- 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.
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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.
- 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
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- METHOD OF MAKING 1-(ACYLOXY)-ALKYL CARBAMATE COMPOUNDS
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Methods of preparing carbamate prodrugs of amine-containing drugs are provided. Carbonates useful in the synthesis of the carbamate prodrugs are also provided.
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Paragraph 0317-0322
(2014/09/03)
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- PROCESSES FOR THE PREPARATION AND PURIFICATION OF GABAPENTIN ENACARBIL
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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.
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Page/Page column 28
(2010/06/17)
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- PROCESSES FOR PREPARING PRODRUGS OF GABAPENTIN AND INTERMEDIATES THEREOF
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Gabapentin prodrugs and intermediates thereof are described.
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Page/Page column 8
(2009/12/28)
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- USE OF PRODRUGS OF GABA ANALOGS FOR TREATING DISEASES
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Methods of using prodrugs of GABA analogs and pharmaceutical compositions thereof to treat migraine, fibromyalgia, amyotrophic lateral sclerosis, irritable bowel syndrome, social phobia, Parkinson's disease, asthma, cough, or chronic obstructive pulmonary disease, and pharmaceutical compositions of prodrugs of GABA analogs useful in treating migraine, fibromyalgia, amyotrophic lateral sclerosis, irritable bowel syndrome, social phobia, Parkinson's disease, asthma, cough, or chronic obstructive pulmonary disease are disclosed.
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Page/Page column 104
(2008/12/06)
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- USE OF GABAPENTIN AND PREGABALIN PRODRUGS FOR TREATING TINNITUS
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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.
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Page/Page column 53
(2008/12/05)
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- Treating vulvodynia using prodrugs of GABA analogs
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Methods of using prodrugs of GABA analogs and pharmaceutical compositions thereof to treat vulvodynia in a patient, and pharmaceutical compositions of prodrugs of GABA analogs useful in treating vulvodynia are disclosed.
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Page/Page column 17
(2010/11/26)
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- Prodrugs of GABA analogs, compositions and uses thereof
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The present invention provides prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs and methods for making prodrugs of GABA analogs. The present invention also provides methods for using prodrugs of GABA analogs and methods for using pharmaceutical compositions of prodrugs of GABA analogs for treating or preventing common diseases and/or disorders.
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Page/Page column 39; 40
(2010/11/24)
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- CRYSTALLINE FORM OF GAMMA-AMINOBUTYRIC ACID ANALOG
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A crystalline form of a gamma-aminobutyric acid analog, and methods of preparing same, are provided.
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Page/Page column 26
(2010/02/11)
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- SYNTHESIS OF ACYLOXYALKYL CARBAMATE PRODRUGS AND INTERMEDIATES THEREOF
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Methods for synthesis of 1-(acyloxy)-alkyl carbamates, particularly, the synthesis of 1-(acyloxy)-alkyl carbamate prodrugs of primary or secondary amine containing drugs are described. Also described are methods for synthesis of 1-(acyloxy)-alkyl N-hydroxysuccinimidyl carbonates which are useful intermediates in the synthesis of 1-(acyloxy)-alkyl carbamates are also described.
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Page/Page column 46-47
(2008/06/13)
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