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Identification
NameDonepezil
Accession NumberDB00843  (APRD00039)
Typesmall molecule
Groupsapproved
Description

Donepezil (Aricept), is a centrally acting reversible acetyl cholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer’s disease where it is used to increase cortical acetylcholine. Donepezil is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. If this proposed mechanism of action is correct, donepezil’s effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. Donepezil has been tested in other cognitive disorders including Lewy body dementia and Vascular dementia, but it is not currently approved for these indications. Donepezil has also been studied in patients with Mild Cognitive Impairment, schizophrenia, attention deficit disorder, post-coronary bypass cognitive impairment, cognitive impairment associated with multiple sclerosis, and Down syndrome.

Structure
Thumb
Synonyms
SynonymLanguageCode
DomepezilNot AvailableIS
DonepezilGermanINN
DonepezilFrenchINN
DonepeziloSpanishINN
DonepezilumLatinINN
Salts
Name/CAS Structure Properties
Donepezil hydrochloride
Thumb Not applicable DBSALT000938
Brand names
NameCompany
AlzepilEgis
AriceptPfizer
Aricept ODTPfizer
DaviaTerapia
DepzilPsyco Remedies
DoneceptActavis
DonecilABL Pharma
DonepAlkem
DonepexSchafer
DonesynSynthon
DopezilMedis
EranzWyeth
Memac Pfizer
Nomi-NoxJohnson
PezaleSandoz
RedumasTeva
ZolpezilActavis
Brand mixtures
Brand NameIngredients
Carrier PlusDonepezil and Memantine
CategoriesNot Available
CAS number120014-06-4
WeightAverage: 379.492
Monoisotopic: 379.214743799
Chemical FormulaC24H29NO3
InChI KeyADEBPBSSDYVVLD-UHFFFAOYSA-N
InChI
InChI=1S/C24H29NO3/c1-27-22-14-19-13-20(24(26)21(19)15-23(22)28-2)12-17-8-10-25(11-9-17)16-18-6-4-3-5-7-18/h3-7,14-15,17,20H,8-13,16H2,1-2H3
IUPAC Name
2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one
SMILES
COC1=C(OC)C=C2C(=O)C(CC3CCN(CC4=CC=CC=C4)CC3)CC2=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassPiperidines
SubclassN-Benzylpiperidines
Direct parentN-Benzylpiperidines
Alternative parentsIndanones; Anisoles; Alkyl Aryl Ethers; Ketones; Tertiary Amines; Polyamines
Substituentsindanone; indane; anisole; phenol ether; alkyl aryl ether; benzene; ketone; tertiary amine; polyamine; ether; carbonyl group; amine; organonitrogen compound
Classification descriptionThis compound belongs to the n-benzylpiperidines. These are heterocyclic Compounds containing a piperidine ring conjugated to a benzyl group through one nitrogen ring atom.
Pharmacology
IndicationFor the palliative treatment of mild to moderate dementia of the Alzheimer's type.
PharmacodynamicsDonepezil is a centrally acting reversible acetyl cholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine. An early pathophysiological feature of Alzheimer's disease that is associated with memory loss and cognitive deficits is a deficiency of acetylcholine as a result of selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus. Donepezil is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. If this proposed mechanism of action is correct, donepezil's effect may lessen as the disease progresses and fewer cholinergic neurons remain functionally intact. There is no evidence that donepezil alters the course of the underlying dementing process.
Mechanism of actionDonepezil is a piperidine derivative that is a centerally active, reversible inhibitor of acetylcholinesterase. This drug is structurally unrelated to other anticholinesterase agents. Donepezil's proposed mechanism of action involves the reversible inhibition of cholinesterases (eg. acetylcholinesterase), which prevents the hydrolysis of acetycholine, and leads to an increased concentration of acetylcholine at cholinergic synapses. Evidence suggests that the anticholinesterase activity of donepezil is relatively specific for acetylcholinesterase in the brain.
AbsorptionDonepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours.
Volume of distribution
  • 12 L/kg
Protein binding96%
Metabolism

Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 in the liver and also undergoes glucuronidation. The main metabolite, 6-O-desmethyl donepezil, has been reported to inhibit AChE to the same extent as donepezil in vitro.

