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donepezil (IPI301 / donepezil, iCure / Donerion)

✓ Approved

Icure Pharmaceutical Incorporation · ACHE · Small Molecule

What is donepezil?

donepezil is a small molecule developed by Icure Pharmaceutical Incorporation. It is approved for therapeutic indications via transdermal.

Drug Profile

Brand NamesIPI301, donepezil, iCure, Donerion
CompanyIcure Pharmaceutical Incorporation
Drug ClassSmall Molecule
Molecular TargetACHE
RouteTransdermal
StatusApproved
Sources: ClinicalTrials.gov, Icure Pharmaceutical Incorporation

Mechanism of Action

Molecular Targets

donepezil acts on 1 molecular target:

ACHEacetylcholinesterase (Cartwright blood group) (N-ACHE, ACEE)
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Therapeutic Indications

donepezil is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Nervous system disordersDementia Alzheimer's type✓ Approved

Related Research Articles

PubMedInflammopharmacology2026-10-15

Synergistic approaches to Alzheimer's disease: exploring the combined efficacy of phytoconstituents and conventional drugs.

Kumar Abhishek A

Cognitive functions deteriorate with Alzheimer's disease (AD), a kind of degenerative disease. Problems with memory, interpersonal interactions, problem-solving, and other cognitive functions that limit a person's ability to do daily tasks are the hallmarks of dementia. This condition affects about 50 million individuals globally. Traditional therapies for AD, like galantamine, donepezil, and memantine, only offer symptomatic alleviation through glutamatergic regulation and cholinergic augmentation, making AD a significant worldwide health concern. This review assesses the possibility of improving the effectiveness of therapy by combining significant phytoconstituents with traditional AD therapies. A complete literature review was carried out using peer-reviewed publications, experimental investigations, and review papers published from 2010 to 2025. The primary objective of the investigation was to study the interaction between phytoconstituents and conventional therapy in the treatment of Alzheimer's disease. Our outcomes demonstrate the powerful multi-target adjuvant properties of curcumin, resveratrol, quercetin, berberine, and luteolin. In particular, Berberine and Quercetin considerably reduce neuroinflammation and oxidative stress through the Nrf2/HO-1 and NF-κB pathways, whereas Curcumin and resveratrol enhance the anti-amyloidogenic effects of conventional medications. Additionally, luteolin exhibits a special capacity to regulate tau hyperphosphorylation, which enhances memantine's stabilising neurotransmitter actions. The primary objective of therapy has shifted from symptomatic relief to disease modification by the synergy between phytoconstituent and conventional drugs. These combinations preserve the structural integrity of the cholinergic synapse by concurrently mitigating oxidative stress and amyloid toxicity. A possible paradigm shift towards holistic neuroprotection is represented by the incorporation of these five essential phytoconstituents into traditional AD regimens. To ensure clinical translatability, future research must now focus on nanoformulations that can overcome the limited bioavailability of substances like curcumin. These methods may improve treatment effectiveness, lessen adverse effects, and reduce the chance of resistance, providing a more thorough method of handling the complexities of AD.

PMID 42875646
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PubMedCurrent drug safety2026-10-14

Bilateral Lower Extremity Edema During Donepezil Treatment: A Case Report.

Kang Kyusik K

Introduction/ Background: Acute bilateral lower-extremity edema is uncommon and often results from medication side effects, acute heart failure, nephrotic syndrome, or bilateral deep vein thrombosis. Drugs such as dihydropyridine calcium channel blockers, corticosteroids, thiazolidinediones, and nonsteroidal anti-inflammatory agents are known to cause edema. Donepezil, a widely used acetylcholinesterase inhibitor for Alzheimer's disease, has not been previously linked to leg edema. Recognizing rare adverse reactions is essential for patient safety, as edema may indicate serious conditions. Case Presentation: A 75-year-old woman with Alzheimer's disease developed bilateral pitting lower leg edema six months after starting treatment with donepezil. She had no history of cardiac, renal, hepatic, or venous diseases. Laboratory tests, electrocardiography, chest X-ray, and computed tomography venogram were normal, except for mild anemia and a slightly reduced estimated glomerular filtration rate. The edema resolved three weeks after discontinuation and did not recur after the administration of rivastigmine. Conclusion: The temporal association and resolution upon drug cessation suggest a probable association. Possible mechanisms may include cholinergic-induced vasodilation, which increases capillary permeability.

