Identification

Name
Phenserine
Accession Number
DB04892
Type
Small Molecule
Groups
Investigational
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
Categories
UNII
SUE285UG3S
CAS number
101246-66-6
Weight
Average: 337.4155
Monoisotopic: 337.179026995
Chemical Formula
C20H23N3O2
InChI Key
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][[email protected]]12N(C)CC[[email protected]@]1(C)C1=C(C=CC(OC(=O)NC3=CC=CC=C3)=C1)N2C

Pharmacology

Indication

For the treatment of Alzheimer's disease (AD).

Structured Indications
Not Available
Pharmacodynamics

Phenserine, 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 action

Phenserine 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.

TargetActionsOrganism
UAcetylcholinesteraseNot AvailableHuman
UCholinesterase
inhibitor
Human
UAmyloid beta A4 proteinNot AvailableHuman
Absorption

Rapidly absorbed and cleared from the body.

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

8 to 10 hours

Clearance
Not Available
Toxicity

The 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

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
PubChem Compound
192706
PubChem Substance
175426894
ChemSpider
167225
BindingDB
10958
ChEMBL
CHEMBL74926

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
PropertyValueSource
melting point (°C)150 °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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Pyrroloindoles
Direct Parent
Pyrroloindoles
Alternative Parents
Phenylcarbamic acid esters / Indoles / Dialkylarylamines / N-alkylpyrrolidines / Pyrroles / Carbamate esters / Organic carbonic acids and derivatives / Azacyclic compounds / Organopnictogen compounds / Organic oxides
show 2 more
Substituents
Pyrroloindole / Phenylcarbamic acid ester / Indole / Dialkylarylamine / Monocyclic benzene moiety / Benzenoid / N-alkylpyrrolidine / Pyrrole / Pyrrolidine / Carbamic acid ester
show 11 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Details
1. Acetylcholinesterase
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
Uniprot Name
Acetylcholinesterase
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
Uniprot Name
Cholinesterase
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]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Transition metal ion binding
Specific Function
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and tra...
Gene Name
APP
Uniprot ID
P05067
Uniprot Name
Amyloid beta A4 protein
Molecular Weight
86942.715 Da
References
  1. Venti A, Giordano T, Eder P, Bush AI, Lahiri DK, Greig NH, Rogers JT: The integrated role of desferrioxamine and phenserine targeted to an iron-responsive element in the APP-mRNA 5'-untranslated region. Ann N Y Acad Sci. 2004 Dec;1035:34-48. [PubMed:15681799]

Drug created on October 21, 2007 11:34 / Updated on December 01, 2017 15:34