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CAS 120014-06-4

CAS 120014-06-4

Chemistry, 1 End Use API, 27 Related Intermediates

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Also known as: 120014-06-4, Aricept, 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1h-inden-1-one, Donepezilo, Donaz, 2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one

Molecular Formula

C₂₄H₂₉NO₃

Molecular Weight

379.5 g/mol

InChI Key

ADEBPBSSDYVVLD-UHFFFAOYSA-N

FDA UNII

8SSC91326P

An indan and piperidine derivative that acts as a selective and reversible inhibitor of ACETYLCHOLINESTERASE. Donepezil is highly selective for the central nervous system and is used in the management of mild to moderate DEMENTIA in ALZHEIMER DISEASE.

Donepezil is a Cholinesterase Inhibitor. The mechanism of action of donepezil is as a Cholinesterase Inhibitor.

1 2D Structure

CAS 120014-06-4

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one

2.1.2 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

2.1.3 InChI Key

ADEBPBSSDYVVLD-UHFFFAOYSA-N

2.1.4 Canonical SMILES

COC1=C(C=C2C(=C1)CC(C2=O)CC3CCN(CC3)CC4=CC=CC=C4)OC

2.2 Other Identifiers

2.2.1 UNII

8SSC91326P

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine Hydrochloride

2. Aricept

3. Donepezil Hydrochloride

4. Donepezilium Oxalate Trihydrate

5. E 2020

6. E-2020

7. E2020

8. Eranz

2.3.2 Depositor-Supplied Synonyms

1. 120014-06-4

2. Aricept

3. 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1h-inden-1-one

4. Donepezilo

5. Donaz

6. 2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one

7. 2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydro-1h-inden-1-one

8. Hsdb 7743

9. 142057-79-2

10. Chembl502

11. (s)-e2020 (free Base)

12. Chebi:53289

13. 8ssc91326p

14. Donepezil (inn)

15. 2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one

16. Donepezil [inn]

17. D-797

18. 1h-inden-1-one, 2,3-dihydro-5,6-dimethoxy-2-((1-(phenylmethyl)-4-piperidinyl)methyl)-

19. 142057-80-5

20. Donepezil [inn:ban]

21. (rs)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxyindan-1-one

22. 1h-inden-1-one, 2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-

23. 2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1h-inden-1-one

24. Nsc 737535

25. Nsc 758882

26. Ncgc00167537-01

27. Donepezilum

28. Domepezil

29. Unii-8ssc91326p

30. 2-((1-benzyl-4-piperidyl)methyl)-5,6-dimethoxy-2,3-dihydroinden-1-one

31. 2,3-dihydro-5,6-dimethoxy-2-((1-(phenylmethyl)-4-piperidinyl)methyl)-1h-inden-1-one

32. Donaz (tn)

33. Spectrum_001664

34. Donepezil [jan]

35. Donepezil [mi]

36. Donepezil [hsdb]

37. Spectrum5_001662

38. Donepezil [vandf]

39. Donepezil [who-dd]

40. Schembl2149

41. Oprea1_188452

42. Kbioss_002144

43. Bdbm8960

44. Gtpl6599

45. Schembl8265876

46. Dtxsid8048317

47. Kbio2_002144

48. Kbio2_004712

49. Kbio2_007280

50. Amy8939

51. Chebi:145499

52. Bcpp000253

53. Hms3886m11

54. Bcp07590

55. Mfcd00912833

56. S5073

57. Stk003905

58. Akos000277311

59. Akos016842349

60. Ac-6969

61. Bcp9000622

62. Ccg-268401

63. Db00843

64. Mrf-0000323

65. D797

66. Hy-14566

67. Sbi-0206789.p001

68. Ft-0601545

69. D07869

70. Ab00640013-07

71. Ab00640013-08

72. Ab00640013_09

73. Ab00640013_10

74. 014d064

75. Q415081

76. Q-100098

77. Brd-a49160188-003-04-4

78. Z1741977105

79. 2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxyindan-1-one

80. (+/-)-2-((1-benzyl-4-piperidyl)methyl)-5,6-dimethoxy-1-indanone

81. (+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one

82. 2-[(1-benzyl-4-piperidyl)methyl]- 5,6-dimethoxy-2,3-dihydroinden-1-one

83. 2,3-dihydro-5,6-dimethoxy-2 [[1-(phenyl Methyl)-4-piperidinyl]methyl]-1h-inden-1-one

84. 2,3-dihydro-5,6-dimethoxy-2[[1-(phenyl Methyl)-4-piperidinyl]methyl]-1h-inden-1-one

85. 5,6-dimethoxy-2-[[1-(phenylmethyl)piperidin-4-yl]methyl]-2,3-dihydroinden-1-one

86. 5,6-dimethoxy-2-((1-(phenylmethyl)-4-piperidinyl)methyl)-2,3-dihydro-1h-inden-1-one

2.4 Create Date

2005-03-25

3 Chemical and Physical Properties

Molecular Formula	C₂₄H₂₉NO₃
Molecular Weight	379.5 g/mol
XLogP3	4.3
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	6
Exact Mass	379.21474379 g/mol
Monoisotopic Mass	379.21474379 g/mol
Topological Polar Surface Area	38.8 Å²
Heavy Atom Count	28
Formal Charge	0
Complexity	510
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	1
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Information

1 of 2
Drug Name	ARICEPT ODT
Active Ingredient	DONEPEZIL HYDROCHLORIDE
Company	EISAI INC (Application Number: N021720)

2 of 2
Drug Name	ARICEPT
Active Ingredient	DONEPEZIL HYDROCHLORIDE
Company	EISAI INC (Application Number: N020690); EISAI INC (Application Number: N022568. Patent: 8481565)

4.2 Therapeutic Uses

Cholinesterase Inhibitors; Nootropic Agents

National Library of Medicine's Medical Subject Headings online file (MeSH, 2009)

Donepezil hydrochloride tablets are indicated for the treatment of dementia of the Alzheimer's type. Efficacy has been demonstrated in patients with mild to moderate Alzheimer's Disease. /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information for Donepezil Hydrochloride (donepezil hydrochloride) tablets, film coated (May 2008). Available from, as of June 29, 2009: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=7596

/EXPTL Ther:/ ... Officially approved for mild-to-moderate and severe /Alzheimer's Disease/ (AD), donepezil has also been shown to be effective in early-stage AD, vascular dementia, Parkinson's disease dementia/Lewy body disease and cognitive symptoms associated with multiple sclerosis. In addition, one study suggested that donepezil may delay the onset of AD in subjects with mild cognitive impairment, a prodrome to AD.

PMID:17472546 Seltzer B; Expert Opin Pharmacother 8 (7): 1011-23 (2007).

4.3 Drug Warning

Donepezil hydrochloride tablets are contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.

Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of donepezil hydrochloride. Syncopal episodes have been reported in association with the use of donepezil hydrochloride.

Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, eg, those with a history of ulcer disease or those receiving concurrent non-steroidal anti-inflammatory drugs (NSAIDS).

Donepezil hydrochloride, as a predictable consequence of its pharmacological properties, has been shown to produce diarrhea, nausea and vomiting. These effects, when they occur, appear more frequently with the 10 mg/day dose than with the 5 mg/day dose. In most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of donepezil hydrochloride.

For more Drug Warnings (Complete) data for Donepezil (12 total), please visit the HSDB record page.

4.4 Drug Indication

Donepezil is indicated for the management of mild to moderate Alzheimers Disease at doses of 5 mg or 10 mg. It is also indicated for the management of moderate to severe Alzheimers Disease in a higher dose of 10 mg or 23 mg administered once daily. Off-label uses include the management of vascular dementia, Parkinson's Disease-associated dementia, and Lewy body dementia, among others. When combined with memantine, the extended-release form of donepezil is indicated to treat the symptoms of moderate to severe dementia.

5 Pharmacology and Biochemistry

5.1 Pharmacology

By inhibiting the acetylcholinesterase enzyme, donepezil improves the cognitive and behavioral signs and symptoms of Alzheimer's Disease, which may include apathy, aggression, confusion, and psychosis.

5.2 MeSH Pharmacological Classification

Cholinesterase Inhibitors

Drugs that inhibit cholinesterases. The neurotransmitter ACETYLCHOLINE is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system. (See all compounds classified as Cholinesterase Inhibitors.)

Nootropic Agents

Drugs used to specifically facilitate learning or memory, particularly to prevent the cognitive deficits associated with dementias. These drugs act by a variety of mechanisms. (See all compounds classified as Nootropic Agents.)

