
MAO-B activity. Vixotrigine has broad spectrum in vivo
antihyperalgesic efficacy. It has successfully completed ICH
mandated toxicology, genotoxicity, and safety pharmacology
studies and, subsequently, a suite of Phase I human volunteer
studies. Vixotrigine is well tolerated in humans at predicted
pharmacologically active exposures and shows rapid absorption,
high oral bioavailability, and a half-life of 12 h in humans
sufficient to support BID or TID dosing in the clinic. A Phase II
study has been conducted showing efficacy in Trigeminal
Neuralgia and is reported elsewhere.36
■ AUTHOR INFORMATION
Corresponding Author
David R. Witty − Convergence Pharmaceuticals Ltd., a Biogen
Company, Babraham Research Campus, Cambridge CB22 3AT,
U.K.; orcid.org/0000-0002-5897-7370; Phone: +44 7717
800512; Email: david.r.witty@gmail.com
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t1/2 (h) Vss (L/kg) CLb (mL/min/kg) F (%)
0.8 2 39
43
2.2 2 12
57
5 2 5
42
Authors
§
Giuseppe Alvaro − Convergence Pharmaceuticals Ltd., a Biogen
Company, Babraham Research Campus, Cambridge CB22 3AT,
U.K.
Dominique Derjean − Convergence Pharmaceuticals Ltd., a
Biogen Company, Babraham Research Campus, Cambridge
CB22 3AT, U.K.
Gerard M. P. Giblin − Convergence Pharmaceuticals Ltd., a
Biogen Company, Babraham Research Campus, Cambridge
CB22 3AT, U.K.
Kevin Gunn − Convergence Pharmaceuticals Ltd., a Biogen
Company, Babraham Research Campus, Cambridge CB22 3AT,
U.K.
§
Charles Large − Convergence Pharmaceuticals Ltd., a Biogen
Company, Babraham Research Campus, Cambridge CB22 3AT,
U.K.
David T. Macpherson − Convergence Pharmaceuticals Ltd., a
Biogen Company, Babraham Research Campus, Cambridge
CB22 3AT, U.K.
Valerie Morisset − Convergence Pharmaceuticals Ltd., a Biogen
Company, Babraham Research Campus, Cambridge CB22 3AT,
U.K.
Davina Owen − Convergence Pharmaceuticals Ltd., a Biogen
Company, Babraham Research Campus, Cambridge CB22 3AT,
U.K.
Joanne Palmer − Convergence Pharmaceuticals Ltd., a Biogen
Company, Babraham Research Campus, Cambridge CB22 3AT,
U.K.
Francois Rugiero − Convergence Pharmaceuticals Ltd., a Biogen
Company, Babraham Research Campus, Cambridge CB22 3AT,
U.K.
Simon Tate − Convergence Pharmaceuticals Ltd., a Biogen
Company, Babraham Research Campus, Cambridge CB22 3AT,
U.K.
Christopher A. Hinckley − Biogen Inc., Cambridge,
Massachusetts 02142, United States
Himanshu Naik − Biogen Inc., Cambridge, Massachusetts 02142,
United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.0c00263
Notes
The authors declare the following competing financial
interest(s): D.W. holds stock in Biogen Inc. and was an
employee of Convergence Pharmaceuticals Ltd. and Biogen Inc.
at the time of the conduct of this work. His involvement ended
after leaving Biogen in 2017, except in the creation of this
manuscript.
§
C.L. and G.A. were project leaders on this work at
GlaxoSmithKline prior to the acquisition of this project by
Convergence Pharmaceuticals Ltd.
https://dx.doi.org/10.1021/acsmedchemlett.0c00263
ACS Med. Chem. Lett. 2020, 11, 1678−1687
ACS Medicinal Chemistry Letters
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pubs.acs.org/acsmedchemlett
ABBREVIATIONS
FU, fraction unbound; MAO, monoamine oxidase; ADME,
absorption, distribution, metabolism, and elimination; CCI,
chronic constriction injury; CFA, Complete Freund’s Adjuvant;
BID, twice a day; sLMA, spontaneous locomotor activity; ICH,
International Council for Harmonisation
■
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ACS Med. Chem. Lett. 2020, 11, 1678−1687