Voltage-gated sodium channel (VGSC)

Cenobamate (YKP-3089) is proposed to exert antiseizure effects by selectively blocking the inactivated state of the sodium channel and by preferentially blocking persistent sodium current. It is also proposed to facilitate increased presynaptic GABA release to potentiate inhibitory synaptic transmission.[1]

Cenobamate (YKP-3089) is a tetrazole derivative with antiseizure properties reported in multiple animal models of epilepsy. YKP3089 has demonstrated anticonvulsant activity in several animal seizure models including 6 Hz, hippocampus kindling, electroshock, PTZ, picrotoxin, and pilocarpine-induced seizure models.[1]

A recent report analyzed the seizure-free rates in two double-blind placebo-controlled studies of patients with refractory partial-onset seizures treated with YKP3089. The first was a phase II randomized, double-blind, placebo-controlled 12-week study of YKP3089 assessing the efficacy and tolerability of 200 mg/day YKP3089 as adjunctive therapy in patients with partial-onset seizures (NCT01397968). The study enrolled approximately 222 patients and the primary outcome measure was percent change in seizure frequency as compared to baseline over the course of a 12-week treatment period. Seizure-free rates were 28% for YKP3089 compared to 9% for placebo. The other phase II, double-blind, placebo-controlled dose–response study was conducted in 437 patients who were randomized to placebo or 100, 200, and 400 mg/day YKP3089 (NCT01866111). YKP3089 100, 200, and 400 mg/day produced seizure-free rates of 3%, 11%, and 20% respectively as compared to 1% with placebo. Adverse effects were dose related and included somnolence, dizziness, diplopia, and gait disturbances. Currently, an open-label, multicenter, safety, and pharmacokinetic study of YKP3089 as adjunctive therapy in patients with partial-onset seizures is recruiting participants with a planned enrollment of 1200 patients (NCT02535091). Results are expected in 2018.

Absorption, Distribution and Excretion
The oral bioavailability of senoside is 88%, with a Tmax of 1–4 hours. High-fat meals have little effect on the pharmacokinetics of senoside. 87.8% of senoside is excreted in the urine and 5.2% in the feces. The apparent volume of distribution of senoside is 40–50 liters. At daily doses of 100–400 mg, the apparent oral clearance of senoside is 0.45–0.63 liters/hour. Metabolism/Metabolites Data on the metabolism of senoside are currently lacking, but it is primarily metabolized via glucuronidation by UGT2B7 and UGT2B4, or oxidized via various cytochromes. Biological Half-Life The terminal half-life of senoside is 50–60 hours.

Hepatotoxicity
In controlled clinical trials, the addition of sannobamate to standard antiepileptic drug therapy resulted in transient, mild to moderate elevations of serum transaminases in 1% to 4% of patients. No clinically significant liver injury with jaundice was observed in pre-registration trials of sannobamate. However, in these trials, among 953 patients treated with sannobamate, 3 experienced drug-induced eosinophilia and DRESS syndrome with elevated serum transaminases; these cases occurred within the first 3 to 6 weeks of treatment, and the subjects had relatively rapid initial dose titration rates (4 to 6 weeks). In a large, open-label study using a longer titration period (12 weeks), no cases of DRESS syndrome were reported in over 1000 subjects. Felbamate, a structure-related carbamate anticonvulsant, is a known cause of drug-induced liver injury and is listed on the black box warning list and restricted in use due to its potential to cause severe hypersensitivity reactions, including acute liver failure and aplastic anemia. Therefore, cenobamate may also cause clinically significant liver injury, which may be severe, but this is rare. Probability Score: D (Possibly a rare cause of clinically significant liver injury in the context of systemic hypersensitivity syndrome). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information on the clinical use of cenobamate during lactation. If a lactating woman must take cenobamate, breastfeeding should not be discontinued, but alternative medications are recommended until more data are available, especially when breastfeeding newborns or premature infants. Monitor the infant for excessive drowsiness. ◉ Effects on Breastfed Infants No published information found as of the revision date. ◉ Effects on Lactation and Breast Milk No published information found as of the revision date. Protein Binding Cenobamate has a 60% protein binding rate in plasma, primarily binding to serum albumin.

[1]. Expert Review of Clinical Pharmacology. 11 (1): 27–45. doi:10.1080/17512433.2018.1386553
[2]. Emerging drugs for focal epilepsy. Expert Opin Emerg Drugs. 2013Mar;18(1):87-95. doi: 10.1517/14728214.2013.750294;

Cenobamate is a Category 5 controlled substance under the U.S. Drug Enforcement Administration (DEA). Category 5 controlled substances are less likely to be abused than Category 4 controlled substances and primarily consist of formulations containing small amounts of specific anesthetic agents. It is a sedative. Cenobamate, also known as YKP-3089, is an antiepileptic drug developed by SK Pharmaceuticals for the treatment of partial seizures. Its exact mechanism of action has not been reported in the literature, but it is known to positively modulate GABAA receptors and inhibit voltage-gated sodium channels. Cenobamate was approved by the FDA on November 21, 2019.
Cenobamate's mechanism of action is as a sodium channel antagonist, a positive regulator of GABA_A receptors, an inhibitor of cytochrome P450 2B6, an inhibitor of cytochrome P450 2C19, an inhibitor of cytochrome P450 3A, an inducer of cytochrome P450 2B6, an inducer of cytochrome P450 2C8, and an inducer of cytochrome P450 3A4.
Cenobamate is a tetrazolium carbamate anticonvulsant used to treat partial-onset epilepsy in adults. Elevated serum transaminases during cenobamate treatment occur at a low to moderate rate and are associated with clinically significant liver injury, often occurring against the backdrop of multi-organ hypersensitivity syndromes (such as eosinophilia and drug-induced systemic symptoms, DRESS).
Drug Indications

Cenobamate is indicated for the treatment of partial-onset epilepsy in adults.

Adjunctive therapy for focal seizures (with or without secondary generalized seizures) in adult patients with epilepsy who have previously received at least two antiepileptic drugs but whose condition remains uncontrolled.
Epilepsy Treatment

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Mechanism of Action
Senobamate inhibits voltage-gated sodium channels and is a positive regulator of GABA_A receptors. However, its exact mechanism of action is unclear. Inhibition of voltage-gated sodium channels increases the threshold for generating action potentials and reduces the number of action potentials.

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Pharmacodynamics
The mechanism of action of senobamate is not well understood, but it modulates GABA_A receptors and inhibits voltage-gated sodium channels. Senobamate is administered once daily, thus providing a long duration of action. It has a wide therapeutic window, and the 750 mg dose is well tolerated. Patients should be informed of the risks of adverse drug reactions including eosinophilia and generalized symptoms (DRESS), QT interval shortening, suicidal behavior, and neurological adverse reactions.

C10H10CLN5O2

267.671700000763

267.052

913088-80-9

913088-80-9 913087-59-9

11962412

Typically exists as solid at room temperature

1.5

1

5

5

18

293

1

C1=CC=C(C(=C1)[C@H](CN2N=CN=N2)OC(=O)N)Cl

GFHAXPJGXSQLPT-VIFPVBQESA-N

InChI=1S/C10H10ClN5O2/c11-8-4-2-1-3-7(8)9(18-10(12)17)5-16-14-6-13-15-16/h1-4,6,9H,5H2,(H2,12,17)/t9-/m0/s1

(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate

YKP-3089; YKP3089; YKP3089; Cenobamate; Xcopri; 913088-80-9; Cenobamate [INN]; UNII-P85X70RZWS; P85X70RZWS; trade name: Xcopr;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)