Ezogabine

Các tên gọi khác (9 ) :

D-23129
Ethyl {2-amino-4-[(4-fluorobenzyl)amino]phenyl}carbamate
Ethyl 2-amino-4-((P-fluorobenzyl)amino)carbanilate
EZG
N-(2-Amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester
N-(2-Amino-4-(4-fluorobenzylamino)phenyl)carbamic acid ethyl ester
Potiga
Retigabine
RTG

Thuốc chống co giật, chống động kinh

Thuốc Gốc

Small Molecule

CAS: 150812-12-7

ATC: N03AX21

CTHH: C₁₆H₁₈FN₃O₂

PTK: 303.3314

Ezogabine (D23129) is a close structural analog of the centrally acting analgesic flupitrine. It is a neuronal potassium channel opener being developed as a first-in-class antiepileptic drug (AED) and is currently being studied in Phase 3 trials as an adjunctive treatment for partial-onset seizures in adult patients with refractory epilepsy. FDA approved in June 10, 2011 under the name of ezogabine.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₁₆H₁₈FN₃O₂

Phân tử khối

303.3314

Monoisotopic mass

303.13830504

InChI

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)

InChI Key

InChIKey=PCOBBVZJEWWZFR-UHFFFAOYSA-N

IUPAC Name

ethyl N-(2-amino-4-{[(4-fluorophenyl)methyl]amino}phenyl)carbamate

Traditional IUPAC Name

retigabine

SMILES

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

Độ hòa tan

3.07e-02 g/l

logP

2.7

logS

-4

pKa (strongest acidic)

13.6

pKa (Strongest Basic)

3.99

PSA

76.38 Å²

Refractivity

87.02 m³·mol^-1

Polarizability

31.97 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

Rule of Five

true

Ghose Filter

true

pKa

10.8

Dược Lực Học : As compared to other antiepileptic agents, ezogabine is unique in that it selectively activates potassium ion channels Kv 7.2-Kv7.5 and not cardiac Kv 7.1, thereby avoiding cardiac side effects. The antiepileptics, as a drug class, are routinely used in the treatment of a number of disease states in addition to epilepsy. Ezogabine is highly efficacious in a broad-spectrum of in vivo epilepsy and seizure models. A comparison of antiepileptic form activity of ezogabine with that of conventional anticonvulsants in in vitro models suggests that retigabine is especially likely to be useful in the treatment of pharmacoresistant epilepsy. Retigabine clearly attenuates pain-like behaviors in various animal models of neuropathic pain; it may also prove to be useful in treatment of clinical anxiety disorders. Clinical data obtained thus far indicate that retigabine is well tolerated in humans when titrated up to its therapeutic dose range. No tolerance, drug dependence, or withdrawal liability has been reported. Thus, retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.

Cơ Chế Tác Dụng : Ezogabine (D23129) is a close structural analog of the centrally acting analgesic flupitrine. It is a neuronal potassium channel opener being developed as a first-in-class antiepileptic drug (AED) and is currently being studied in Phase 3 trials as an adjunctive treatment for partial-onset seizures in adult patients with refractory epilepsy. FDA approved in June 10, 2011 under the name of ezogabine. Ezogabine has a novel mechanism of action that involves opening of neuronal Kv7.2-7.5 (formerly KCNQ2-5) voltage activated potassium channels. These channels (primarily Kv7.2/7.3) enable generation of the M-current, a sub-threshold potassium current that serves to stabilize the membrane potential and control neuronal excitability. In addition to acting on potassium ion channels, retigabine also affects GABA neurotransmission in the GABA-A receptor, which is a key inhibitory receptor in the central nervous system and is implicated in epilepsy. Malfunctioning of the GABA-A receptor leads to hyperexcitability in the brain, which causes seizures, making this receptor an important target for antiepileptic therapeutics. Apart from increasing the concentration of GABA in the brain (by either enhancing GABA synthesis or blocking GABA metabolism), retigabine allosterically potentiates GABA-induced current in rat cortical neurons in a concentration-dependent manner. Numerous studies have demonstrated that retigabine is effective in a broad spectrum of in vivo epilepsy and seizure models.

Dược Động Học :

▧ Absorption :
Rapidly absorbed and distributed, with an absolute oral bioavailability of 60%. Pharmacokinetics of ezogabine suggest first-order kinetics. Tmax, single oral dose = 30-120 minutes; Time to steady state = 3 days
▧ Volume of Distribution :
8.7 L/kg
▧ Protein binding :
Approximately 80% protein bound.
▧ Metabolism :
Ezogabine is metabolized exclusively via phase II hepatic N-glucurodination and acetylation. N-glucurodination is the major metabolic pathway of the two and form two major N-glucuronide metabolites. The enzymes involved are UGT1A1, 1A9, 1A4, and 1A3. However, the product of the N-acetyl pathway is a weak, active metabolite referred to as NAMR. The enzyme that is involved in the N-acetyl pathway is called N-acetyltransferase 2. The pharmacokinetics of NAMR and ezogabine are similar. The cytochrome P450 enzyme system is not involved with the metabolism of ezogabine.
▧ Route of Elimination :
Urine (85%, 36% of total dose as unchanged drug, 18% of total dose as NAMR) and feces (14%, 3% of total dose as unchanged drug)
▧ Half Life :
Terminal half-life = 7.5 hours
▧ Clearance :
0.58 - 0.76 L/h·kg. Clearance may differ between ethnic groups with Black Americans having 20% lower clearance than Caucasian Americans.

Độc Tính : Lethal Dose, acute, oral, rat = 100 mg/kg; Lethal Dose, chronic, oral, rat = 5.1 mg/kg/day, 90-day; Most common adverse effects that lead to discontinuation of therapy include dizziness and somnolence.

Chỉ Định : Adjuvant treatment of partial-onset seizures.

Tương Tác Thuốc :

Carbamazepine Ezogabine increases the clearance of carbamazepine (30%). The mechanism of this interaction is unknown.
Lamotrigine In healthy adults, the AUCs of lamotrigine and ezogabine were both increased. The clinical significance of this is still unknown. Multiple doses of ezogabine also increase the clearance and decrease the terminal half-life of lamotrigine.
Ondansetron Concurrent use of ezogabine and ondansetron can increase QTc interval. Consider alternate therapy.
Phenytoin Ezogabine increases the clearance of phenytoin (30%). The mechanism of this interaction is unknown.

Liều Lượng & Cách Dùng : Tablet - Oral - 50 mg, 200 mg, 300 mg, 400 mg

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : GlaxoSmithKline

Sản phẩm biệt dược : Potiga

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB04953

PubChem Compound

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=121892

PubChem Substance

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=10239851

KEGG Compound

http://www.genome.jp/dbget-bin/www_bget?cpd:C13826

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D09569

ChemSpider

http://www.chemspider.com/Chemical-Structure.108740.html

BindingDB

http://www.bindingdb.org/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50143558

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0173-0814-59

PharmGKB

http://www.pharmgkb.org/drug/PA144997862

Wikipedia

http://en.wikipedia.org/wiki/Retigabine

RxList

http://www.rxlist.com/potiga-drug.htm

Drugs.com

http://www.drugs.com/mtm/ezogabine.html

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