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Identification
NamePhenserine
Accession NumberDB04892
TypeSmall Molecule
GroupsInvestigational
Description

Phenserine is under development by Axonyx, a US biopharmaceutical company that focuses on treatments for dementia. Phenserine is a next generation acetylcholinesterase (AChE) inhibitor indicated for the treatment of AD. Unlike currently marketed AChE inhibitors, it has a dual mechanism of action that also includes anti-amyloid activity, which may confer disease-modifying effects in patients with AD. If this is substantiated in an ongoing clinical trial then phenserine may open the door to an entirely new type of treatment for AD. Axonyx announced on 20 September 2005 that phenserine was ineffective in two curtailed phase 3 trials.

Structure
Thumb
Synonyms
(-)-eseroline phenylcarbamate
(-)-phenserine
External Identifiers 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
SaltsNot Available
CategoriesNot Available
UNIISUE285UG3S
CAS number101246-66-6
WeightAverage: 337.4155
Monoisotopic: 337.179026995
Chemical FormulaC20H23N3O2
InChI KeyInChIKey=PBHFNBQPZCRWQP-QUCCMNQESA-N
InChI
InChI=1S/C20H23N3O2/c1-20-11-12-22(2)18(20)23(3)17-10-9-15(13-16(17)20)25-19(24)21-14-7-5-4-6-8-14/h4-10,13,18H,11-12H2,1-3H3,(H,21,24)/t18-,20+/m1/s1
IUPAC Name
(3aS,8aR)-1,3a,8-trimethyl-1H,2H,3H,3aH,8H,8aH-pyrrolo[2,3-b]indol-5-yl N-phenylcarbamate
SMILES
[H][C@]12N(C)CC[C@@]1(C)C1=C(C=CC(OC(=O)NC3=CC=CC=C3)=C1)N2C
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as pyrroloindoles. These are compounds containing a pyrroloindole moiety, which is a tricyclic heterocycle which consists of a pyrrole ring fused to an indole. Pyrrole is 5-membered ring consisting of four carbon atoms and one nitrogen atom. Indole is a bicyclic compound consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassIndoles and derivatives
Sub ClassPyrroloindoles
Direct ParentPyrroloindoles
Alternative Parents
Substituents
  • Pyrroloindole
  • Phenylcarbamate
  • Indole
  • Dialkylarylamine
  • Benzenoid
  • N-alkylpyrrolidine
  • Monocyclic benzene moiety
  • Pyrrolidine
  • Pyrrole
  • Tertiary aliphatic amine
  • Tertiary amine
  • Azacycle
  • Monocarboxylic acid or derivatives
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the treatment of Alzheimer's disease (AD).
PharmacodynamicsPhenserine, a phenylcarbamate of physostigmine, is a reversible acetyl-selective cholinesterase inhibitor. In studies of rats with lesions of the forebrain cholinergic system, injections of phenserine was found to significantly decrease the levels of secreted beta-APP in the CSF of the rats. A study on cultured human brain cells found that phenserine reduces Abeta levels by regulating beta-APP translation.
Mechanism of actionPhenserine is a highly selective, reversible acetylcholinesterase inhibitor, a mechanism of action known to improve memory and cognition in Alzheimer’s subjects. Phenserine may prove to concentrate in the brain rapidly which would reduce the incidence of drug toxicity and side effects.
Related Articles
AbsorptionRapidly absorbed and cleared from the body.
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half life8 to 10 hours
ClearanceNot Available
ToxicityThe toxicity of phenserine, a derivate of physostigmine, is dramatically less. Doses of 20 mg/kg (rats, intravenous) of phenserine have not been associated with toxicity or deaths.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9959
Caco-2 permeable+0.5664
P-glycoprotein substrateSubstrate0.6917
P-glycoprotein inhibitor IInhibitor0.6794
P-glycoprotein inhibitor IIInhibitor0.6073
Renal organic cation transporterNon-inhibitor0.6463
CYP450 2C9 substrateNon-substrate0.7167
CYP450 2D6 substrateNon-substrate0.6433
CYP450 3A4 substrateSubstrate0.7843
CYP450 1A2 substrateNon-inhibitor0.8426
CYP450 2C9 inhibitorNon-inhibitor0.8863
CYP450 2D6 inhibitorInhibitor0.8163
CYP450 2C19 inhibitorNon-inhibitor0.8352
CYP450 3A4 inhibitorNon-inhibitor0.5605
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6125
Ames testNon AMES toxic0.8444
CarcinogenicityNon-carcinogens0.9126
BiodegradationNot ready biodegradable0.9256
Rat acute toxicity4.3485 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8968
hERG inhibition (predictor II)Non-inhibitor0.6199
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point150 °CNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0509 mg/mLALOGPS
logP3.38ALOGPS
logP4.25ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)12.86ChemAxon
pKa (Strongest Basic)6.58ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area44.81 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity99.96 m3·mol-1ChemAxon
Polarizability37.09 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Greig NH, Ruckle J, Comer P, Brownell L, Holloway HW, Flanagan DR Jr, Canfield CJ, Burford RG: Anticholinesterase and pharmacokinetic profile of phenserine in healthy elderly human subjects. Curr Alzheimer Res. 2005 Oct;2(4):483-92. [PubMed:16248851 ]
  2. Klein J: Phenserine. Expert Opin Investig Drugs. 2007 Jul;16(7):1087-97. [PubMed:17594192 ]
  3. Thatte U: Phenserine (Axonyx/NIH). IDrugs. 2000 Oct;3(10):1222-8. [PubMed:16049844 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Serine hydrolase activity
Specific Function:
Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.
Gene Name:
ACHE
Uniprot ID:
P22303
Molecular Weight:
67795.525 Da
References
  1. Greig NH, Ruckle J, Comer P, Brownell L, Holloway HW, Flanagan DR Jr, Canfield CJ, Burford RG: Anticholinesterase and pharmacokinetic profile of phenserine in healthy elderly human subjects. Curr Alzheimer Res. 2005 Oct;2(4):483-92. [PubMed:16248851 ]
  2. Klein J: Phenserine. Expert Opin Investig Drugs. 2007 Jul;16(7):1087-97. [PubMed:17594192 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Identical protein binding
Specific Function:
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name:
BCHE
Uniprot ID:
P06276
Molecular Weight:
68417.575 Da
References
  1. Janas AM, Cunningham SC, Duffy KB, Devan BD, Greig NH, Holloway HW, Yu QS, Markowska AL, Ingram DK, Spangler EL: The cholinesterase inhibitor, phenserine, improves Morris water maze performance of scopolamine-treated rats. Life Sci. 2005 Jan 21;76(10):1073-81. [PubMed:15620572 ]
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Drug created on October 21, 2007 11:34 / Updated on September 16, 2013 17:26