Donepezil hydrochloride
[CAS# 120011-70-3]

Identification

• Classification: Biochemical >> Inhibitor >> Neuronal signaling >> AChR inhibitor
• Name: Donepezil hydrochloride
• Synonyms: 2,3-Dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride
• Molecular Formula: C₂₄H₂₉NO₃.HCl
• Molecular Weight: 415.95
• CAS Registry Number: 120011-70-3
• EC Number: 620-543-2
• SMILES: COC1=C(C=C2C(=C1)CC(C2=O)CC3CCN(CC3)CC4=CC=CC=C4)OC.Cl

Properties

• Solubility: Soluble 75 mM (water), 10 mM (DMSO) (Expl.)

Safety Data

• Hazard Symbols: GHS06;GHS07 Danger
• Risk Statements: H300-H301-H319
• Safety Statements: P264-P264+P265-P270-P280-P301+P316-P305+P351+P338-P321-P330-P337+P317-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	3	H301
Eye irritation	Eye Irrit.	2	H319
Eye irritation	Eye Irrit.	2A	H319
Acute toxicity	Acute Tox.	1	H300
Acute toxicity	Acute Tox.	2	H300
Acute toxicity	Acute Tox.	4	H302
Acute toxicity	Acute Tox.	4	H332
Skin irritation	Skin Irrit.	2	H315
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute toxicity	Acute Tox.	4	H312
Germ cell mutagenicity	Muta.	1A	H340
Serious eye damage	Eye Dam.	1	H318
Chronic hazardous to the aquatic environment	Aquatic Chronic	4	H413

Discovery and Applications

Donepezil hydrochloride is the hydrochloride salt form of donepezil, a centrally acting, reversible acetylcholinesterase inhibitor used in the treatment of neurodegenerative disorders. It is most commonly prescribed for the symptomatic management of Alzheimer’s disease. The compound increases the concentration of acetylcholine in the brain by inhibiting the enzyme acetylcholinesterase, which breaks down acetylcholine in the synaptic cleft. This mechanism of action aims to enhance cholinergic function, which is typically impaired in patients with Alzheimer’s disease.

The discovery of donepezil hydrochloride emerged from research efforts in the 1980s by Eisai Co., Ltd., in collaboration with the Pfizer Inc. subsidiary Parke-Davis. The goal was to develop an acetylcholinesterase inhibitor with high specificity for the central nervous system, minimal peripheral side effects, and favorable pharmacokinetic properties. Donepezil was identified as a lead candidate due to its high selectivity for brain acetylcholinesterase over butyrylcholinesterase and its ability to cross the blood-brain barrier efficiently.

Following preclinical development and clinical trials, donepezil hydrochloride was approved by the U.S. Food and Drug Administration (FDA) in 1996 for the treatment of mild to moderate Alzheimer’s disease. It was later approved for use in patients with severe forms of the disease. Donepezil hydrochloride was marketed under the brand name Aricept and became one of the most widely used medications for the symptomatic management of Alzheimer’s disease worldwide.

Donepezil hydrochloride is available in oral tablet and orally disintegrating tablet forms. The drug exhibits favorable pharmacokinetics, including high oral bioavailability, long elimination half-life of approximately 70 hours, and once-daily dosing. It is primarily metabolized in the liver by cytochrome P450 enzymes, especially CYP2D6 and CYP3A4, with renal and biliary excretion of its metabolites.

In clinical use, donepezil hydrochloride is indicated to improve cognitive function and reduce the progression of symptoms in individuals with Alzheimer’s disease. It does not cure or halt the progression of the disease but can provide temporary stabilization or modest improvement in cognitive measures such as memory, attention, and reasoning. It is often used in combination with other therapies or supportive care strategies.

Beyond Alzheimer’s disease, donepezil hydrochloride has also been studied for use in other neurological disorders, including vascular dementia, Parkinson’s disease dementia, and dementia with Lewy bodies. However, regulatory approvals for these indications vary by region, and its primary indication remains Alzheimer’s disease.

Donepezil hydrochloride is generally well tolerated, though common side effects include nausea, diarrhea, insomnia, muscle cramps, and fatigue. Less common but serious adverse reactions include bradycardia, syncope, and gastrointestinal bleeding. These effects are associated with enhanced cholinergic activity and are typically dose-dependent.

The therapeutic relevance of donepezil hydrochloride has been supported by numerous clinical studies that demonstrate its efficacy in improving or stabilizing cognitive performance and daily functioning in patients with Alzheimer’s disease. It remains a first-line pharmacologic option in the management of dementia symptoms and is widely used as part of comprehensive care strategies for affected patients.

In summary, donepezil hydrochloride is a centrally acting acetylcholinesterase inhibitor developed for the treatment of Alzheimer’s disease. Its discovery was based on the need for selective and effective cholinergic enhancement in the brain, and it remains an important therapeutic agent in the symptomatic management of cognitive decline.

References

2003. A Large, Community-Based, Open-Label Trial of Donepezil in the Treatment of Alzheimer’s Disease. Dementia and Geriatric Cognitive Disorders, 15(4).
DOI: 10.1159/000069988

2005. Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment. The New England Journal of Medicine, 352(23).
DOI: 10.1056/nejmoa050151

2008. Effectiveness and Safety of Donepezil in Hispanic Patients with Alzheimer’s Disease: A 12-Week Open-Label Study. Journal of the National Medical Association, 100(11).
DOI: 10.1016/s0027-9684(15)31515-7