Felbamate Chemical Properties

Melting point:

148-1500C

Boiling point:

511.9±50.0 °C(Predicted)

Density 

1.275±0.06 g/cm3(Predicted)

Flash point:

9℃

storage temp. 

Keep in dark place,Inert atmosphere,Room temperature

solubility 

alcohol: soluble

pka

12.99±0.50(Predicted)

form 

Solid

color 

White

BCS Class

2

CAS DataBase Reference

25451-15-4(CAS DataBase Reference)

NIST Chemistry Reference

Felbamate(25451-15-4)

Safety Information

RIDADR 

UN1230 - class 3 - PG 2 - Methanol

WGK Germany 

2

RTECS 

TZ1070000

HS Code 

2924296000

Hazardous Substances Data

25451-15-4(Hazardous Substances Data)

Toxicity

LD50 i.p. in mice: 4000 mg/kg (Ludwig et al.)

MSDS

• Language:English Provider:SigmaAldrich

Felbamate Usage And Synthesis

Description

Felbamate, characterized by its low toxicity and wide margin of safety, is efficacious in treating refractory patients with generalized tonic-clonic and complex partial seizures as monotherapy and adjunctive therapy.It has also been demonstrated to have a neuroprotective effect in cerebral ischemia and hypoxia. It has been suggested that the mechanism of its anticonvulsant activity is possibly through an interaction with the strychnineinsensitive receptor site on the NMDA receptor complex.

Chemical Properties

White Powder. Solubility in water 0.33 mg/mL, in ethanol 5.0 mg/mL, and in DMF 333.4 mg/mL.

Originator

Carter-Wallace (U.S.A.)

Uses

Antiepileptic, structurally similar to meprobamate.

Definition

ChEBI: The bis(carbamate ester) of 2-phenylpropane-1,3-diol. An anticonvulsant, it is used in the treatment of epilepsy.

brand name

Felbatol

Biological Functions

Felbamate (Felbatol) was introduced with the expectation that it would become a major drug in the treatment of epilepsy. Felbamate exhibited few manifestations of serious toxicity in early clinical trials. Soon after its introduction, however, it became apparent that its use was associated with a high incidence of aplastic anemia. Consequently, felbamate is indicated only for patients whose epilepsy is so severe that the risk of aplastic anemia is considered acceptable.
While its mechanism of action has not been clearly established, felbamate shows some activity as an inhibitor of voltage-dependent sodium channels in a manner similar to that of phenytoin and carbamazepine. Felbamate also interacts at the strychnine-insensitive glycine recognition site on the NMDA receptor– ionophore complex.Whether this effect is important to its anticonvulsant activity is not clear.

Hazard

Low toxicity by ingestion. Human systemic effects.

Biological Activity

Anticonvulsant, acting as an antagonist at the NMDA-associated glycine binding site.

Biochem/physiol Actions

Anticonvulsant agent that is an allosteric antagonist at the NR2B subunit of the NMDA glutamate receptor; also has γ-aminobutyric acid (GABAA) receptor agonist properties.

Mechanism of action

Gabapentin is a water-soluble amino acid originally designed to be a GABA-mimetic analogue capable of penetrating the CNS. Surprisingly, it has no direct GABA-mimetic activity, nor is it active on sodium channels. The mechanism of action remains unknown, although it has been suggested that gabapentin may alter the metabolism or release of GABA. Gabapentin raises brain GABA levels in patients with epilepsy. Recent studies have demonstrated gabapentin binding to calcium channels in a manner that can be allosterically modulated.
Gabapentin is indicated as an adjunct for use against partial seizures with or without secondary generalization, in patients older than 12 years, and as adjunct for the treatment of partial seizures in children 3 to 12 years of age. It also is approved for the treatment of postherpetic neuralgia.