SubstrateEnzymesProduct
Donepezil
5-O-DesmethyldonepezilDetails
Donepezil
6-O-DesmethyldonepezilDetails
Donepezil
Donepezil metabolite M4Details
Donepezil
Not Available
Donepezil metabolite M3Details
Donepezil
Not Available
Donepezil metabolite M5Details
Donepezil
Not Available
Donepezil metabolite M6Details
Donepezil metabolite M3
Not Available
Donepezil metabolite M7Details
Donepezil metabolite M7
Not Available
Donepezil metabolite M7 sulfateDetails
Donepezil metabolite M4
Not Available
Donepezil metabolite M8Details
5-O-Desmethyldonepezil
Not Available
Donepezil metabolite M9Details
6-O-Desmethyldonepezil
Not Available
Donepezil metabolite M9Details
Donepezil metabolite M9
Not Available
Donepezil metabolite M10Details
5-O-Desmethyldonepezil
Not Available
Donepezil metabolite M7Details
Donepezil metabolite M7
Not Available
Donepezil metabolite M10Details
6-O-Desmethyldonepezil
Not Available
Donepezil metabolite M11Details
5-O-Desmethyldonepezil
Not Available
Donepezil metabolite M12Details
Donepezil metabolite M9
Not Available
Donepezil metabolite M13Details
Donepezil metabolite M9
Not Available
Donepezil metabolite M14Details
Route of eliminationDonepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified.
Half life70 hours
Clearance
  • apparent plasma cl=0.13 L/hr/kg
ToxicitySymptoms of overdose include severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9966
Blood Brain Barrier + 0.9953
Caco-2 permeable + 0.7742
P-glycoprotein substrate Substrate 0.7721
P-glycoprotein inhibitor I Inhibitor 0.7641
P-glycoprotein inhibitor II Inhibitor 0.8202
Renal organic cation transporter Inhibitor 0.7696
CYP450 2C9 substrate Non-substrate 0.8465
CYP450 2D6 substrate Substrate 0.8919
CYP450 3A4 substrate Substrate 0.7202
CYP450 1A2 substrate Inhibitor 0.5072
CYP450 2C9 substrate Non-inhibitor 0.8189
CYP450 2D6 substrate Inhibitor 0.8684
CYP450 2C19 substrate Non-inhibitor 0.8356
CYP450 3A4 substrate Non-inhibitor 0.7411
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6138
Ames test Non AMES toxic 0.6441
Carcinogenicity Non-carcinogens 0.9528
Biodegradation Not ready biodegradable 0.9145
Rat acute toxicity 3.0123 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.5386
hERG inhibition (predictor II) Inhibitor 0.8095
Pharmacoeconomics
Manufacturers
  • Eisai inc
  • Mutual pharmaceutical co inc
  • Teva pharmaceuticals usa inc
Packagers
Dosage forms
FormRouteStrength
TabletOral
Tablet, orally disintegratingOral
Prices
Unit descriptionCostUnit
Aricept ODT 30 5 mg Dispersible Tablet Box272.99USDbox
Aricept 10 mg tablet10.93USDtablet
Aricept 5 mg tablet9.78USDtablet
Aricept odt 10 mg tablet8.03USDtablet
Aricept odt 5 mg tablet8.03USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States77275482002-06-232022-06-23
United States48958411993-11-252010-11-25
Canada22528062005-11-222017-06-06
Canada13388081996-12-242013-12-24
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point206.72 °CNot Available
water solubility2.931 mg/LNot Available
logP3.6Not Available
Predicted Properties
PropertyValueSource
water solubility4.50e-03 g/lALOGPS
logP4.14ALOGPS
logP4.21ChemAxon
logS-4.9ALOGPS
pKa (strongest acidic)17.02ChemAxon
pKa (strongest basic)8.62ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count0ChemAxon
polar surface area38.77ChemAxon
rotatable bond count6ChemAxon
refractivity112.11ChemAxon
polarizability44.34ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Akio Imai, Hideaki Watanabe, Takashi Kajima, Yasushi Ishihama, Akiyo Ohtsuka, Tomohide Tanaka, Yukio Narabu, “Polymorphs of donepezil hydrochloride and process for production.” U.S. Patent US5985864, issued December, 1988.

