Ezogabine

Summary

Ezogabine (CHEMBL41355) is an approved small-molecule anticonvulsant (ATC N03AX21) targeting KCNQ2, KCNQ3, and KCNQ4; indicated across 6 conditions including epilepsy and visual epilepsy.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: N03AX21
• Targets: 4 (KCNQ2, KCNQ3, KCNQ4…)
• Indications: 6 conditions
• Clinical trials: 24
• Chemistry: 303.33 Da · C16H18FN3O2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL41355
Name	Ezogabine
Type	Small molecule
Max phase	4
FDA approved	no
PubChem CID	121892
ChEBI	CHEBI:68584
ATC	N03AX21
Molecular formula	C16H18FN3O2
Molecular weight	303.33
InChIKey	PCOBBVZJEWWZFR-UHFFFAOYSA-N

SMILES: CCOC(=O)NC1=C(C=C(C=C1)NCC2=CC=C(C=C2)F)N

IUPAC name: ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate

ChEBI definition: A substituted aniline that is benzene-1,2,4-triamine bearing ethoxycarbonyl and 4-fluorobenzyl substituents at positions N-1 and N-4 respectively. An anticonvulsant used to treat seizures associated with epilepsy in adults.

Pharmacological roles (ChEBI): anticonvulsant, potassium channel modulator.

Also known as: AWD-21360, D-23129, Ezogabine, GKE-841, GW-582892X, GW582892X, Potiga, Retigabina, Retigabine, Trobalt, WAY-143841, XEN-496

Patent coverage: 1,142 distinct patent families (3,996 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 3,431 (86%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
KCNQ2	Kv7.2	Activation	5.6	0%	O43526
KCNQ3	Kv7.3		6.2	0.1%	O43525
KCNQ4	Kv7.4		5.2	0.6%	P56696
KCNQ5	Kv7.5		5	1.2%	Q9NR82

Broader ChEMBL bioactivity targets: 8 (assay-derived). Sample: Voltage-gated potassium channel, KQT; KCNQ2(Kv7.2)/KCNQ3(Kv7.3), Potassium voltage-gated channel subfamily KQT member 2, Potassium voltage-gated channel subfamily KQT member 3, Potassium voltage-gated channel subfamily KQT member 5, Potassium voltage-gated channel subfamily KQT member 2, Potassium voltage-gated channel subfamily KQT member 4, Potassium voltage-gated channel subfamily KQT member 2/member 3, Potassium voltage-gated channel subfamily KQT member 2.

Bioactivity

ChEMBL activities: 21 potent at pChembl ≥ 5 of 22 total. Top 100 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
KCNQ2	6.46	EC50	350	nM	CHEMBL_ACT_18289928
KCNQ2	6.46	EC50	350	nM	CHEMBL_ACT_18673034
KCNQ3	6.37	EC50	430	nM	CHEMBL_ACT_5299044
KCNQ5	6.1	EC50	800	nM	CHEMBL_ACT_19259790
KCNQ2	6.03	EC50	930	nM	CHEMBL_ACT_19259781
Q9Z351	5.89	EC50	1300	nM	CHEMBL_ACT_13498720
Q9Z351	5.89	EC50	1300	nM	CHEMBL_ACT_1435027
Q9Z351	5.89	EC50	1300	nM	CHEMBL_ACT_155417
KCNQ3	5.76	EC50	1720	nM	CHEMBL_ACT_19259763
KCNQ3	5.74	EC50	1837	nM	CHEMBL_ACT_25698981
KCNQ4	5.7	EC50	1980	nM	CHEMBL_ACT_19259787
O88943	5.69	EC50	2040	nM	CHEMBL_ACT_24863749
KCNQ2	5.69	EC50	2040	nM	CHEMBL_ACT_25698979
O88943	5.66	EC50	2170	nM	CHEMBL_ACT_19173116
KCNQ3	5.6	EC50	2500	nM	CHEMBL_ACT_24783332
KCNQ5	5.46	EC50	3450	nM	CHEMBL_ACT_19173112
KCNQ3	5.41	EC50	3900	nM	CHEMBL_ACT_19259784
KCNQ2	5.38	EC50	4210	nM	CHEMBL_ACT_24734256
O88943	5.38	EC50	4150	nM	CHEMBL_ACT_24863751
KCNQ3	5.36	EC50	4380	nM	CHEMBL_ACT_19051146
KCNQ4	5.23	EC50	5900	nM	CHEMBL_ACT_19173108

Target pathways

Aggregated over 4 target gene(s): KCNQ2, KCNQ3, KCNQ4, KCNQ5.

Top Reactome pathways

12 total, by targets touching each:

Pathway	Targets	Genes
Neuronal System	4	KCNQ2, KCNQ3, KCNQ4, KCNQ5
Potassium Channels	4	KCNQ2, KCNQ3, KCNQ4, KCNQ5
Voltage gated Potassium channels	4	KCNQ2, KCNQ3, KCNQ4, KCNQ5
Developmental Biology	2	KCNQ2, KCNQ3
L1CAM interactions	2	KCNQ2, KCNQ3
Axon guidance	2	KCNQ2, KCNQ3
Interaction between L1 and Ankyrins	2	KCNQ2, KCNQ3
Nervous system development	2	KCNQ2, KCNQ3
Sensory processing of sound	1	KCNQ4
Sensory processing of sound by inner hair cells of the cochlea	1	KCNQ4
Sensory processing of sound by outer hair cells of the cochlea	1	KCNQ4
Sensory Perception	1	KCNQ4

Dominant GO biological processes

GO term	Targets
potassium ion transmembrane transport	4
monoatomic ion transport	4
potassium ion transport	4
monoatomic ion transmembrane transport	4
transmembrane transport	4
chemical synaptic transmission	2
sensory perception of sound	2
action potential	1
nervous system development	1
protein targeting	1
protein import into nucleus	1
exocytosis	1
endocytosis	1
gene expression	1
response to auditory stimulus	1

Indications & clinical

Indications

2 approved indications. FDA phase 4, plus an anticancer drug’s labelled cancer uses (which ChEMBL often logs at phase 3).

