NAV

Arbaclofen Placarbil

Identification

Generic Name
Arbaclofen Placarbil
DrugBank Accession Number
DB08892
Background

Arbaclofen Placerbil is a prodrug of Arbaclofen, which is a selective gamma-amino-butyric acid type B receptor agonist and the R-enantiomer of baclofen. It was discovered, and has been patented by XenoPort as a new chemical entity with an improved pharmacokinetic profile compared to baclofen, which allows for sustained release properties.

Arbaclofen Placerbil was believed to have therapeutic potential in treating gastroesophogeal reflux disease (GERD) and plasticity; however due to discouraging clinical trial results, the drug was abandoned by XenoPort in 2011 for the treatment of GERD. On May 20th, 2013, XenoPort announced plans to terminate the development of Arbaclofen Placerbil for the treatment of multiple sclerosis.

Type
Small Molecule
Groups
Investigational
Structure
3D
Similar Structures
Weight
Average: 399.87
Monoisotopic: 399.1448653
Chemical Formula
C19H26ClNO6
Synonyms
  • Arbaclofen Placarbil
  • XP19986
External IDs
  • XP19986
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Pharmacology

Indication

Investigated for the treatment of spasticity in multiple sclerosis, acute back spasms, and GERD.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

R-baclofen is postulated to aid in spasticity by acting as an agonist of the inhibitory gamma aminobutyric acid neurotransmission pathway.

TargetActionsOrganism
AGamma-aminobutyric acid type B receptor subunit 1
agonist
Humans
AGamma-aminobutyric acid type B receptor subunit 2
agonist
Humans
Absorption

Unlike baclofen, absorption of R-baclofen(arbaclofen) is not limited to the upper small intestine. The ability of arbaclofen to be absorbed throughout the gastrointestinal tract allowed for the development of the sustained release formulation, arbaclofen placarbil (AP).

In one study of AP absorption in 10 healthy volunteers, one 20mg oral dose of AP, in the presence of food, resulted in a Tmax of 5.05h.

The oral bioavailability of R-baclofen in rats when AP was dosed at 10mg/kg was 44 ± 12%, and when dosed at 1mg/kg, oral bioavailability was 68 ± 6%.

In monkeys and dogs, the oral bioavailability of R-baclofen when AP was orally dosed was high: 94 ± 16%, and 92 ± 7%, respectively. In comparison, when oral R-balofen was dosed oral bioavailability was 39 ± 21% in monkeys and 49 ± 20% in dogs.

Colonic absorption studies measuring R-baclofen bioavailability post intracolonic dosing in rats and monkeys, have revealed low bioavailability with the administration of R-baclofen (7 ± 3% and 3 ± 2%, respectively), and significantly higher R-baclofen bioavailability with intracolonic dosing of AP suspension ( 37 ± 9% and 37 ± 15%, in rats and monkeys respectively). Intracolonic dosing of AP suspension also resulted in high biolavailability of R-baclofen in dogs (77 ± 23%).

Absorption throughout the intestine is both passive and active and occurs via the monocarboxylate type 1 transporter.

Volume of distribution

Radioactive labeling has shown AP to be widely distributed throughout the body. Tissue distribution occurs mostly to the kidneys and liver.

Protein binding

Not Available

Metabolism

In experimental studies using human liver S9 Arbaclofen placarbil was not shown to be a substrate for CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.

Arbaclofen placarbil, the acyloxyalkyl carbamate prodrug of R-arbaclofen, is believed to undergo hydrolysis by the esterase enzyme human carboxylesterase-2 into the parent amine, R-baclfen. Carbon dioxide, isobutyric acid, isobutyraldehyde, are also expected to be produced in equimolar quantities.

The productions of isobutyric acid has been confirmed in vitro untilizing mass spectrometry and gas chromatography.

Route of elimination

84-88% renal elimination as R-baclofen. Less than 1% fecal elimination. (2)

Half-life

IV bolus administration of AP to rats showed that AP was converted to R-baclofen with a half life of 6 minutes.

Clearance

Blood clearance of an IV bolus of AR in rats resulted in a total blood clearance of 15.81 ± 10.2 L/h/kg in rats.
In comparison, blood clearance of an IV bolus of R-baclofen in rats, monkeys, and dogs, resulted in half lives ranging from 1.6-3.4hours, with total blood clearances reported to be 0.51± 0.13L/h/kg in rats, 0.31±0.11L/h/kg in monkeys, and 0.24L±0.01L/h/kg in dogs. (2)

In studied utilizing radioactive tracers attached to R-baclofen, 97% of radioactivity was recovered in the urine.

