EZOGABINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C16H18FN3O2
Molecular Weight	303.3314
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CCOC(=O)NC1=CC=C(NCC2=CC=C(F)C=C2)C=C1N

InChI

InChIKey=PCOBBVZJEWWZFR-UHFFFAOYSA-N

InChI=1S/C16H18FN3O2/c1-2-22-16(21)20-15-8-7-13(9-14(15)18)19-10-11-3-5-12(17)6-4-11/h3-9,19H,2,10,18H2,1H3,(H,20,21)

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Description

Ezogabine (U.S. adopted name) or retigabine (international nonproprietary name) is one of a family of aminopyrroles with anticonvulsant activity. It is used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. The drug was approved by the European Medicines Agency under the trade name Trobalt and by the United States Food and Drug Administration (FDA), under the trade name Potiga. The mechanism by which ezogabine exerts its therapeutic effects has not been fully elucidated. In vitro studies indicate that ezogabine enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating KCNQ channels, ezogabine is thought to stabilize the resting membrane potential and reduce brain excitability. This mechanism of action is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including migraine, tinnitus and neuropathic pain. In vitro studies suggest that ezogabine may also exert therapeutic effects through augmentation of GABA-mediated currents.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
KCNQ (Kv7) potassium channel 10	Activator 1,447		1.6 µM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Partial-onset seizures 6	Secondary		Approved 8,583	POTIGA

C_max

Value	Dose	Analyte	Population
414 ng/mL	100 mg single, oral	EZOGABINE plasma	Homo sapiens
498 ng/mL	100 mg 2 times / day multiple, oral	EZOGABINE plasma	Homo sapiens
819 ng/mL	200 mg single, oral	EZOGABINE plasma	Homo sapiens
978 ng/mL	200 mg 2 times / day multiple, oral	EZOGABINE plasma	Homo sapiens
842 ng/mL	250 mg single, oral	EZOGABINE plasma	Homo sapiens
993 ng/mL	250 mg 2 times / day multiple, oral	EZOGABINE plasma	Homo sapiens
551.9 ng/mL	200 mg single, oral	EZOGABINE plasma	Homo sapiens
561 ng/mL	200 mg single, oral	EZOGABINE plasma	Homo sapiens
938.7 ng/mL	400 mg single, oral	EZOGABINE plasma	Homo sapiens
728.8 ng/mL	400 mg single, oral	EZOGABINE plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
1831 ng × h/mL	100 mg single, oral	EZOGABINE plasma	Homo sapiens
1914 ng × h/mL	100 mg 2 times / day multiple, oral	EZOGABINE plasma	Homo sapiens
5134 ng × h/mL	200 mg single, oral	EZOGABINE plasma	Homo sapiens
5279 ng × h/mL	200 mg 2 times / day multiple, oral	EZOGABINE plasma	Homo sapiens
5136 ng × h/mL	250 mg single, oral	EZOGABINE plasma	Homo sapiens
5184 ng × h/mL	250 mg 2 times / day multiple, oral	EZOGABINE plasma	Homo sapiens
3972.5 ng × h/mL	200 mg single, oral	EZOGABINE plasma	Homo sapiens
4393.8 ng × h/mL	200 mg single, oral	EZOGABINE plasma	Homo sapiens
7895.9 ng × h/mL	400 mg single, oral	EZOGABINE plasma	Homo sapiens
7355.9 ng × h/mL	400 mg single, oral	EZOGABINE plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
8.4 h	100 mg single, oral	EZOGABINE plasma	Homo sapiens
7.2 h	100 mg 2 times / day multiple, oral	EZOGABINE plasma	Homo sapiens
7.4 h	200 mg single, oral	EZOGABINE plasma	Homo sapiens
7 h	200 mg 2 times / day multiple, oral	EZOGABINE plasma	Homo sapiens
7.9 h	250 mg single, oral	EZOGABINE plasma	Homo sapiens
6.8 h	250 mg 2 times / day multiple, oral	EZOGABINE plasma	Homo sapiens
6.28 h	400 mg single, oral	EZOGABINE plasma	Homo sapiens
7.57 h	400 mg single, oral	EZOGABINE plasma	Homo sapiens