US5985864
General Reference
  1. Xiong G, Doraiswamy PM: Combination drug therapy for Alzheimer’s disease: what is evidence-based, and what is not? Geriatrics. 2005 Jun;60(6):22-6. Pubmed
  2. Yesavage JA, Mumenthaler MS, Taylor JL, Friedman L, O’Hara R, Sheikh J, Tinklenberg J, Whitehouse PJ: Donepezil and flight simulator performance: effects on retention of complex skills. Neurology. 2002 Jul 9;59(1):123-5. Pubmed
  3. Sugimoto H: Donepezil hydrochloride: a treatment drug for Alzheimer’s disease. Chem Rec. 2001;1(1):63-73. Pubmed
External Links
ResourceLink
KEGG DrugD00670
PubChem Compound3152
PubChem Substance46504803
ChemSpider3040
BindingDB8960
ChEBI53289
ChEMBLCHEMBL502
Therapeutic Targets DatabaseDAP000560
PharmGKBPA449394
Drug Product Database2232044
RxListhttp://www.rxlist.com/cgi/generic/donepezil.htm
Drugs.comhttp://www.drugs.com/cdi/donepezil.html
WikipediaDonepezil
ATC CodesN06DA02
AHFS Codes
  • 12:04.00
PDB Entries
FDA labelshow(303 KB)
MSDSshow(58.2 KB)
Interactions
Drug Interactions
Drug
AcepromazinePossible antagonism of action
AceprometazinePossible antagonism of action
AlimemazinePossible antagonism of action
AlverinePossible antagonism of action
AmantadinePossible antagonism of action
AmitriptylinePossible antagonism of action
AmoxapinePossible antagonism of action
AtropinePossible antagonism of action
AzatadinePossible antagonism of action
BenzatropinePossible antagonism of action
BiperidenPossible antagonism of action
BrompheniraminePossible antagonism of action
CarbinoxaminePossible antagonism of action
ChlorphenaminePossible antagonism of action
ChlorpromazinePossible antagonism of action
ChlorprothixenePossible antagonism of action
CimetidinePossible antagonism of action
ClemastinePossible antagonism of action
ClidiniumPossible antagonism of action
ClomipraminePossible antagonism of action
ClozapinePossible antagonism of action
CyclizinePossible antagonism of action
CyclobenzaprinePossible antagonism of action
CyproheptadinePossible antagonism of action
DarifenacinPossible antagonism of action
DesipraminePossible antagonism of action
DexbrompheniraminePossible antagonism of action
DicyclominePossible antagonism of action
DimenhydrinatePossible antagonism of action
DiphenhydraminePossible antagonism of action
DiphenoxylatePossible antagonism of action
DiphenylpyralinePossible antagonism of action
DisopyramidePossible antagonism of action
DoxepinPossible antagonism of action
DoxylaminePossible antagonism of action
EthopropazinePossible antagonism of action
FlavoxatePossible antagonism of action
FlupentixolPossible antagonism of action
GlutethimidePossible antagonism of action
GlycopyrrolatePossible antagonism of action
HydroxyzinePossible antagonism of action
HyoscyaminePossible antagonism of action
ImipraminePossible antagonism of action
IsocarboxazidPossible antagonism of action
IsopropamidePossible antagonism of action
LoxapinePossible antagonism of action
MaprotilinePossible antagonism of action
MeclizinePossible antagonism of action
MesoridazinePossible antagonism of action
MethdilazinePossible antagonism of action
MethotrimeprazinePossible antagonism of action
Methylscopolamine bromidePossible antagonism of action
MirtazapinePossible antagonism of action
MoclobemidePossible antagonism of action
MolindonePossible antagonism of action
NortriptylinePossible antagonism of action
OlanzapinePossible antagonism of action
OrphenadrinePossible antagonism of action
OxybutyninPossible antagonism of action
PerphenazinePossible antagonism of action
PethidinePossible antagonism of action
PhenelzinePossible antagonism of action
PhenindaminePossible antagonism of action
PimozidePossible antagonism of action
PipotiazinePossible antagonism of action
ProcainamidePossible antagonism of action
ProchlorperazinePossible antagonism of action
ProcyclidinePossible antagonism of action
PromazinePossible antagonism of action
PromethazinePossible antagonism of action
PropanthelinePossible antagonism of action
PropericiazinePossible antagonism of action
ProtriptylinePossible antagonism of action
QuetiapinePossible antagonism of action
QuinidinePossible antagonism of action
Quinidine barbituratePossible antagonism of action
RisperidonePossible antagonism of action
ScopolaminePossible antagonism of action
SertralinePossible antagonism of action
SolifenacinPossible antagonism of action
ThioproperazinePossible antagonism of action
ThioridazinePossible antagonism of action
ThiothixenePossible antagonism of action
TizanidinePossible antagonism of action
TolterodinePossible antagonism of action
TranylcyprominePossible antagonism of action
TrazodonePossible antagonism of action
TrifluoperazinePossible antagonism of action
TriflupromazinePossible antagonism of action
TrihexyphenidylPossible antagonism of action
TrimethobenzamideThe therapeutic effects of the anticholinergic, Trimethobenzamide, and/or the acetylcholinesterase inhibitor (central), Donepezil, may be reduced due to antagonism. Monitor therapeutic effects of both agents.
TrimipraminePossible antagonism of action
TripelennaminePossible antagonism of action
TriprolidinePossible antagonism of action
TrospiumThe therapeutic effects of the anticholinergic, Trospium, and/or the acetylcholinesterase inhibitor (central), Donepezil, may be reduced due to antagonism. Monitor therapeutic effects of both agents.
ZiprasidonePossible antagonism of action
ZuclopenthixolPossible antagonism of action
Zuclopenthixol acetatePossible antagonism of action.
Zuclopenthixol decanoatePossible antagonism of action.
Food Interactions
  • Avoid alcohol.
  • Take without regard to meals.