5.3 FDA Pharmacological Classification

5.3.1 Active Moiety

DONEPEZIL

5.3.2 FDA UNII

8SSC91326P

5.3.3 Pharmacological Classes

Mechanisms of Action [MoA] - Cholinesterase Inhibitors

5.4 ATC Code

N06DA02

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

N - Nervous system

N06 - Psychoanaleptics

N06D - Anti-dementia drugs

N06DA - Anticholinesterases

N06DA02 - Donepezil

5.5 Absorption, Distribution and Excretion

Absorption

Donepezil is slowly absorbed via the gastrointestinal tract after oral administration. Tmax is 3 to 4 hours with a bioavailability of 100% and steady-state concentrations are attained within 15 to 21 days of administration. The Tmax in one pharmacokinetic study determined a Tmax of 4.1 1.5 hours. The Cmax of 5 mg donepezil tablets is estimated to be 8.34 ng/mL, according to the Canadian monograph. The AUC of 5 mg donepezil tablets has been determined to be 221.90-225.36 ng.hr/mL.

Route of Elimination

In a study of radiolabeled administration donepezil in healthy adults, 57% of measured radioactivity was identified in the urine, and 5% was identified in the feces.

Volume of Distribution

The volume of distribution of donepezil is 11.8 1.7 L/kg for a 5-mg dose and 11.6 1.91 L/kg for a 10-mg dose. It is largely distributed in the extravascular compartments. Donepezil crosses the blood-brain barrier and cerebrospinal fluid concentrations at the above doses have been measured at 15.7%. The volume of distribution at steady-state according to the FDA label for donepezil ranges from 12 - 16 L/kg.

Clearance

According to the FDA label, the average apparent plasma clearance of this drug is 0.13 0.19 L/hr/kg. A 5 mg dose of donepezil in healthy patients was shown to have a plasma clearance of 0.1100.02 L/h/kg. In 10 patients diagnosed with alcoholic cirrhosis, showed a mean decrease in clearance by 20% when compared to the clearance in 10 healthy subjects. In 4 patients with severe renal impairment compared to 4 healthy subjects, no significant change in clearance was noted.

Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours. Pharmacokinetics are linear over a dose range of 1 to 10 mg given once daily. Neither food nor time of administration (morning vs. evening dose) influences the rate or extent of absorption of donepezil hydrochloride tablets.

... The mean apparent plasma clearance (Cl/F) is 0.13 L/hr/kg. Following multiple dose administration, donepezil accumulates in plasma by 4 to 7 fold and steady state is reached within 15 days. The steady state volume of distribution is 12 L/kg.

In a study of 10 patients with stable alcoholic cirrhosis, the clearance of donepezil hydrochloride was decreased by 20% relative to 10 healthy age and sex matched subjects.

In a study of 11 patients with moderate to severe renal impairment (ClCr < 18 mL/min/1.73 sq m) the clearance of donepezil hydrochloride did not differ from 11 age and sex matched healthy subjects.

For more Absorption, Distribution and Excretion (Complete) data for Donepezil (12 total), please visit the HSDB record page.

5.6 Metabolism/Metabolites

Donepezil is metabolized by first pass metabolism in the liver, primarily by CYP3A4, in addition to CYP2D6. After this, O-dealkylation, hydroxylation, N-oxidation, hydrolysis, and O-glucuronidation occur, producing various metabolites with similar half-lives to the unchanged parent drug. A study of the pharmacokinetics of radiolabeled donepezil demonstrated that about 53% of plasma radioactivity appeared as donepezil in the unchanged form, and 11% was identified as the metabolite 6-O-desmethyl donepezil, which exerts similar potency inhibition of the acetylcholinesterase enzyme. This drug is heavily metabolized to four primary metabolites, two of which are considered pharmacologically active, as well as to multiple inactive and unidentified metabolites.

Donepezil 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. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Following administration of 14C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found in plasma at concentrations equal to about 20% of donepezil.

The aim of this study was to investigate the metabolism and elimination of donepezil HCl in humans, following the administration of a single 5 mg (liquid) oral dose containing a mixture of unlabelled and 14C-labelled donepezil. ... Unchanged donepezil accounted for the largest component of the recovered dose in each matrix. Three metabolic pathways were identified: (i) O-dealkylation and hydroxylation to metabolites M1 and M2, with subsequent glucuronidation to metabolites M11 and M12; (ii) hydrolysis to metabolite M4; and (iii) N-oxidation to metabolite M6. In plasma, the parent compound accounted for about 25% of the dose recovered during each sampling period, as well as of the cumulative dose recovered. The recovered residue showed higher levels of the hydroxylated metabolites M1 and M2 than of their glucuronide conjugates M11 and M12, respectively. In urine, the parent compound accounted for 17%, on average, of the dose recovered from each pooled sample, as well as of the total recovered dose. The major metabolite was the hydrolysis product M4, followed by the glucuronidated conjugates M11 and M12. In feces, the parent compound also predominated, although it accounted for only 1%, of the recovered dose. A large percentage of the radioactivity in feces consisted of unidentified very polar metabolites, which were retained at the TLC origin. Of the extracted metabolites, the hydroxylation products M1 and M2 were the most abundant, followed by the hydrolysis product M4 and the N-oxidation product M6. Donepezil is hepatically metabolized and the predominant route for the elimination of both parent drug and its metabolites is renal, as 79% of the recovered dose was found in the urine with the remaining 21% found in the feces. Moreover, the parent compound, donepezil, is the predominant elimination product in urine. The major metabolites of donepezil include M1 and M2 (via O-dealkylation and hydroxylation), M11 and M12 (via glucuronidation of M1 and M2, respectively), M4 (via hydrolysis) and M6 (via N-oxidation).