Pharmacokinetics

The pharmacokinetic properties for gabapentin generally are favorable, with a bioavailability of 60% when given in low doses and somewhat less when given at higher doses because of saturable intestinal uptake by the L-amino-acid transporter. The L-amino-acid transporter is very susceptible to substrate saturation (low Km value). Its absorption and distribution into the CNS appears to be dependent on this amino acid transporter. Following the administration of an oral dose, gabapentin reaches peak plasma concentration in 2 to 3 hours. Additionally, it exhibits linear pharmacokinetics. Moreover, it is not extensively metabolized, nor is it an inducer of hepatic metabolizing enzymes. The elimination of unmetabolized gabapentin occurs by the renal route. Although its therapeutic range is not well characterized, gabapentin has a broad therapeutic index. This implies that a wide range of doses can be used, based on individual patient needs, without significant limitation because of dose-dependent side effects. Protein binding is negligible. Its elimination half-life of 5 to 7 hours is not affected by the dose or by other drugs, and its short half-life necessitates multiple daily administration.

Clinical Use

Felbamate is a dicarbamate that is structurally similar to the antianxiety drug meprobamate. It was approved by the U.S. FDA for antiseizure use in 1993. Following the occurrence of rare cases of aplastic anemia and of severe hepatotoxicity associated with the use of felbamate during early 1994, however, a black box warning was added to the drug's package insert). Despite this, felbamate continues to be used in many patients, although not as a first-line treatment. These toxicity effects may be attributed to the formation of toxic metabolites. Although felbamate use is now uncommon, it is used for severe refractory seizures, either partial, myoclonic, or atonic, or in Lennox-Gastaut syndrome

Side effects

Adverse effects of gabapentin are uncommon and not serious. The CNS effects include mild to moderate sedation, fatigue, ataxia, headache, dizziness, and diplopia. Gabapentin may exacerbate myoclonus, but the effect is mild and does not require discontinuance of the drug. It has been associated with the development of neuropsychiatric adverse events in children.
Drug interactions are infrequent with gabapentin. It does not induce hepatic metabolizing enzymes, nor do other AEDs affect its metabolism and elimination. Antacids may decrease absorption. Gabapentin dosage may need to be decreased in patients with renal disease or in the elderly.

Synthesis

The synthesis of felbamate was first published in 1959. 2-Phenyl-1,3-propanediole is reacted with ethylcarbamate to yield felbamate.

Veterinary Drugs and Treatments

Felbamate is an anticonvulsant agent that may useful for treating seizure disorders (especially complex partial seizures) in dogs. A potential advantage of felbamate therapy is that when used alone or in combination with phenobarbital and/or bromides, it does not appear to cause additive sedation.

Metabolism

Although the metabolism of felbamate has not been fully characterized, felbamate is esterase hydrolyzed to its monocarbamate metabolite, 2-phenyl-1,3-propanediol monocarbamate, which subsequently is oxidized via aldehyde dehydrogenase to its major human metabolite 3-carbamoyl-2-phenylpropionic acid. Other metabolites include the p-hydroxy and mercapturic acid metabolites of felbamate, which have been identified in human urine. Felbamate is a substrate for CYP2C19, with minor activity for CYP3A4 and CYP2E1. Thompson et al. has provided evidence for the formation of the reactive metabolite, 3-carbamoyl-2-phenylpropionaldehyde (CBMA), from the alcohol oxidation of 2-phenyl-1,3-propanediol monocarbamate. CBMA then undergoes spontaneous elimination to another reactive intermediate, 2-phenylpropenal (more commonly known as atropaldehyde), which is proposed to play a role in the development of toxicity during felbamate therapy. CBMA or a further product has been shown to provoke an immune response in mice. Evidence for in vivo atropaldehyde formation was confirmed with the identification of its mercapturic acid conjugates in human urine after felbamate administration. This is consistent with the hypothesis that atropaldehyde reacts rapidly with thiol nucleophiles, such as glutathione, to form mercapturates. More recently, a fluorine analogue of felbamate was synthesized in which the benzylic C2 hydrogen of the propane chain was replaced with fluorine, preventing the formation of atropaldehyde and confirming that the acidic benzylic hydrogen plays a pivotal role in its formation. This analogue is presently undergoing drug development. Felbamate administration exhibited linear kinetics, with a half-life of 20 to 23 hours in the absence of enzyme-inducing AEDs. Approximately 50% of an oral dose of felbamate is excreted unchanged.

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