PMID 42872450
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PubMedMini reviews in medicinal chemistry2026-10-14

Therapeutic Significance of Natural vs. Synthetic Coumarins in Alzheimer's Disease.

Patel Richa R, Sinha Shweta S, Shukla Karuna S KS, Singh Bandana B et al.

Coumarin, a naturally occurring aromatic compound bearing a benzopyrone scaffold, represents a versatile motif in synthetic drug design. Recent therapeutic developments have highlighted its potential as a privileged pharmacophore for neurodegenerative disorders (NDs), with particular efficacy targeting Alzheimer's disease (AD). This study presents a critical, comparative review of natural versus synthetic coumarins, evaluating their neuroprotective mechanisms across various preclinical, non-transgenic models of sporadic Alzheimer's disease (sAD). Natural coumarins (e.g., umbelliferone, esculetin, and scopoletin) exert potent antioxidant, anti-inflammatory, and moderate enzyme-inhibitory activities, particularly against acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation. These phytochemicals attenuate neurodegeneration by modulating oxidative stress and neuroinflammatory pathways across various cellular and rodent models, including 5xFAD mice, as well as streptozotocin (STZ)-and scopolamine (SCOP)- induced Alzheimer's disease (AD) rat models. However, their clinical utility remains constrained by poor bioavailability and modest potency. To address these limitations, synthetic coumarin derivatives, including coumarin-pyrrolidine, coumarin-triazole, coumarin-chalcone, and coumarin-donepezil hybrids, as well as hydroxycoumarins, have been developed. These heterocyclic hybrid architectures exhibit superior therapeutic potency, enhanced blood-brain barrier (BBB) permeability, and synergistic inhibition of core pathological targets, including AChE activity and Aβ aggregation. Both in vivo preclinical models and in silico docking simulations substantiate the neuroprotective capacity of coumarin-based frameworks, demonstrating substantial cognitive rescue, restored synaptic plasticity, and favorable safety margins. Moving beyond the baseline safety of naturally derived coumarins, structural optimization and hybrid design strategies serve as a compelling framework for developing potent, multi-target therapeutics for neurodegenerative diseases. According to the review, Alzheimer's disease treatment is shifting from natural coumarins to multi-target-directed ligands (MTDLs) because natural compounds, such as esculetin, scopoletin, and daphnetin, are often limited by narrow target specificity and lower potency than synthetic coumarin derivatives. Herein, the authors review the biological activities of natural coumarins and their synthetic analogs as potential therapeutics for Alzheimer's disease (AD). This study systematically compared and evaluated the therapeutic efficacy and structural scaffold variations of both natural and synthetic derivatives. To support their translational potential, this study also summarizes current ADMET profiles and pharmacokinetic evaluations, which represent key prerequisites for clinical advancement.

PMID 42872643
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PubMedNatural product research2026-10-13

Ergostane-type steroids from Euphorbia thymifolia with acetylcholinesterase inhibitory effects.

Wang Chun-Gu CG, Wang Fan-Fan FF, Shao Yuan-Ling YL, Qin Feng F et al.

Thymifolisteroid A (1), a previously undescribed ergostane-type steroid, and five known related compounds (2-6), were obtained from Euphorbia thymifolia. The known compounds were identified as 3β-hydroxy-4α,14α-dimethyl-5α-ergosta-8,24(28)-dien-7-one (2), β-sitosterol (3), β-sitosteryl-3-O-glucopyranoside (4), 5α-stigmastane-3,6-dione (5) and (6β)-6-hydroxyergost-4-en-3-one (6). Their chemical structures and absolute configuration were determined through comprehensive spectroscopic and mass spectrometric (MS) analyses. Biological evaluation revealed that compound 3 possessed moderate acetylcholinesterase (AChE) inhibitory activity, with an IC50 value of 14.43 ± 0.68 μM, compared with 4.19 ± 0.25 μM for the positive control drug donepezil. Furthermore, molecular docking and molecular dynamics simulations jointly suggested that compound 3 can stably bind to the active site of AChE.

