478296-72-9 Usage
Description
Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained doseproportional exposure to gabapentin and predictable bioavailability. In April 2011, Gabapentin enacarbil is approved by the US Food and Drug Administration for the treatment of moderate-to-severe primary restless legssyndrome (RLS) in adults.Gabapentin enacarbil 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.
Originator
Xenoport (United States)
Uses
Gabapentin enacarbil (HORIZANT GlaxoSmithKline/XenoPort) is a prodrug of gabapentin used as an anticonvulsant as well as a treatment for neurogenic pain, with the same mechanism of action as pregabalin.
Definition
ChEBI: 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.
Preparation
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.
Brand name
Horizant
Pharmacokinetics
Gabapentin enacarbil is an acyloxyalkylcarbamate prodrug of analgesic and anticonvulsant drug gabapentin which has problematic pharmacokinetic properties, including short half-life, saturable absorption, high inter-patient variability, and lack of linear dose–response relationship. Gabapentin enacarbil was designed to be absorbed throughout the entire length of the gastrointestinal tract, and its absorption is mediated by high-capacity nutrient transporters, including monocarboxylate transporter 1 (MCT-1) and sodium-dependent multivitamin transporter (SMVT). Prodrug modification produced an extended release of gabapentin with twofold improved, more predictable, and dose-proportional oral bioavailability in humans. During and after its absorption, gabapentin enacarbil is efficiently hydrolyzed by nonspecific esterases to yield gabapentin. Currently, gabapentin enacarbil is commercially available for the treatment of restless legs syndrome and post-herpetic neuralgia of adults.Structure and hydrolysis of gabapentin enacarbil to the active gabapentin
Clinical Use
Gabapentin 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.
Synthesis
Gabapentin 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.
Mode of action
Gabapentin enacarbil is a prodrug of gabapentin and, accordingly, its therapeutic effects in RLS and PHN are attributable to gabapentin. The mechanism of action by which gabapentin is efficacious in PHN is unknown but in animal models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). Gabapentin prevents pain-related responses in several models of neuropathic pain in rats and mice (e.g., spinal nerve ligation models, spinal cord injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test), but does not alter immediate pain-related behaviors (rat tail flick test, formalin footpad acute phase). The relevance of these models to human pain is not known.
Check Digit Verification of cas no
The CAS Registry Mumber 478296-72-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 4,7,8,2,9 and 6 respectively; the second part has 2 digits, 7 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 478296-72:
(8*4)+(7*7)+(6*8)+(5*2)+(4*9)+(3*6)+(2*7)+(1*2)=209
209 % 10 = 9
So 478296-72-9 is a valid CAS Registry Number.
InChI:InChI=1/C16H27NO6/c1-11(2)14(20)22-12(3)23-15(21)17-10-16(9-13(18)19)7-5-4-6-8-16/h11-12H,4-10H2,1-3H3,(H,17,21)(H,18,19)
478296-72-9Relevant articles and documents
XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters.
Cundy, Kenneth C,Branch, Russell,Chernov-Rogan, Tania,Dias, Tracy,Estrada, Tono,Hold, Karin,Koller, Kerry,Liu, Xiaoli,Mann, Adam,Panuwat, Matt,Raillard, Stephen P,Upadhyay, Shubhra,Wu, Quincey Q,Xiang, Jia-Ning,Yan, Hui,Zerangue, Noa,Zhou, Cindy X,Barrett, Ronald W,Gallop, Mark A
, p. 315 - 323 (2004)
Gabapentin is thought to be absorbed from the intestine of humans and animals by a low-capacity solute transporter localized in the upper small intestine. Saturation of this transporter at doses used clinically leads to dose-dependent pharmacokinetics and high interpatient variability, potentially resulting in suboptimal drug exposure in some patients. XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid] is a novel prodrug of gabapentin designed to be absorbed throughout the intestine by high-capacity nutrient transporters. XP13512 was stable at physiological pH but rapidly converted to gabapentin in intestinal and liver tissue from rats, dogs, monkeys, and humans. XP13512 was not a substrate or inhibitor of major cytochrome P450 isoforms in transfected baculosomes or liver homogenates. The separated isomers of XP13512 showed similar cleavage in human tissues. The prodrug demonstrated active apical to basolateral transport across Caco-2 cell monolayers and pH-dependent passive permeability across artificial membranes. XP13512 inhibited uptake of (14)C-lactate by human embryonic kidney cells expressing monocarboxylate transporter type-1, and direct uptake of prodrug by these cells was confirmed using liquid chromatography-tandem mass spectrometry. XP13512 inhibited uptake of (3)H-biotin into Chinese hamster ovary cells overexpressing human sodium-dependent multivitamin transporter (SMVT). Specific transport by SMVT was confirmed by oocyte electrophysiology studies and direct uptake studies in human embryonic kidney cells after tetracycline-induced expression of SMVT. XP13512 is therefore a substrate for several high-capacity absorption pathways present throughout the intestine. Therefore, administration of the prodrug should result in improved gabapentin bioavailability, dose proportionality, and colonic absorption compared with administration of gabapentin.
PROCESSES FOR THE PREPARATION AND PURIFICATION OF GABAPENTIN ENACARBIL
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Page/Page column 28, (2010/06/17)
Gabapentin enacarbil was prepared and purified from intermediates such as 1- haloalkyl carbamate or carbonate and diacid acetal skeleton. For example, a 1-haloalkyl carbonate or carbamate was prepared by combining a C1 to C 10 alcohol or C1 to C10 primary amine, a solvent selected from the group consisting of: acetonitrile, C3 to C7 ketone, C5 to C 10 ether, C2 to C7 ester, C5 to C 10 hydrocarbon and a combination thereof; a 1-haloalkyl halo formate of the following formula:(I) wherein each X is independently selected from Br, I, or Cl; R1 is alkyl or H; and a C6 to C21 tertiary amine.
USE OF GABAPENTIN AND PREGABALIN PRODRUGS FOR TREATING TINNITUS
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Page/Page column 55-56, (2008/12/05)
Methods of using prodrugs of gabapentin or pregabalin and pharmaceutical compositions thereof to treat tinnitus, and pharmaceutical compositions of prodrugs of gabapentin or pregabalin useful in treating tinnitus are disclosed.
