Arbaclofen

Identification

Name
Arbaclofen
Accession Number
DB08891
Description

Arbaclofen, or STX209, is the R-enantiomer of baclofen. It is believed to be a selective gamma-amino butyric acid type B receptor agonist, and has been investigated as a treatment for autism spectrum disorder and fragile X syndrome in randomized, double blind, placebo controlled trials. It has also been investigated as a treatment for spasticity due to multiple sclerosis and spinal cord injury. Arbaclofen was investigated as a treatment for gastroesophageal reflux disease (GERD); however, with disappointing results.

Type
Small Molecule
Groups
Investigational
Structure
Thumb
Weight
Average: 213.661
Monoisotopic: 213.05565634
Chemical Formula
C10H12ClNO2
Synonyms
  • (R)-4-amino-3-(4-chlorophenyl)butan­oic acid
  • (R)-Baclofen
External IDs
  • OS440
  • STX-209
  • STX209

Pharmacology

Indication

Investigated in clinical trials as a potential treatment for spasticity in multiple sclerosis, autism spectrum disorder, and social withdrawal in fragile X syndrome.

Contraindications & Blackbox Warnings
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Pharmacodynamics
Not Available
Mechanism of action

Arbaclofen, or R-baclofen, acts upstream of the mGluR5 receptor to increase inhibitory neurotransmission. It is the isomer of baclofen which harbors antispastic activity.

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 arbaclofen is not limited to the upper small intestine. Arbaclofen can also be absorbed in the lower small intestine and the colon, allowing for the development of sustained release formulations.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination

>80% of R-baclofen is renally eliminated unchanged.

Half-life
Not Available
Clearance

Blood clearance of an IV bolus of R-baclofen in rats, monkeys, and dogs, resulted in a half life of 1.6-3.4hours, in one study. Total blood clearance was reported to be 0.51±0.13L/h/kg in rats, 0.31±0.11L/h/kg in monkeys, and 0.24±0.01L/h/kg in dogs. (2)

Adverse Effects
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Toxicity
Not Available
Affected organisms
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.
Not Available
Food Interactions
Not Available

Products

Categories

Drug Categories
Not Available
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 / Aralkylamines / Amino fatty acids / Aryl chlorides / Amino acids / Monocarboxylic acids and derivatives / Carboxylic acids / Organopnictogen compounds / Organochlorides
show 4 more
Substituents
3-phenylpropanoic-acid / Amine / Amino acid / Amino fatty acid / Aralkylamine / Aromatic homomonocyclic compound / Aryl chloride / Aryl halide / Benzenoid / Carbonyl group
show 18 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
NYU6UTW25B
CAS number
69308-37-8
InChI Key
KPYSYYIEGFHWSV-QMMMGPOBSA-N
InChI
InChI=1S/C10H12ClNO2/c11-9-3-1-7(2-4-9)8(6-12)5-10(13)14/h1-4,8H,5-6,12H2,(H,13,14)/t8-/m0/s1
IUPAC Name
(3R)-4-amino-3-(4-chlorophenyl)butanoic acid
SMILES
[H][[email protected]@](CN)(CC(O)=O)C1=CC=C(Cl)C=C1

References

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. [PubMed:21577221]
  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. [PubMed:19502531]
PubChem Compound
44602
PubChem Substance
347827809
ChemSpider
40580
BindingDB
50032964
ChEMBL
CHEMBL301742
ZINC
ZINC000000000061
PDBe Ligand
2C0
Wikipedia
Arbaclofen_placarbil
PDB Entries
4ms4 / 7c7q

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentDisseminated Sclerosis / Spasticity, Muscle1
3CompletedTreatmentDisseminated Sclerosis / Spasticity2
3CompletedTreatmentDisseminated Sclerosis / Spasticity, Muscle1
3CompletedTreatmentFragile X Syndrome (FXS)2
3TerminatedTreatmentAutism Spectrum Conditions/Disorders1
3TerminatedTreatmentFragile X Syndrome (FXS)1
3WithdrawnOtherDisseminated Sclerosis / Sperm1
2CompletedTreatmentAutism Spectrum Conditions/Disorders2
2CompletedTreatmentFragile X Syndrome (FXS)1
2CompletedTreatmentGastro-esophageal Reflux Disease (GERD)1

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)206-208 °CNot Available
water solubility 2090 mg/LNot Available
logP 1.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.712 mg/mLALOGPS
logP-0.82ALOGPS
logP-0.78ChemAxon
logS-2.5ALOGPS
pKa (Strongest Acidic)3.89ChemAxon
pKa (Strongest Basic)9.79ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area63.32 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity54.83 m3·mol-1ChemAxon
Polarizability21.11 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
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-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udj-0910000000-f7b2a59bcc1e1195bf1f

Targets

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. [PubMed:8388192]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  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. [PubMed:10386831]
  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. [PubMed:19303900]
  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. [PubMed:10444662]
  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. [PubMed:10482760]
  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. [PubMed:10494996]
  8. Pittman QJ: The action is at the terminal. J Physiol. 1999 Nov 1;520 Pt 3:629. [PubMed:10545129]
  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. [PubMed:10094428]
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. [PubMed:10658574]
  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. [PubMed:15235087]
  3. Bowery NG: GABAB receptor pharmacology. Annu Rev Pharmacol Toxicol. 1993;33:109-47. [PubMed:8388192]
  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. [PubMed:10751439]
  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. [PubMed:11008066]
  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. [PubMed:19303900]
  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. [PubMed:10328880]
  8. Pittman QJ: The action is at the terminal. J Physiol. 1999 Nov 1;520 Pt 3:629. [PubMed:10545129]

Drug created on May 30, 2013 13:42 / Updated on June 12, 2020 10:52

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