PMID 42868346
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PubMedNeuropsychiatric disease and treatment2026-10-11

Caregiver-Reported Behavioral Changes After Donepezil Transdermal Patch Therapy in Alzheimer's Disease: An Exploratory Real-World Network Analysis.

Shimazu Tomokazu T, Hoshino Eri E, Nakaseko Maki M, Homma Kanako K et al.

To characterize caregiver-reported behavioral changes after donepezil transdermal patch therapy and to examine the descriptive connectivity of co-occurring improvements in patients with Alzheimer's disease (AD). This retrospective, single-center observational study included 26 patients meeting the 2011 National Institute on Aging-Alzheimer's Association criteria for probable AD dementia. Approximately 2-4 months after patch initiation, caregivers rated nine behavioral domains using routine, non-validated single-item change assessments as improved, unchanged, or worsened relative to the pre-treatment state. A descriptive co-improvement network was used solely to summarize pairwise co-occurrence of binary improvement indicators using phi-coefficients and observed strength centrality. Because of the small sample and sparse binary events, all network measures were treated as sample-specific descriptive quantities rather than inferential estimates. The most frequently improved domains were smiling/positive affect (12/26, 46.2%), calmness (9/26, 34.6%), and night-time sleep (8/26, 30.8%). Calmness had the highest observed strength centrality (2.467), followed by grooming behavior (2.059), hobbies/interests (2.009), and housework/instrumental activities of daily living (1.938). Calmness remained the highest-strength node in all 26 leave-one-participant-out sensitivity analyses. No treatment discontinuations or serious adverse events were documented. Caregiver-perceived calmness, assessed as a single non-validated change item, was the most highly connected domain in this small descriptive co-improvement network. The findings are exploratory and do not establish treatment efficacy, a validated agitation-related outcome, temporal direction, or mechanism. Prospective studies using standardized behavioral measures are needed.

PMID 42857741
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PubMedJournal of visualized experiments : JoVE2026-10-11

Qi-Fu-Yin Attenuates Frailty by Regulating Gut Microbiota and Neuroendocrine Hormones in 5xFamilial Alzheimer's Disease Transgenic Mice.

Yang Xiuzhao X, Ye Tianyuan T, He Yun Y, Zhao Junqi J et al.

Frailty is a common and debilitating feature of Alzheimer's disease (AD), yet effective therapeutic strategies targeting both cognitive decline and physical frailty remain limited. Qi-Fu-Yin (QFY), a traditional Chinese herbal formulation, has been used to treat aging-related disorders, but its effects on frailty in AD and the underlying mechanisms are unclear. This study aimed to evaluate whether QFY alleviates frailty in 5xFamilial Alzheimer's Disease (FAD) transgenic mice and to explore the potential involvement of gut microbiota and neuroendocrine hormones. Mice were treated with QFY at low (2.8 g/kg), medium (5.6 g/kg), or high (11.2 g/kg) doses, or with donepezil as a positive control, for 194 days. Frailty-related behaviors were assessed using CatWalk gait analysis, grip strength, rotarod, nest-building, and aging scoring. Plasma hormone levels were measured, and fecal gut microbiota composition and function were analyzed by 16S rRNA sequencing and metagenomic analysis. QFY treatment significantly improved gait parameters, grip strength, motor coordination, nesting ability, and reduced aging scores in 5xFAD mice, with effects comparable to or superior to those of donepezil. QFY also restored aberrant levels of estradiol, testosterone, and corticosterone, and reshaped gut microbiota composition, particularly by increasing the abundance of Adlercreutzia, which negatively correlated with senescence and testosterone levels. Functional metagenomics revealed that QFY partially restored disease-associated microbial pathways, including those involved in carbohydrate metabolism and virulence. These findings suggest that QFY alleviates frailty in 5xFAD mice, with effects associated with concurrent modulation of gut microbiota and neuroendocrine function, though causal relationships require further validation. These findings support further investigation of QFY as a potential intervention for AD-associated frailty.

PMID 42858079
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