Targets

1. Acetylcholinesterase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Acetylcholinesterase P22303 Details

References:

  1. Davis KL: Alzheimer’s disease: seeking new ways to preserve brain function. Interview by Alice V. Luddington. Geriatrics. 1999 Feb;54(2):42-7; quiz 48. Pubmed
  2. Kryger G, Silman I, Sussman JL: Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. Structure. 1999 Mar 15;7(3):297-307. Pubmed
  3. Shepherd G, Klein-Schwartz W, Edwards R: Donepezil overdose: a tenfold dosing error. Ann Pharmacother. 1999 Jul-Aug;33(7-8):812-5. Pubmed
  4. Kosasa T, Kuriya Y, Matsui K, Yamanishi Y: Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats. Eur J Pharmacol. 1999 Sep 10;380(2-3):101-7. Pubmed
  5. Jann MW: Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer’s disease. Pharmacotherapy. 2000 Jan;20(1):1-12. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Sugimoto H: Donepezil hydrochloride: a treatment drug for Alzheimer’s disease. Chem Rec. 2001;1(1):63-73. Pubmed
  8. Ki YS, Park EY, Lee HW, Oh MS, Cho YW, Kwon YK, Moon JH, Lee KT: Donepezil, a potent acetylcholinesterase inhibitor, induces caspase-dependent apoptosis in human promyelocytic leukemia HL-60 cells. Biol Pharm Bull. 2010;33(6):1054-9. Pubmed
  9. Repantis D, Laisney O, Heuser I: Acetylcholinesterase inhibitors and memantine for neuroenhancement in healthy individuals: a systematic review. Pharmacol Res. 2010 Jun;61(6):473-81. Epub 2010 Mar 1. Pubmed

2. 5-hydroxytryptamine receptor 2A

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other/unknown

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 2A P28223 Details

References:

  1. Hayslett RL, Tizabi Y: Effects of donepezil, nicotine and haloperidol on the central serotonergic system in mice: implications for Tourette’s syndrome. Pharmacol Biochem Behav. 2005 Aug;81(4):879-86. Pubmed
  2. Hayslett RL, Tizabi Y: Effects of donepezil on DOI-induced head twitch response in mice: implications for Tourette syndrome. Pharmacol Biochem Behav. 2003 Dec;76(3-4):409-15. Pubmed

Enzymes

1. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

Comments
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12