PMID:9839761 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873810 Tiseo PJ et al; Br J Clin Pharmacol 46 (Suppl 1): 19-24 (1998).

Donepezil has known human metabolites that include 5,6-dimethoxy-2-(piperidin-4-ylmethyl)-2,3-dihydroinden-1-one, 5-O-Desmethyl Donepezil, and 6-O-Desmethyl Donepezil.

S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

5.7 Biological Half-Life

The average elimination half-life of donepezil is about 70 hours according to the results of various studies and the FDA label for donepezil.. One pharmacokinetic study determined the average terminal half-life to be 81.522.0 h

The elimination half life of donepezil is about 70 hours.

A 79-year-old woman with Alzheimer's disease was admitted due to acute cholinergic symptoms induced by overdose (45 mg) of donepezil (DPZ) ... The plasma concentration of DPZ was 54.6 ng/mL on admission and gradually decreased to the normal limits in about 90 hr. The calculative half-life of DPZ was about 55 hr ...

PMID:14658400 Yano H et al; Rinsho Shinkeigaku 43 (8): 482-6 (2003).

5.8 Mechanism of Action

The commonly accepted cholinergic hypothesis proposes that a portion of the cognitive and behavioral decline associated with Alzheimer's are the result of decreased cholinergic transmission in the central nervous system. Donepezil selectively and reversibly inhibits the acetylcholinesterase enzyme, which normally breaks down acetylcholine. The main pharmacological actions of this drug are believed to occur as the result of this enzyme inhibition, enhancing cholinergic transmission, which relieves the symptoms of Alzheimer's dementia. In addition to the above, other mechanisms of action of donepezil are possible, including the opposition of glutamate-induced excitatory transmission via downregulation of NMDA receptors and the regulation of amyloid proteins, which have demonstrated significant effects on the disease process of Alzheimer's. Other possible targets for donepezil may also include the inhibition various inflammatory signaling pathways, exerting neuroprotective effects.

Donepezil hydrochloride, a piperidine derivative, is a centrally active, reversible inhibitor of acetylcholinesterase. The drug is structurally unrelated to other anticholinesterase agents (eg, tacrine, physostigmine).

American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1293

The precise mechanism(s) of action of donepezil in patients with dementia of the Alzheimer's type (Alzheimer's disease) has not been fully elucidated. The drug is an anticholinesterase agent that binds reversibly with and inactivates cholinesterases (eg, acetylcholinesterase), thus inhibiting hydrolysis of acetylcholine. As a result, the concentration of acetylcholine increases at cholinergic synapses. In vitro data and data in animals indicate that the anticholinesterase activity of donepezil is relatively specific for acetylcholinesterase in the brain compared with butyrylcholinesterase inhibition in peripheral tissues.

American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1293

A deficiency of acetylcholine caused by selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus is recognized as one of the early pathophysiologic features of Alzheimer's disease associated with memory loss and cognitive deficits. Because the resultant cortical deficiency of this neurotransmitter is believed to account for some of the clinical manifestations of mild to moderate dementia, enhancement of cholinergic function with an anticholinesterase agent, such as tacrine or donepezil, is one of the pharmacologic approaches to treatment. Because widespread degeneration of multiple central neuronal systems eventually occurs in patients with Alzheimer's disease, potentially beneficial effects of anticholinesterase agents theoretically would diminish as the disease process advances and fewer cholinergic neurons remain functioning.

American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1293

Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's Disease attribute some of them to a deficiency of cholinergic neurotransmission. Donepezil hydrochloride 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. There is no evidence that donepezil alters the course of the underlying dementing process.

For more Mechanism of Action (Complete) data for Donepezil (6 total), please visit the HSDB record page.