VIGABATRIN

Description

Vigabatrin, the gamma-vinyl derivative of GABA, is a new anticonvulsant reportedly effective in the treatment of intractable seizures unresponsive to currently available therapy. Mechanistically vigabatrin is a potent irreversible GABA aminotransferase inhibitor which modifies the enzyme's active-site by Michael addition. Other potential indications have been suggested for vigabatrin, including depression and schizophrenia.

Chemical properties

White or almost white powder.

Originator

Merrell Dow (United Kingdom)

The Uses of VIGABATRIN

Vigabatrin is a selective GABA transaminase inhibitor.

The Uses of VIGABATRIN

antineoplastic

The Uses of VIGABATRIN

antibiotic

What are the applications of Application

Vigabatrin is a structural analog of GABA and a selective GABA transaminase inhibitor that does not bind to GABA receptors.

Definition

ChEBI: A gamma-amino acid having a gamma-vinyl GABA structure. It is an irreversible inhibitor of gamma-aminobutyric 664 acid transaminase

Manufacturing Process

Step A: 4-Formyloxy-3-hydroxy-1-butene
A solution of erythritol (50 g, 0.5 mole) in aqueous formic acid (150 g, 75%) was heated above 100°C, 12 hours, then water and formic acid were distilled off and the reaction mixture was heated above 200°C with a Bunsen burner. The product was collected by distillation (b.p. 230°C, 30 g) and should be rectified (b.p. 90°C, 15 mm).
Step B: Ethyl 6-formyloxy-4-hexanoate
A solution of 4-formyloxy-3-hydroxy-1-butene (1.06 g, 10 mmol) and propionic acid (1 drop) in triethylorthoacetate (6 g, 40 mmol) was heated at 140°C under conditions for distillative removal of ethanol. After 2 hours, the excess of ethylorthoacetate was removed by distillation in vacuo. The residue was hydrolysed with water and extracted with AcOEt. The product was purified by flash chromatography on SiO 2 (eluant AcOEt:hexane, 2:8) (1 g, 60%) but distillative purification is preferred when larger quantities are involved.
Step C: Ethyl 6-hydroxy-4-hexanoate
A solution of 6-formyloxy-6-hexanoate (0.9 g, 5 mmol) in absolute EtOH (10 mL) containing few drops of a saturated solution of alcoholic HCl gas was left 2 hours at 20°C. The solvent was removed in vacuo and the residue was used for the next step without further purification (0.7 g, quantitative). This compound was found to be partially decomposed by flash chromatography on SiO 2 .
Step D: Ethyl 4-trichloroacetamido-5-hexanoate
Sodium hydride (0.03 g of a 50% dispersion in oil, 0.5 mmol, was added to a solution of ethyl 6-hydroxy-4-hexanoate (0.7 g, 5 mmol) and trichloroacetonitrile (0.6 g, 5 mmol) in anhydrous ether (50 mL) under N2at0°C. After 1hour, ethanol (0.5 mmol) was added and the solvent was removed in vacuo. The formation of the imidate was controlled by NMR (NH, about.8.5 ppm). A solution of the crude imidate in xylene (30 mL) was heated at reflux 48 hours. Then the solvent was removed in vacuo and the residue was purified by flash chromatography on SiO 2 (eluant AcOEt:hexane, 2:8) to give the title product (1.1 g, about 70%). A sample was distilled for analysis (b.p. 150°C, 0.5 mm Hg).
Step E: 4-Amino-5-hexenoic acid
A suspension of ethyl 4-trichloroacetoamido-5-hexanoate (0.3 g, 1 mmol) in 6 N HCl (10 mL) was heated under reflux 6 hours. Then the mixture was concentrated in vacuo, diluted with water (10 mL), washed twice with AcOEt, and dried in uacuo to give the title product (0.18 g, 100%). NMR, TLC (NH 4 OH:EtOH, 3:7) are identical with those of an authentic sample of 4- amino-5-hexenoic acid

brand name

Sabril (Hoechst Marion Roussel);Sobril tab 25 mg.

Therapeutic Function

Antiepileptic

World Health Organization (WHO)

Vigabatrin, an irreversible inhibitor of GABA-transaminase was introduced in 1989 as a anticonvulsant for management of epilepsy unresponsive to other antiepilepsy agents. In 1991 it was refused registration in Norway because it induced toxic changes, including microvacuolation in the brain of two animal species, at doses that are close to therapeutic dosage levels in man. It is still marketed in Sweden and the United Kingdom.

Biological Functions

Vigabatrin (Sabril) is a relatively specific irreversible inhibitor of GABA-transaminase (GABA-T), the major enzyme responsible for the metabolism of GABA in the mammalian CNS. As a result of inhibition of GABA-T, there is an increase in the concentration of GABA in the brain and consequently an increase in inhibitory neurotransmission. Vigabatrin is well absorbed orally and is distributed to all body systems.The major route of elimination for vigabatrin is renal excretion of the parent compound; no metabolites have been identified in humans.
At present, the primary indication for vigabatrin is in the treatment of patients with partial seizures, but it appears to be an effective and generally well tolerated antiepileptic medication for other seizure types as well. It should not be used in patients with absence epilepsy or with myoclonic seizures. Vigabatrin is not approved as an AED in the United States, although it is approved in many other countries.

General Description

Vigabatrin, a 4-vinyl analog of GABA, produces its pharmacologicalaction by irreversibly blocking GABA catabolismcatalyzed by GABA-T as discussed earlier. It is marketedin Europe and Canada as an adjunctive treatment ofpatients with partial seizures, but it has yet to gain FDA approvalin the United States even after extensive clinical trials.The main concern with this drug is its ability to causea reversible visual field defect associated with retinal functionin the eyes.

Biological Activity

Selective GABA-T inhibitor. Anticonvulsant.

Clinical Use

Antiepileptic

Synthesis

The reaction of 1,4-dichloro-2- butene with diethyl malonate in the presence of sodium ethoxide as catalyst in refluxing ethanol gives 1,1-bis(ethoxycarbonyl)-2-vinylcyclopropane (8), which by reaction with gaseous ammonia in DMF is converted into 3-carboxamido- 5-vinyl-2-pyrrolidone (9). This compound is treated with HCl in refluxing acetic acid to yield vigabatrin.

Drug interactions

Potentially hazardous interactions with other drugs
Antidepressants: anticonvulsant effect antagonised, convulsive threshold lowered; avoid with St John’s wort.
Antiepileptics: concentration of phenytoin reduced.
Antimalarials: mefloquine antagonises anticonvulsant effect.
Antipsychotics: anticonvulsant effect antagonised.
Orlistat: increased risk of convulsions.

Metabolism

Vigabatrin is not significantly metabolised. About 60-80
% of an oral dose is excreted in urine as unchanged drug.