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Gabapentin enacarbil

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Gabapentin enacarbil Basic information
Gabapentin enacarbil Chemical Properties
Gabapentin enacarbil Usage And Synthesis
  • DescriptionIn April 2011, the U.S. FDA approved gabapentin enacarbil (XP- 13512) for the treatment of moderate-to-severe Restless Legs Syndrome (RLS) in adults. Gabapentin enacarbil is a novel prodrug of gabapentin that was designed to be recognized as a substrate for two high-capacity nutrient transports, monocarboxylate transporter type 1 and sodium-dependent multivitamin transporter, and to be efficiently cleaved after absorption to give gabapentin. The separated enantiomers of gabapentin enacarbil have similar cleavage rates in human tissues. Preclinical studies showed that gabapentin enacarbil provides good systemic exposure of gabapentin in rats and monkeys. Gabapentin enacarbil is prepared as a racemic mixture from gabapentin either by sequential coupling with 1-chloroethyl chloroformate in the presence of trimethylsilyl chloride and triethylamine followed by addition of isobutyric acid or by direct coupling with an activated 1-(isobutyryloxy) ethyl carbonate.
  • OriginatorXenoport (United States)
  • DefinitionChEBI: A carbamate ester that is the N-[1-(isobutyryloxy)ethoxy]carbonyl derivative of [1-(aminomethyl)cyclohexyl]acetic acid. The prodrug for gabapentin, used for treatment of neuropathic pain and restless legs syndrome.
  • brand nameHorizant
  • Clinical UseGabapentin enacarbil is a prodrug of gabapentin (Neurontin, Pfizer) which binds to the a2-d subunit of L-type voltage-regulated calcium channels, reducing the release of several neurotransmitters. 122,123 Gabapentin enacarbil was discovered at XenoPort, codeveloped with GlaxoSmithKline, is marketed under the brand name Horizant, and is approved for the treatment of moderate to severe restless leg syndrome. Gabapentin enacarbil was designed to increase the absorption of gabapentin through the interaction with sodium-dependent multivitamin transporter (SMVT) and monocarboxylate transporter type 1 (MCT-1). As a result, the drug demonstrated much better oral bioavailability and more consistent exposure compared to the parent.
  • Chemical SynthesisGabapentin 155 was treated with chlorotrimethylsilane and triethylamine followed by acylation with 1-chloroethyl chloroformate 156 to give acid 157 after hydrolysis of the intermediate silyl ester. This acid was then used without purification and reacted with isobutyric acid (158) and triethylamine to afford gabapentin enacarbil (XIII) in 9.1% overall yield after crystallization. Alternatively, gabapentin 155 was reacted directly with the fully elaborated p-nitrophenyl activated side chain 161 in the presence of potassium carbonate. The resulting mixture of products and p-nitrophenol was treated with 10% Pd/C and potassium formate followed by acidic workup to remove the resulting aniline, providing gabaentin enacarbil (XIII) in 36% overall yield from p-nitrophenol 159 after crystallization. The required activated side chain 161 was prepared from p-nitrophenol 159 via a two-step, one-pot process involving acylation of the phenol with 1-chloroethyl chloroformate 156 in triethylamine. This provided intermediate 160 which was alkylated with isobutyric acid (158) in the presence of zinc oxide and potassium iodide, ultimately furnishing the mixed carbonate 161.

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