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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

PubMediScience2026-07-24

Tuberostemonine ameliorates Alzheimer's disease pathology by suppression of the p38 MAPK signaling pathway.

Li Yingzhou Y, Xu Xiaoxia X, Meng Ziyao Z, Chen Linjie L et al.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with limited therapeutic options. Here, we report that tuberostemonine (Tub), an alkaloid from Stemona tuberosa, exerts neuroprotective effects in AD models. In Aβ1-42-treated PC12 cells, Tub reduced cytotoxicity, apoptosis, and oxidative stress while restoring mitochondrial function. In APP/PS1 transgenic mice, Tub administration improved cognitive performance, reduced amyloid-β plaque deposition, attenuated microglial activation, and attenuated neuronal loss, with efficacy superior to donepezil. Mechanistically, Tub selectively inhibited p38 MAPK phosphorylation without affecting ERK or JNK pathways, as confirmed by pharmacological inhibition and activation experiments. These findings identify Tub as a promising multi-target natural compound for AD intervention through p38 MAPK pathway modulation.

PMID 42495541
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PubMedFrontiers in neurology2026-07-24

Mitochondrial protein alterations in vascular dementia: evidence from Mendelian randomization, transcriptomics, and a chronic hypoperfusion model.

Liu Qian Q, Tan Huizhong H, Tong Keke K, Luo Ruhai R et al.

Mitochondrial dysfunction is a key pathological feature of vascular dementia (VaD), yet the specific systemic and localized proteins involved remain unclear. We aim to utilize Mendelian randomization (MR) of plasma proteomics and Gene Expression Omnibus (GEO) datasets to identify systemic circulating biomarkers associated with VaD risk, and subsequently use in vivo models to investigate whether these systemic signals correspond to actual neuropathological mitochondrial changes in the brain. We first identified candidate proteins associated with VaD risk through a two-sample MR analysis of plasma proteomics and GWAS data. Candidate genes were then assessed for differential expression using the GEO dataset GSE122063. Finally, the proteins were validated in a Bilateral Common Carotid Artery Occlusion (2-VO) rat model by evaluating pathological features and measuring its expression levels via Western Blot. Mendelian randomization analysis identified four proteins nominally linked to VaD: protective factors (AIFM1, COX5B) and risk factors (NDUFV2, NUDT5). However, cross-referencing these genetic predictions with GEO transcriptomics (GSE122063) and a 2-VO rat model revealed distinct tiers of evidentiary support. COX5B emerged as the most robust targets, demonstrating unidirectional consistency across all three analytical layers. NUDT5 showed partial consistency, supported by genetic and animal data, though its transcriptomic alteration fell short of the threshold. Conversely, AIFM1 and NDUFV2 displayed clear directional contradictions between the genetic/transcriptomic data and actual in vivo protein expression. Notably, while donepezil improved VaD pathology, it did not alter the expression of these proteins. Rather than universally validating all four genetic candidates, this rigorous multi-layer triangulation specifically pinpoints the dysregulation of COX5B as high-confidence, consistent drivers of mitochondrial impairment in VaD. Acknowledging the inconsistent complexities of AIFM1, NDUFV2, and NUDT5. Therapeutic strategies targeting the cleanly triangulated protein offer a more reliable, disease-modifying approach for VaD intervention.

PMID 42494396
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PubMedClinical case reports2026-07-23

QTc Shortening After Oral Calcium Supplementation in a Poststroke Rehabilitation Patient Being Considered for Donepezil: A Case Report.

Sims Benjamin B, Oram Meghan M, Startup Joshua J

In a 70-year-old inpatient rehabilitation patient after multifocal ischemic stroke, QTc prolongation delayed consideration of donepezil for aphasia. Mild hypocalcemia was treated with oral calcium carbonate, after which QTc shortened from 464 to 412 ms. Calcium supplementation may support QTc optimization, though causality remains uncertain.

