Identification
NameBrasofensine
Accession NumberDB04857
TypeSmall Molecule
GroupsInvestigational
Description

Brasofensine is an orally administered dopamine reuptake inhibitor being developed for the treatment of Parkinson's Disease. Phase I/II trials for brasofensine have been completed in the U.K. In November 2001, NeuroSearch confirmed that the drug's development was discontinued in favor of NS 2230.

Structure
Thumb
SynonymsNot Available
External IDs BMS-204756 / NS-2214
Product Ingredients Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Categories
UNII1YP2S94RVH
CAS number171655-91-7
WeightAverage: 327.25
Monoisotopic: 326.0952687
Chemical FormulaC16H20Cl2N2O
InChI KeyNRLIFEGHTNUYFL-QJDHNRDASA-N
InChI
InChI=1S/C16H20Cl2N2O/c1-20-11-4-6-16(20)13(9-19-21-2)12(8-11)10-3-5-14(17)15(18)7-10/h3,5,7,9,11-13,16H,4,6,8H2,1-2H3/b19-9+/t11-,12+,13+,16+/m0/s1
IUPAC Name
(E)-{[(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]methylidene}(methoxy)amine
SMILES
[H][C@@]12CC[C@@]([H])(N1C)[C@]([H])(\C=N\OC)[[email protected]](C2)C1=CC(Cl)=C(Cl)C=C1
Pharmacology
Indication

For the treatment of Parkinson's Disease.

Structured Indications Not Available
Pharmacodynamics

Brasofensine is an inhibitor of the synaptic dopamine transporter. It is a geometric isomer of the E-form; the Z-isomer is denoted as BMS-205912.

Mechanism of action

When the neurotransmitter dopamine is released into the synaptic cleft, brasofensine prevents it from entering back into the source nerve cell, thereby allowing a longer period of synaptic activity.

TargetKindPharmacological actionActionsOrganismUniProt ID
D(2) dopamine receptorProteinunknownNot AvailableHumanP14416 details
Related Articles
Absorption

Brasofensine is rapidly absorbed after oral administration in rats and monkeys, with peak plasma concentrations occurring 0.5-1 hr, but 3-8 hr for brasofensine in humans.

Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Brasofensine undergoes extensive first-pass metabolism following oral administration in humans, monkeys, and rats. It primarily underwent O- and N-demethylation and isomerization. Some of the desmethyl metabolites were further converted to glucuronides. These primary metabolites and glucuronides of demethyl brasofensine (M1 and M2) were major circulating metabolites in humans, and were also observed in rat and monkey plasma.

Route of eliminationNot Available
Half life

Plasma terminal elimination half-lives were ~2 hr in rats, ~4 hr in monkeys, but ~24 hr in humans.

ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions Not Available
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General References
  1. Zhu M, Whigan DB, Chang SY, Dockens RC: Disposition and metabolism of [14C]brasofensine in rats, monkeys, and humans. Drug Metab Dispos. 2008 Jan;36(1):24-35. Epub 2007 Oct 1. [PubMed:17908924 ]
  2. Johnston TH, Brotchie JM: Drugs in development for Parkinson's disease. Curr Opin Investig Drugs. 2004 Jul;5(7):720-6. [PubMed:15298067 ]
  3. Frackiewicz EJ, Jhee SS, Shiovitz TM, Webster J, Topham C, Dockens RC, Whigan D, Salazar DE, Cutler NR: Brasofensine treatment for Parkinson's disease in combination with levodopa/carbidopa. Ann Pharmacother. 2002 Feb;36(2):225-30. [PubMed:11847938 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Clinical Trials
Clinical Trials Not Available
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00111 mg/mLALOGPS
logP4.31ALOGPS
logP3.8ChemAxon
logS-5.5ALOGPS
pKa (Strongest Basic)9.45ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area24.83 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity86.73 m3·mol-1ChemAxon
Polarizability34.52 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9958
Blood Brain Barrier+0.981
Caco-2 permeable+0.542
P-glycoprotein substrateSubstrate0.5252
P-glycoprotein inhibitor IInhibitor0.8049
P-glycoprotein inhibitor IIInhibitor0.6967
Renal organic cation transporterInhibitor0.7405
CYP450 2C9 substrateNon-substrate0.7579
CYP450 2D6 substrateNon-substrate0.7336
CYP450 3A4 substrateSubstrate0.6995
CYP450 1A2 substrateNon-inhibitor0.6403
CYP450 2C9 inhibitorNon-inhibitor0.6043
CYP450 2D6 inhibitorNon-inhibitor0.713
CYP450 2C19 inhibitorNon-inhibitor0.5759
CYP450 3A4 inhibitorNon-inhibitor0.8336
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5348
Ames testNon AMES toxic0.6484
CarcinogenicityNon-carcinogens0.7764
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.7447 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9187
hERG inhibition (predictor II)Non-inhibitor0.5467
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenyltropanes. These are compounds containing a phenyl group linked to a tropane moiety. Tropane is an organonitrogenous [3.2.1] bicyclic organic compound.
KingdomOrganic compounds
Super ClassAlkaloids and derivatives
ClassTropane alkaloids
Sub ClassPhenyltropanes
Direct ParentPhenyltropanes
Alternative ParentsPhenylpiperidines / Dichlorobenzenes / Aralkylamines / N-alkylpyrrolidines / Aryl chlorides / Trialkylamines / Oxime ethers / Azacyclic compounds / Organooxygen compounds / Organochlorides
SubstituentsPhenyltropane / Phenylpiperidine / 1,2-dichlorobenzene / Aralkylamine / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / Benzenoid / N-alkylpyrrolidine
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Potassium channel regulator activity
Specific Function:
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name:
DRD2
Uniprot ID:
P14416
Uniprot Name:
D(2) dopamine receptor
Molecular Weight:
50618.91 Da
References
  1. Zhu M, Whigan DB, Chang SY, Dockens RC: Disposition and metabolism of [14C]brasofensine in rats, monkeys, and humans. Drug Metab Dispos. 2008 Jan;36(1):24-35. Epub 2007 Oct 1. [PubMed:17908924 ]
Drug created on October 18, 2007 18:19 / Updated on June 11, 2017 20:59