Indication	Phase	MONDO	EFO
epilepsy	4	MONDO:0005027	EFO:0000474
visual epilepsy	4	MONDO:0001386	HP:0001250

3 diseases in clinical trials (phase 1–3, investigational — not approved indications). Highest ChEMBL trial phase per disease; a non-cancer approved use is occasionally logged at phase 3 here.

Disease (in trials)	Phase	MONDO	EFO
major depressive disorder	2	MONDO:0002009	MONDO:0002009
depressive disorder	2	MONDO:0002050	MONDO:0002050
amyotrophic lateral sclerosis	2	MONDO:0004976	MONDO:0004976

1 further indication record had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 24.

Phase distribution

Phase	Trials
PHASE3	7
PHASE2	6
PHASE1	6
PHASE4	2
Not specified	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01607346	PHASE4	TERMINATED	An Open Label Study to Evaluate the Effects of Ezogabine/Retigabine Added to Existing Anti-epileptic Drug(s) on Urinary Voiding Function in Subjects With Partial Onset Seizures
NCT01721317	PHASE4	TERMINATED	Dose-Optimization, Adjunctive Treatment Study of Ezogabine/Retigabine Immediate Release in Partial-onset Seizures
NCT00232596	PHASE3	COMPLETED	Retigabine (Adjunctive Therapy) Efficacy and Safety Study for Partial Onset Refractory Seizures in Epilepsy
NCT00235755	PHASE3	COMPLETED	Retigabine Efficacy and Safety Trial for Partial Onset Refractory Seizures in Epilepsy
NCT01648101	PHASE3	TERMINATED	Assessment of the Efficacy and Safety of 2 Doses of Retigabine Immediate Release (900 mg/Day and 600 mg/Day) Used as Adjunctive Therapy in Adult Asian Subjects With Drug-resistant Partial-onset Seizures
NCT01668654	PHASE3	TERMINATED	Long-term, Open-label Safety Extension Study of Retigabine/Ezogabine in Pediatric Subjects (>= 12 Years Old) With POS or LGS
NCT01823159	PHASE3	COMPLETED	Cortical Excitability Changes Induced by Retigabine: a Transcranial Magnetic Stimulation Study
NCT04639310	PHASE3	TERMINATED	XEN496 (Ezogabine) in Children With KCNQ2 Developmental and Epileptic Encephalopathy
NCT04912856	PHASE3	TERMINATED	An Open-Label Extension of the Study XEN496 (Ezogabine) in Children With KCNQ2-DEE
NCT00612105	PHASE2	COMPLETED	Safety/Efficacy Study of Retigabine vs. Placebo in Post-Herpetic Neuralgia (PHN)
NCT00623415	PHASE2	TERMINATED	Flupirtine as Oral Treatment in Multiple Sclerosis
NCT01494584	PHASE2	TERMINATED	Study in Pediatric Subjects With Epilepsy
NCT02149836	PHASE2	COMPLETED	Study to Treat Major Depressive Disorder (MDD) With a New Medication
NCT02450552	PHASE2	COMPLETED	Clinical Trial of Ezogabine (Retigabine) in ALS Subjects
NCT03043560	PHASE2	COMPLETED	Study to Treat Major Depressive Disorder With a New Medication
NCT01450865	PHASE1	COMPLETED	Effect of the Kv7-channel Opener Flupirtine on the Excitability of Human Peripheral Myelinated Axons in Vivo
NCT01462669	PHASE1	COMPLETED	Crossover Study to Evaluate the Pharmacokinetics of Ezogabine/Retigabine in Taiwanese Subjects
NCT01480609	PHASE1	COMPLETED	Effect of Haemodialysis on the Pharmacokinetics of Ezogabine/Retigabine and Its N-acetyl Metabolite
NCT01583036	PHASE1	COMPLETED	An Open-label, Single-centre Study Evaluating the Pharmacokinetics of Digoxin Alone and When Administered at Various Doses of Ezogabine/Retigabine in Healthy Adults. The Pharmacokinetics of Ezogabine/Retigabine and the N-acetyl Metabolite of Ezogabine/Retigabine (NAMR) Will Also be Assessed
NCT01676246	PHASE1	COMPLETED	Pharmacokinetics, Metabolism and Analgesic Effects of Flupirtine
NCT01691872	PHASE1	WITHDRAWN	Pharmacokinetic Study of Retigabine Extended Release (XR) Formulation in Healthy Adult Japanese and Caucasian Subjects
NCT06971250	EARLY_PHASE1	COMPLETED	Peripheral KV7 Activation for Pain Relief
NCT01457989	Not specified	COMPLETED	Meta-Analysis Plan for Pooled Data for Studies VRX-RET-E22-303 and VRX-RET-E22-304
NCT01587339	Not specified	COMPLETED	Systematic Review: Retigabine for Adjunctive Therapy in Partial Epilepsy

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline or drug-level clinical/variant annotations in PharmGKB for this molecule.

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

4 molecules share ≥1 primary target. Top 4 by shared-target count:

Molecule	Source	Status	Shared targets
FLINDOKALNER	ChEMBL	Phase 3	KCNQ2, KCNQ3, KCNQ4, KCNQ5
FLUPIRTINE	ChEMBL	Phase 4 (approved)	KCNQ2, KCNQ3
AZETUKALNER	ChEMBL	Phase 3	KCNQ2
Quinidine	PubChem	Approved	KCNQ2