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
	inhibitor 2,438	inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 2,153 CYP2A6 879 CYP2C8 1,057 CYP2C19 2,057 CYP2E1 1,060 CYP3A4/5 296 P-gp 1,741	UGT1A1 479 UGT1A3 470 UGT1A9 423 UGT1A4 399 UGT1A6 343 UGT1A7 249 UGT1A10 331 UGT2B4 278 UGT2B7 456 UGT2B15 236 CYP 450 32 P-gp 2,052	CYP1A2 832 CYP3A4/5 133 CYP2C 17 P-gp 301

Drug as perpetrator

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Target	Modality	Activity	Metabolite
P-gp 1,932	inhibitor 4,027	likely	N-AMR 3
CYP1A2 2,333	inducer 1,966	no
CYP1A2 2,333	inhibitor 4,027	no
CYP2A6 911	inhibitor 4,027	no
CYP2C 37	inducer 1,966	no

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Drug as victim

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Target	Modality	Activity
CYP 450 32	substrate 4,014	no evidence
P-gp 2,052	substrate 4,014	no
UGT1A10 331	substrate 4,014	no
UGT1A6 343	substrate 4,014	no
UGT1A7 249	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:68584	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:68584
ChemicalBook	CB7506804	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7506804
eMolecules	2729733	https://www.emolecules.com/cgi-bin/more?vid=2729733
MolPort	MolPort-003-850-148	https://www.molport.com/shop/molecule-link/MolPort-003-850-148
ZINC	ZINC000000016154	http://zinc15.docking.org/substances/ZINC000000016154

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PubMed

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Title	Date	PubMed
		252160861
Characterization of KCNQ5/Q3 potassium channels expressed in mammalian cells.	2001 Jan	11159685
Influence of retigabine on the anticonvulsant activity of some antiepileptic drugs against audiogenic seizures in DBA/2 mice.	2001 Mar	11284448
Pharmacokinetic interaction between retigabine and lamotrigine in healthy subjects.	2003 Apr	12698305
The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain.	2003 Jan 24	12559370

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Patents

Sample Use Guides

In Vivo Use Guide

Potiga should be given orally in 3 equally divided doses daily, with or without food. The initial dosage should be 100 mg 3 times daily (300 mg per day) and should be increased gradually at weekly intervals by no more than 50 mg 3 times daily (increase in the daily dose of no more than 150 mg per day) up to a maintenance dosage of 200 mg to 400 mg 3 times daily (600 mg to 1,200 mg per day), based on individual patient response and tolerability.

Route of Administration: Oral

In Vitro Use Guide

KCNQ4 channels, stably expressed in HEK293 cells, were activated by retigabine (ezogabine) in a reversible and concentration-dependent manner in the concentration range 0.1-10 uM. Retigabine shifted the KCNQ4 channel activation curves towards more negative potentials by about 10 mV.

Show entries

Name

Type

Language

RETIGABINE

Preferred Name

English

EZOGABINE

Official Name

English

Retigabine [WHO-DD]

Common Name

English

POTIGA

Brand Name

English

AWD-21360

Code

English

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Classification Tree

Code System

Code

Established Pharmacologic Class

NDF-RT

N0000182729

Sec. 1308.11 Schedule V.

DEA NO.

2779

BRAIN DISEASES

EMA ASSESSMENT REPORTS

TROBALT (AUTHORIZED: EPILEPSY)

Designated

FDA ORPHAN DRUG

639118

Other antiepileptics

WHO-VATC

QN03AX21

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Code System

Code

Type

Description

PUBCHEM

121892

PRIMARY

MERCK INDEX

m5229

PRIMARY

Merck Index

HSDB

8171

PRIMARY

WIKIPEDIA

Retigabine

PRIMARY

IUPHAR

2601

PRIMARY

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ACTIVE MOIETY


					12G01I6BBU

EZOGABINE

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator