Phenserine

Identification

Generic Name
Phenserine
DrugBank Accession Number
DB04892
Background

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.

Type
Small Molecule
Groups
Investigational
Structure
Weight
Average: 337.4155
Monoisotopic: 337.179026995
Chemical Formula
C20H23N3O2
Synonyms
  • (-)-eseroline phenylcarbamate
  • (-)-phenserine

Pharmacology

Indication

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

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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
UCholinesterase
inhibitor
Humans
UAmyloid beta A4 proteinNot AvailableHumans
UAcetylcholinesteraseNot AvailableHumans
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

Adverse Effects
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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.

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.
DrugInteraction
AcebutololPhenserine may increase the bradycardic activities of Acebutolol.
AcetylcholineThe risk or severity of adverse effects can be increased when Phenserine is combined with Acetylcholine.
AclidiniumPhenserine may increase the neuromuscular blocking activities of Aclidinium.
AmantadineThe therapeutic efficacy of Amantadine can be decreased when used in combination with Phenserine.
AmifampridineThe risk or severity of adverse effects can be increased when Phenserine is combined with Amifampridine.
Food Interactions
Not Available

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
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
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Substituents
Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carbamic acid ester / Carbonic acid derivative / Carbonyl group / Dialkylarylamine / Hydrocarbon derivative / Indole / Monocyclic benzene moiety
show 11 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
SUE285UG3S
CAS number
101246-66-6
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][C@]12N(C)CC[C@@]1(C)C1=C(C=CC(OC(=O)NC3=CC=CC=C3)=C1)N2C

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. [Article]
  2. Klein J: Phenserine. Expert Opin Investig Drugs. 2007 Jul;16(7):1087-97. [Article]
  3. Thatte U: Phenserine (Axonyx/NIH). IDrugs. 2000 Oct;3(10):1222-8. [Article]
PubChem Compound
192706
PubChem Substance
175426894
ChemSpider
167225
BindingDB
10958
ChEMBL
CHEMBL74926
ZINC
ZINC000052968892

Clinical Trials

Clinical Trials
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns

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/MSsplash10-000i-0039000000-028baf5ce2c6d4fe262d
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-1249000000-403b07c9acc3f19de818
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-0039000000-a660f08d65df024bc22e
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0v4j-9743000000-1f1be00517b978712482
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-1091000000-949780f34ffce98cf448
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-02al-4981000000-aa13e4abd99d0e15b919
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-181.79996
predicted
DeepCCS 1.0 (2019)
[M+H]+184.15794
predicted
DeepCCS 1.0 (2019)
[M+Na]+190.60362
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
Details
3. Acetylcholinesterase
Kind
Protein
Organism
Humans
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. [Article]
  2. Klein J: Phenserine. Expert Opin Investig Drugs. 2007 Jul;16(7):1087-97. [Article]

Drug created at October 21, 2007 17:34 / Updated at June 12, 2020 16:52