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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 KeyInChIKey=ADEBPBSSDYVVLD-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
    Donepezil metabolite M3Details
    Donepezil
      Donepezil metabolite M5Details
      Donepezil
        Donepezil metabolite M6Details
        Donepezil metabolite M3
          Donepezil metabolite M7Details
          Donepezil metabolite M7
            Donepezil metabolite M7 sulfateDetails
            Donepezil metabolite M4
              Donepezil metabolite M8Details
              5-O-Desmethyldonepezil
                Donepezil metabolite M9Details
                6-O-Desmethyldonepezil
                  Donepezil metabolite M9Details
                  Donepezil metabolite M9
                    Donepezil metabolite M10Details
                    5-O-Desmethyldonepezil
                      Donepezil metabolite M7Details
                      Donepezil metabolite M7
                        Donepezil metabolite M10Details
                        6-O-Desmethyldonepezil
                          Donepezil metabolite M11Details
                          5-O-Desmethyldonepezil
                            Donepezil metabolite M12Details
                            Donepezil metabolite M9
                              Donepezil metabolite M13Details
                              Donepezil metabolite M9
                                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.

                                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

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