PMID 42487656
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PubMedJournal of computer-aided molecular design2026-07-22

Design, synthesis, biological evaluation, and in silico analysis of novel coumarin carboxamides as acetylcholinesterase and butyrylcholinesterase inhibitors and anticancer agents.

Ural Kadircan K, Ozpolat Bulent B, Comert Onder Ferah F

In this study, coumarin-3-carboxamide derivatives were designed and evaluated through a comprehensive in silico and in vitro combined approaches to identify cholinesterase inhibitors. Molecular docking, molecular dynamics (MD) simulations, and MM/GBSA analyses revealed strong binding affinities and stable interactions within key catalytic regions of AChE and BChE, with AChE-CM4 (ΔGbind = -60.27 ± 5.88 kcal/mol) and BChE-CM5 (ΔGbind = -54.95 ± 6.90 kcal/mol) emerging as the most promising complexes. ADME predictions indicated generally favorable pharmacokinetic profiles for the compounds; however, the predicted blood-brain barrier permeability levels were low to moderate. In vitro enzyme inhibition studies validated the computational results, showing that CM4 (IC50 = 19.04 ± 1.67 nM) and CM8 (IC50 = 17.73 ± 0.66 nM) exhibited significantly greater AChE inhibition than donepezil (IC50 = 27.27 ± 1.22 nM; p < 0.001), with CM3 (IC50 = 24.84 ± 1.99 nM) comparable to donepezil, while all derivatives (CM1-CM9) significantly outperformed tacrine against BChE (p < 0.001). Moreover, CM6 and CM9 inhibited colony formation in brain, breast, and colon cancer cell lines at concentrations below 5 µM. As a result, the alignment of computational and biological data highlights these coumarin-3-carboxamides as compelling lead candidates with both neuroprotective and anticancer potential for further pharmacological development.

PMID 42481895
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PubMedBioorganic chemistry2026-07-17

Rational design and synthesis of dispiroindene-pyrrolidinedione scaffolds as multi-target directed ligands: potent AChE inhibitors with antioxidant activity and favorable biocompatibility in SH-SY5Y cells.

Morsy Nagy A NA, El-Shiekh Riham A RA, Ebrahium Mohamad M MM, Srour Aladdin M AM

Addressing the urgent need for multi-target therapies in Alzheimer's disease, we report the rational design and one-pot, multi-component synthesis of novel substituted dispiroindene-pyrrolidinedione scaffolds (4a-r). Systematic biological evaluation identified five lead compounds (4g, 4j, 4k, 4m, and 4p) with potent inhibitory activity. Derivative 4k emerged as the primary lead, exhibiting an IC50 for Acetylcholinesterase (AChE) of 2.58 ± 0.11 μM and a remarkable selectivity index of 15.71, significantly exceeding that of donepezil (4.37), the reference drug. Concurrently, the series demonstrated notable affinity for Butyrylcholinesterase (BChE), with several derivatives exhibiting submicromolar to low micromolar inhibition. Furthermore, these scaffolds demonstrated superior antioxidant potential; notably, compound 4p achieved an IC50 value of 25.23 ± 1.25 μM, demonstrating an approximate 5-fold increase in radical scavenging potency relative to ascorbic acid (128.20 μM). In vitro safety assays on SH-SY5Y human neuroblastoma cells confirmed excellent biocompatibility, with compound 4m displaying an IC50 of 125.00 ± 6.91 μM, nearly four times less toxic than donepezil (32.84 μM). Molecular docking validated these results, showing robust π-π stacking and halogen-based stabilization within the catalytic anionic site. These findings, supported by ADME profiles predicting high blood-brain barrier permeability, position the dispiroindene-pyrrolidinedione framework as a highly effective, low-toxicity, multi-functional candidate for the development of Alzheimer's disease therapeutics.

PMID 42462519
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PubMedDusunen adam : Bakirkoy Ruh ve Sinir Hastaliklari Hastanesi yayin organi2026-07-16

Donepezil-induced manic episodes in two patients with different types of dementia.

Yilmaz Melek Kandemir MK

PMID 42459577
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