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Integrate drug-drug
interactions in your software
1,2-BenzodiazepineThe risk or severity of CNS depression can be increased when Arbaclofen Placarbil is combined with 1,2-Benzodiazepine.
AcetazolamideThe risk or severity of CNS depression can be increased when Acetazolamide is combined with Arbaclofen Placarbil.
AcetophenazineThe risk or severity of CNS depression can be increased when Acetophenazine is combined with Arbaclofen Placarbil.
AgomelatineThe risk or severity of CNS depression can be increased when Agomelatine is combined with Arbaclofen Placarbil.
AlfentanilThe risk or severity of CNS depression can be increased when Alfentanil is combined with Arbaclofen Placarbil.
Food Interactions
Not Available

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as gamma amino acids and derivatives. These are amino acids having a (-NH2) group attached to the gamma carbon atom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Gamma amino acids and derivatives
Alternative Parents
Phenylpropanoic acids / Chlorobenzenes / Dicarboxylic acids and derivatives / Aryl chlorides / Carbamate esters / Carboxylic acid esters / Carboxylic acids / Acetals / Organopnictogen compounds / Organonitrogen compounds
show 4 more
Substituents
3-phenylpropanoic-acid / Acetal / Aromatic homomonocyclic compound / Aryl chloride / Aryl halide / Benzenoid / Carbamic acid ester / Carbonyl group / Carboxylic acid / Carboxylic acid ester
show 14 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
W89H91R7VX
CAS number
847353-30-4
InChI Key
JXTAALBWJQJLGN-KSSFIOAISA-N
InChI
InChI=1S/C19H26ClNO6/c1-11(2)17(24)26-18(12(3)4)27-19(25)21-10-14(9-16(22)23)13-5-7-15(20)8-6-13/h5-8,11-12,14,18H,9-10H2,1-4H3,(H,21,25)(H,22,23)/t14-,18-/m0/s1
IUPAC Name
(3R)-3-(4-chlorophenyl)-4-({[(1S)-2-methyl-1-[(2-methylpropanoyl)oxy]propoxy]carbonyl}amino)butanoic acid
SMILES
CC(C)[C@H](OC(=O)NC[C@H](CC(O)=O)C1=CC=C(Cl)C=C1)OC(=O)C(C)C

References

Synthesis Reference

Lal, Ritu, et al. "Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen." Journal of Pharmacology and Experimental Therapeutics 330.3 (2009): 911-921.

General References
  1. Nance PW, Huff FJ, Martinez-Arizala A, Ayyoub Z, Chen D, Bian A, Stamler D: Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury. Spinal Cord. 2011 Sep;49(9):974-80. doi: 10.1038/sc.2011.43. Epub 2011 May 17. [Article]
  2. Lal R, Sukbuntherng J, Tai EH, Upadhyay S, Yao F, Warren MS, Luo W, Bu L, Nguyen S, Zamora J, Peng G, Dias T, Bao Y, Ludwikow M, Phan T, Scheuerman RA, Yan H, Gao M, Wu QQ, Annamalai T, Raillard SP, Koller K, Gallop MA, Cundy KC: Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen. J Pharmacol Exp Ther. 2009 Sep;330(3):911-21. doi: 10.1124/jpet.108.149773. Epub 2009 Jun 5. [Article]
KEGG Drug
D08861
PubChem Compound
11281011
PubChem Substance
347827810
ChemSpider
9456008
ChEMBL
CHEMBL2107312
ZINC
ZINC000014209416

