Brasofensine

Identification

Name
Brasofensine
Accession Number
DB04857
Type
Small Molecule
Groups
Investigational
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
Synonyms
Not Available
External IDs
BMS-204756 / NS-2214
Categories
UNII
1YP2S94RVH
CAS number
171655-91-7
Weight
Average: 327.25
Monoisotopic: 326.0952687
Chemical Formula
C16H20Cl2N2O
InChI Key
NRLIFEGHTNUYFL-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][[email protected]@]12CC[[email protected]@]([H])(N1C)[[email protected]]([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.

TargetActionsOrganism
UD(2) dopamine receptorNot AvailableHuman
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 distribution
Not Available
Protein binding
Not 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 elimination
Not Available
Half life

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

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

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
KEGG Drug
D03153
PubChem Compound
9614919
PubChem Substance
175426867
ChemSpider
7888898
ChEMBL
CHEMBL2104184

Clinical Trials

Clinical Trials
Not Available

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 Solubility0.00111 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
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

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Alkaloids and derivatives
Class
Tropane alkaloids
Sub Class
Phenyltropanes
Direct Parent
Phenyltropanes
Alternative Parents
Phenylpiperidines / Dichlorobenzenes / Aralkylamines / N-alkylpyrrolidines / Aryl chlorides / Trialkylamines / Oxime ethers / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds
show 2 more
Substituents
Phenyltropane / Phenylpiperidine / 1,2-dichlorobenzene / Chlorobenzene / Halobenzene / Aralkylamine / Benzenoid / N-alkylpyrrolidine / Piperidine / Aryl chloride
show 18 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not 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 December 01, 2017 15:33