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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

PubMedChemical biology & drug design2026-05-24

Novel Donepezil-Chalcone Hybrids as Potential Multifunctional Anti-Alzheimer's Disease Agents: Design, Synthesis, Computational Simulation, and In Vitro/In Vivo Biological Evaluation.

Lin Zhiqi Z, Jiang Zhenze Z, Chen Die D, Liu Yuanxiu Y et al.

A novel series of donepezil-chalcone including pyridine, piperazine, phenylamide skeleton hybrids were designed, synthesized, and evaluated for their inhibitory activities against AChE and BChE. Subsequently, a subset of these derivatives was investigation to inhibit Aβ1-42 aggregation and promote Aβ1-42 disaggregation effects. Among them, compounds 8b, 8c, 8j, and 8ab possessing good activity were further assayed for their inhibitory effects on BACE-1 and GSK3β, as well as their PI displacement activity. 8b (AChE, IC50: 0.11 μM; BChE, IC50: 0.18 μM; Aβ1-42 aggregation, IC50: 3.40 μM; their ability to promote Aβ1-42 disaggregation, IC50: 4.53 μM; BACE-1, IC50: 1.82 μM; GSK3β, IC50: 0.98 μM) exhibited prominent bioactivities across the above assays. Meanwhile, the molecular docking and the molecular dynamics simulations were performed to analyze the interactions between 8b and the key amino acid residues of the target proteins, which verified the stability of the corresponding protein ligand complexes. Furthermore, 8b significantly attenuated the cytotoxicity induced by Fe3+ and Cu2+ in BV-2 microglial cells, L-Glu in HT-22 hippocampal neuronal cells, and Aβ1-42 in both BV-2 and SH-SY5Y neuroblastoma cells. Additionally, 8b reduced the levels of intracellular ROS and NO in LPS-stimulated BV-2 cells, demonstrating potent anti-inflammatory and neuroprotective properties. Acute toxicity tests in mice confirmed the safety profile of 8b. In in vivo studies, compound 8b effectively protected against neuroinflammation 8b ameliorated cognitive deficits in mice induced by AlCl3 combined with L-galactose, which was associated with the upregulation of p-GSK3β and the downregulation of p-Tau expression. In conclusion, 8b holds great potential as a promising multitarget-directed new lead compound for the treatment of AD.

PMID 42175774
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PubMedScientific reports2026-05-24

Lenalidomide ameliorates cognitive impairment via putative AChE inhibition: an in silico and in vivo study in a scopolamine-induced cognitive impairment model.

Sheikh Salehin S, Shadin Md M, Eity Tanzila Akter TA, Oni Most Israt Jahan MIJ et al.

Alzheimer's disease (AD) causes progressive cognitive decline, and current therapies provide limited benefit. This study evaluated the neuroprotective effects of lenalidomide (LLM), a thalidomide derivative, in a scopolamine-induced mouse model of cognitive impairment, with emphasis on its acetylcholinesterase (AChE) inhibitory potential. Mice received LLM (5, 10, and 20 mg/kg), donepezil (DNP) (3 mg/kg), or a combination and were assessed using Y-maze, passive avoidance, novel object recognition, and Morris water maze tests. In silico analysis, including molecular docking, 100 ns molecular dynamics simulation and ADMET profiling were performed to investigate the interaction of LLM with AChE. Memory performance showed a significant and dose-dependent improvement after the treatment of LLM. The 20 mg/kg dose exhibited effects comparable to DNP. LLM and DNP work together to increase effectiveness. Docking and simulation analyses revealed strong, stable binding to AChE while ADMET values indicated good drug-likeness. LLM exhibits neuroprotective and cognition enhancing effects in the scopolamine-induced model. In silico study also shows its potential as an AChE inhibitor. The study's anti-inflammatory mechanisms might also be helpful but need more exploration.

PMID 42177211
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PubMedScientific reports2026-05-23

Synthesis and in vitro/in silico evaluation studies of arensulfonylhydrazinoxamoyl amine and amino acid derivatives as preliminary acetylcholinesterase inhibitors.

Sharhan Olla O, Al-Madhagi Wafa M WM, Al-Ghubari Mohammed M MM, Al-Gailani Yousef A YA et al.

