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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

PubMedActa crystallographica. Section C, Structural chemistry2026-09-17

Crystal structure, intermolecular interactions, Hirshfeld surface analysis, theoretical studies and biological evaluation of (E)-5-(benzyloxy)-2-{[(2,5-dimethoxyphenyl)imino]methyl}phenol, a new Schiff base.

Ghichi Nadir N, Lemoui Redouane R, Yahiaouid Ahmed Abderrahim AA, Mezhoud Bilel B et al.

In the present work, we report on the synthesis, characterization and biological evaluation of (E)-5-(benzyloxy)-2-{[(2,5-dimethoxyphenyl)imino]methyl}phenol Schiff base, C22H21NO4 (BDIMPh). The compound was synthesized via the condensation reaction between 4-benzyloxy-2-hydroxybenzaldehyde and 2,4-dimethoxyaniline. It was characterized using 1H, 13C NMR and FT-IR spectroscopies, and its crystal structure was determined by single-crystal X-ray crystallography. BDIMPh crystallizes with two crystallographically independent molecules in the asymmetric unit. The structural model also includes the reported disorder features, which are discussed on the basis of the crystallographic refinement. The two molecules of BDMPh have the same E configuration about the C=N bond. In the crystal, the independent molecules are linked to their inversion-related molecule via C-H...O hydrogen bonds. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to quantify the intermolecular contacts present in the crystal. Quantum theory of atoms in molecules (QTAIM) analysis was performed to characterize selected intra- and intermolecular interactions. The optimized geometry showed good agreement with the experimental X-ray crystal structure. The antioxidant activity of BDIMPh was evaluated using the DPPH and ABTS radical-scavenging assays. BDIMPh exhibited moderate radical-scavenging activity under the experimental conditions and showed higher IC50 values than the reference antioxidants. The enzyme inhibitory activity of BDIMPh was investigated against acetylcholinesterase (AChE), glutathione S-transferase (GST), α-glucosidase and tyrosinase. BDIMPh exhibited measurable enzyme-dependent inhibitory activity against AChE, GST and α-glucosidase, whereas comparatively weak inhibition was observed against tyrosinase. The IC50 values were 2.899 ± 0.851 µM for AChE, 3.850 ± 0.721 µM for GST and 3.284 ± 0.738 µM for α-glucosidase. Compared with the corresponding reference inhibitors, BDIMPh showed a slightly higher IC50 value than donepezil for AChE, a slightly lower IC50 value than ethacrynic acid for GST and a higher IC50 value than acarbose for α-glucosidase. These results indicate an enzyme-dependent inhibitory profile rather than uniformly superior activity relative to the reference inhibitors.

PMID 42750397
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PubMedBehavioural pharmacology2026-09-15

Formoterol attenuates lipopolysaccharide-induced mnemonic impairment in the delayed nonmatch to position task in rats.

McAuslan Matthew M, Kozareva Danka D, Dunphy-Doherty Fionn F, Corrigan Myles M et al.

The delayed nonmatch to position (DNMTP) task is an instrumental learning paradigm applied to assess higher executive functions including attention and working memory in rats. In this study, the effect of systemic challenge with the acute inflammatory stimulus [lipopolysaccharide (LPS) 0.25 mg/kg, intraperitoneally] was assessed in Wistar rats on performance in the DNMTP task. By means of validation, the effect of treatment with the muscarinic receptor antagonist scopolamine [0.02 mg/kg, subcutaneously (s.c.)], known to disrupt performance in the task, and its reversal by coadministration of the cognitive-enhancing agent and acetylcholinesterase inhibitor donepezil (0.3 mg/kg, s.c.) were confirmed. Sex differences emerged between males' and females' mnemonic response to LPS 24-h postadministration with males showing reduced performance in the DNMTP task at higher working memory loads compared with females. Noradrenaline is an endogenous neurotransmitter with innate anti-inflammatory properties. The impact of targeting the noradrenergic system with the β2-adrenoceptor agonist Formoterol was further assessed on LPS-induced cognitive impairment in the DNMTP task. Coadministration of Formoterol (0.5 mg/kg, s.c.) attenuated LPS-driven mnemonic impairments in males but not females. Overall, the results show the DNMTP task is a paradigm sensitive to acute systemic inflammation and indicate that Formoterol may have useful anti-inflammatory properties in mitigating inflammatory-associated cognitive impairment.