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentMultiple Sclerosis1
2CompletedTreatmentAlcohol Use Disorders (AUD)1
2CompletedTreatmentBack pain1
2CompletedTreatmentGastro-esophageal Reflux Disease (GERD)2
2CompletedTreatmentGastroesophageal Reflux1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0111 mg/mLALOGPS
logP3.31ALOGPS
logP4.37Chemaxon
logS-4.6ALOGPS
pKa (Strongest Acidic)3.96Chemaxon
pKa (Strongest Basic)-7.1Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area101.93 Å2Chemaxon
Rotatable Bond Count11Chemaxon
Refractivity99.08 m3·mol-1Chemaxon
Polarizability40.47 Å3Chemaxon
Number of Rings1Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0006-9412000000-81502525b7f9d5d01a52
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0002-4935000000-086e8e8305ebdd3036ab
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-000i-9641000000-bc740d039e82ba97613d
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0gvo-9631000000-2f102d710d07e944ae6e
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-000i-9330000000-43d00d6aff448cb5014c
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-4931000000-952a6fc4c393e97fc643
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001r-9341000000-2dd3eebdaa031a6806ce
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-190.22145
predicted
DeepCCS 1.0 (2019)
[M+H]+192.61702
predicted
DeepCCS 1.0 (2019)
[M+Na]+198.71312
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Details1. Gamma-aminobutyric acid type B receptor subunit 1
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
G-protein coupled gaba receptor activity
Specific Function
Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coup...
Gene Name
GABBR1
Uniprot ID
Q9UBS5
Uniprot Name
Gamma-aminobutyric acid type B receptor subunit 1
Molecular Weight
108319.4 Da
References
  1. Bowery NG: GABAB receptor pharmacology. Annu Rev Pharmacol Toxicol. 1993;33:109-47. [Article]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  3. Garcia-Gil L, de Miguel R, Romero J, Perez A, Ramos JA, Fernandez-Ruiz JJ: Perinatal delta9-tetrahydrocannabinol exposure augmented the magnitude of motor inhibition caused by GABA(B), but not GABA(A), receptor agonists in adult rats. Neurotoxicol Teratol. 1999 May-Jun;21(3):277-83. [Article]
  4. Lehmann A: GABAB receptors as drug targets to treat gastroesophageal reflux disease. Pharmacol Ther. 2009 Jun;122(3):239-45. doi: 10.1016/j.pharmthera.2009.02.008. Epub 2009 Mar 19. [Article]
  5. Motalli R, Louvel J, Tancredi V, Kurcewicz I, Wan-Chow-Wah D, Pumain R, Avoli M: GABA(B) receptor activation promotes seizure activity in the juvenile rat hippocampus. J Neurophysiol. 1999 Aug;82(2):638-47. [Article]
  6. Mott DD, Li Q, Okazaki MM, Turner DA, Lewis DV: GABAB-Receptor-mediated currents in interneurons of the dentate-hilus border. J Neurophysiol. 1999 Sep;82(3):1438-50. [Article]
  7. Ogasawara T, Itoh Y, Tamura M, Mushiroi T, Ukai Y, Kise M, Kimura K: Involvement of cholinergic and GABAergic systems in the reversal of memory disruption by NS-105, a cognition enhancer. Pharmacol Biochem Behav. 1999 Sep;64(1):41-52. [Article]
  8. Pittman QJ: The action is at the terminal. J Physiol. 1999 Nov 1;520 Pt 3:629. [Article]
  9. Stringer JL, Lorenzo N: The reduction in paired-pulse inhibition in the rat hippocampus by gabapentin is independent of GABA(B) receptor receptor activation. Epilepsy Res. 1999 Feb;33(2-3):169-76. [Article]
Details2. Gamma-aminobutyric acid type B receptor subunit 2
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
G-protein coupled gaba receptor activity
Specific Function
Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coup...
Gene Name
GABBR2
Uniprot ID
O75899
Uniprot Name
Gamma-aminobutyric acid type B receptor subunit 2
Molecular Weight
105820.52 Da
References
  1. Belley M, Sullivan R, Reeves A, Evans J, O'Neill G, Ng GY: Synthesis of the nanomolar photoaffinity GABA(B) receptor ligand CGP 71872 reveals diversity in the tissue distribution of GABA(B) receptor forms. Bioorg Med Chem. 1999 Dec;7(12):2697-704. [Article]
  2. Braun M, Wendt A, Buschard K, Salehi A, Sewing S, Gromada J, Rorsman P: GABAB receptor activation inhibits exocytosis in rat pancreatic beta-cells by G-protein-dependent activation of calcineurin. J Physiol. 2004 Sep 1;559(Pt 2):397-409. Epub 2004 Jul 2. [Article]
  3. Bowery NG: GABAB receptor pharmacology. Annu Rev Pharmacol Toxicol. 1993;33:109-47. [Article]
  4. Filippov AK, Couve A, Pangalos MN, Walsh FS, Brown DA, Moss SJ: Heteromeric assembly of GABA(B)R1 and GABA(B)R2 receptor subunits inhibits Ca(2+) current in sympathetic neurons. J Neurosci. 2000 Apr 15;20(8):2867-74. [Article]
  5. Jones KA, Tamm JA, Craig DA, Ph D, Yao W, Panico R: Signal transduction by GABA(B) receptor heterodimers. Neuropsychopharmacology. 2000 Oct;23(4 Suppl):S41-9. [Article]
  6. Lehmann A: GABAB receptors as drug targets to treat gastroesophageal reflux disease. Pharmacol Ther. 2009 Jun;122(3):239-45. doi: 10.1016/j.pharmthera.2009.02.008. Epub 2009 Mar 19. [Article]
  7. Martin SC, Russek SJ, Farb DH: Molecular identification of the human GABABR2: cell surface expression and coupling to adenylyl cyclase in the absence of GABABR1. Mol Cell Neurosci. 1999 Mar;13(3):180-91. [Article]
  8. Pittman QJ: The action is at the terminal. J Physiol. 1999 Nov 1;520 Pt 3:629. [Article]

Transporters

Details1. Monocarboxylate transporter 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Symporter activity
Specific Function
Proton-coupled monocarboxylate transporter. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucin...
Gene Name
SLC16A1
Uniprot ID
P53985
Uniprot Name
Monocarboxylate transporter 1
Molecular Weight
53943.685 Da
References
  1. Lal R, Sukbuntherng J, Tai EH, Upadhyay S, Yao F, Warren MS, Luo W, Bu L, Nguyen S, Zamora J, Peng G, Dias T, Bao Y, Ludwikow M, Phan T, Scheuerman RA, Yan H, Gao M, Wu QQ, Annamalai T, Raillard SP, Koller K, Gallop MA, Cundy KC: Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen. J Pharmacol Exp Ther. 2009 Sep;330(3):911-21. doi: 10.1124/jpet.108.149773. Epub 2009 Jun 5. [Article]
  2. Halestrap AP, Price NT: The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J. 1999 Oct 15;343 Pt 2:281-99. [Article]

Drug created at May 30, 2013 20:39 / Updated at February 21, 2021 18:52