PMID 42740448
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PubMedMedicine2026-09-15

Transcriptomic integration reveals immune heterogeneity in vascular dementia and identifies ELF2 as a candidate therapeutic target.

Liang Li L, Shen Cuiqin C, Huang Shiren S, Hu Minglu M et al.

Vascular dementia (VaD) is the second most prevalent form of dementia after Alzheimer's disease and is primarily driven by chronic cerebral hypoperfusion and neurovascular dysfunction. Growing evidence indicates that immune dysregulation and neuroglial-vascular injury play critical roles in disease progression; however, the molecular regulators underlying these processes remain insufficiently characterized. This study aimed to delineate immune heterogeneity and neuroglial-vascular alterations in VaD and to identify key regulatory targets involved in disease pathogenesis. Bulk RNA sequencing data (GSE122063) and single-cell transcriptomic data (GSE282111) were retrieved from the Gene Expression Omnibus database and integratively analyzed to characterize immune infiltration patterns and cellular dysregulation. Immune profiling was performed using CIBERSORT and single-sample gene set enrichment analysis. Disease-associated cell subsets and hub genes were identified using Seurat, Scissor, and high-dimensional weighted gene co-expression network analysis (hdWGCNA). Pseudotime trajectory analysis and molecular docking were subsequently applied to investigate gene expression dynamics and potential therapeutic relevance. Bulk transcriptomic analysis revealed a pronounced pro-inflammatory shift in VaD brain tissue, characterized by increased infiltration of M1 macrophages, neutrophils, and activated dendritic cells, alongside reduced levels of M2 macrophages, resting CD4+ memory T cells, and regulatory T cells. Single-cell analysis demonstrated marked loss of oligodendrocytes, astrocytes, and endothelial cells in VaD. Scissor integration showed positive associations between VaD and oligodendrocytes, astrocytes, and endothelial cells, whereas microglia and oligodendrocyte progenitor cells were negatively associated. hdWGCNA identified 3 co-expression modules; intersection of the blue module with bulk differentially expressed genes highlighted DOCK3, ELF2, and Sin3A associated protein 25, with ELF2 uniquely co-expressed across relevant cell types. Pseudotime analysis indicated sustained downregulation of ELF2 during VaD-related cellular differentiation. Molecular docking analysis suggested strong binding affinities between ELF2 and nicergoline (-7.23 kcal/mol), nimodipine (-6.92 kcal/mol), and donepezil (-6.29 kcal/mol). This integrative transcriptomic study reveals disrupted immune balance and neuroglial-vascular cell homeostasis in vascular dementia, and prioritizes ELF2 as a candidate regulator associated with immune heterogeneity in VaD.

PMID 42736768
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PubMedDrug development research2026-09-14

Design, Synthesis and Molecular Docking Studies of Some Novel Hydrazone Derivatives Based on Trimetazidine as Selective and Potent AChE Inhibitors.

Doğan Muhammed Oğuzhan MO, Özkan Begüm Nurpelin Sağlık BNS, Karaduman Abdullah Burak AB, Karakuş Sevgi S et al.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and cholinergic dysfunction is considered one of the fundamental pathological factors of this disease. Guided by the clinically used acetylcholinesterase (AChE) inhibitor donepezil, we explored trimetazidine dihydrochloride as an accessible starting scaffold to generate donepezil-like features and to develop new anti-AD candidates. Accordingly, 20 novel hydrazone derivatives were designed and synthesized based on trimetazidine dihydrochloride, and their structures were confirmed by spectroscopic methods. The compounds were evaluated for in vitro inhibition of AChE and butyrylcholinesterase (BChE) using donepezil and tacrine as reference inhibitors, respectively. Several derivatives displayed pronounced AChE inhibition, whereas most compounds showed weak or negligible activity toward BChE, indicating a generally favorable AChE-selective profile. Among the series, compounds 3p, 3q and 3r exhibited selective inhibitory activity against AChE comparable to donepezil, with IC50 values of 0.030 ± 0.001 μM, 0.085 ± 0.003 μM and 0.034 ± 0.001 μM, respectively. To rationalize the observed activity trends, molecular docking studies were performed, suggesting that the most active ligands adopt donepezil-like binding modes spanning the catalytic and peripheral anionic sites and are further stabilized by π-π/π-cation contacts and hydrogen-bonding interactions within the active gorge. Overall, these findings identify trimetazidine-derived hydrazide-hydrazones as a promising chemotype for the development of selective AChE inhibitors and provide a basis for further optimization and advanced biological validation.

PMID 42734044
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PubMedMaterials today. Bio2026-09-11

Multi-functional bionic nanoparticles for precise neuronal targeting and synergistic therapy in Alzheimer's disease.

Na Yue Y, Liu Chi C, Bi Xinming X, Liu Shumeng S et al.

Alzheimer's disease (AD) is characterized by core pathological mechanisms including amyloid-β plaque aggregation, cholinergic dysfunction, and neuronal apoptosis. Given the complex interplay of these pathways, combination therapies are emerging as more effective strategies than single-target approaches. The success of such therapies depends on rational target selection and optimal regimen design. Herein, we developed a multifunctional biomimetic nanocarrier, B6/Tet1-RBCm-NPs (BTRN), for precise neuron-targeted combination therapy. The nanoparticles (NPs) core was fabricated using safe, biocompatible poly (lactic-co-glycolic acid) (PLGA) to co-deliver natural product genistein and mature marketed donepezil, which act synergistically to enhance therapeutic efficacy. The core was further modified with endogenous red blood cell membranes, providing effective immune evasion and a prolonged circulation lifetime. Functionalization with the blood-brain barrier (BBB)-penetrating peptide B6 and the neuron-targeting peptide Tet1 confers excellent BBB penetration and specific accumulation in diseased neurons. Collectively, BTRN treats AD through multiple mechanisms, including reducing Aβ production, regulating cholinergic function, and inhibiting neuronal apoptosis. This biomimetic system presents a promising therapeutic strategy and offers valuable insights for the clinical translation of combination therapies in AD.

PMID 42725138
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PubMedWound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society2026-09-09

Topical Donepezil for Cholinergic Modulation in Chronic Wound Repair.

Qu Hui-Qi HQ, Kao Charlly C, Hakonarson Hakon H

Chronic wounds result from combined defects in vascular perfusion, inflammatory resolution, and epithelial repair. The skin's non-neuronal cholinergic system (NNCS), formed by keratinocytes, endothelial cells, fibroblasts, and immune cells that synthesise and respond to acetylcholine (ACh), helps coordinate these processes through muscarinic and nicotinic receptors. Inhibition of acetylcholinesterase (AChE) increases local ACh concentrations and may engage two key pathways supported by preclinical data: M3 muscarinic receptor (M3 mAChR)-endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-mediated vasodilation, and α7 nicotinic acetylcholine receptor (α7-nAChR)-mediated suppression of pro-inflammatory cytokines. Donepezil is a reversible, selective AChE inhibitor with physicochemical properties compatible with dermal administration. Low-dose or microneedle dermal delivery has produced dermal exposure with limited systemic uptake in animal and ex vivo skin studies. In preclinical diabetic wound models, nicotinic receptor activation accelerated healing, reduced inflammatory signalling, and improved control of bacterial burden. We hypothesise that topical donepezil formulated for localised dermal delivery could restore cholinergic signalling within the wound microenvironment by increasing local ACh concentrations. This approach may complement metabolic therapies that support arginine-NO coupling and redox balance. Controlled pilot studies should assess local cutaneous pharmacodynamics, perfusion responses, and wound-closure outcomes.

PMID 42711953
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