Two arensulfonylhydrazinoxamoyl derivatives were synthesised via a modified two-step procedure involving oxalyl activation followed by sulfonation and were fully characterized using IR, UV-Vis, 1H NMR, and MS analyses, confirming their structures and high purity. The biological profiles of the compounds were evaluated using combined in vitro and in silico approaches. Both derivatives exhibited measurable acetylcholinesterase (AChE) inhibitory activity, with compound 2 showing greater potency (IC₅₀ = 6.51 ± 0.33 µM) than compound 1 (IC₅₀ = 24.05 ± 1.29 µM), although both less active than the reference inhibitor donepezil. Cytotoxicity evaluation revealed weak activity against MCF-7 breast cancer cells and moderate activity against HepG2 liver cancer cells, with compound 2 again demonstrating superior activity (IC₅₀ = 811.5 ± 32.2 µM). Molecular docking studies supported favourable binding of both compounds within the active gorge of human AChE (PDB: 4EY7), while interactions with BACE1 were weak and non-specific. In silico ADME/T analysis suggested acceptable drug-likeness with no violations of Lipinski's rule, although the high polarity of compound 1 indicated low oral absorption. PASS predictions did not indicate Alzheimer-specific activity but suggested general potential protease- and kinase-related inhibition. Overall, these compounds represent preliminary scaffolds with modest AChE inhibition and limited cytotoxicity, requiring structural optimisation for further therapeutic development.

PMID 42173995
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PubMedNeurochemistry international2026-05-22

Paeonol ameliorates scopolamine- and β-amyloid 1-42 oligomer-induced cognitive impairments through modulation of the TGR5-PKA-cAMP response element-binding-brain-derived neurotrophic factor pathway and inhibition of acetylcholinesterase.

Lee Ye-Won YW, Cho Ye Eun YE, Kim So-Yeon SY, Cho So-Young SY et al.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and cholinergic signaling deficits. Paeonol (2-hydroxy-4-methoxyacetophenone), a phenolic compound derived from Paeonia suffruticosa, has well-documented neuroprotective activity, but potential cognitive benefits and the underlying mechanisms have not been widely examined. Here, we investigated the potential of paeonol to improve cognitive function in scopolamine- and Aβ1-42 oligomer-induced mouse models of AD. Paeonol significantly improved the performance of both models in the Y-maze, novel object recognition, and passive avoidance tests, particularly at 10 mg/kg. Western blotting of excised brain tissue revealed that paeonol treatment reversed scopolamine- and Aβ1-42 oligomer-induced suppression of hippocampal PKA and cAMP response element-binding (CREB) phosphorylation and concomitantly enhanced brain-derived neurotrophic factor (BDNF) expression. Notably, paeonol also reversed scopolamine- and Aβ1-42-induced downregulation of Takeda G-protein-coupled receptor 5 (TGR5), an upstream regulator of the PKA-CREB-BDNF pathway, and molecular docking simulations predicted a possible paeonol-TGR5 interaction. Moreover, paeonol suppressed scopolamine-induced elevation of acetylcholinesterase activity with efficacy comparable to the clinical inhibitor donepezil. These findings support the potential of paeonol as a naturally sourced multitarget therapeutic agent for AD.

PMID 42167685
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PubMedGeriatrics & gerontology international2026-05-21

Transient Episodes of Unresponsiveness in a Medication-Sensitive Older Adult With Probable Dementia With Lewy Bodies: A Case Report of Very-Low-Dose Donepezil Titration.

Kambe Taiki T, Mitsuhashi Kaoru K

PMID 42161352
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PubMedCurrent pharmaceutical design2026-05-21

Multi-Target Neuroprotection of Salvia officinalis Aqueous Extract in a Scopolamine-Induced Model of Alzheimer's Disease: Comparative Efficacy Versus Donepezil.

Abdalla Esraa Ahmed EA, Fayed Aysam M AM, Hussein Mohammed Abdalla MA, Abdel-Aziz Amal A et al.

Alzheimer's disease (AD) is a complex, age-related, neurodegenerative disorder that involves cognitive deterioration, oxidative stress, and neuroinflammation. Symptomatic relief is limited with conventional treatments such as donepezil, sparking a significant interest in multi-target botanicals. We examined the neuroprotective effects of Salvia officinalis aqueous extract (SAGE) on a scopolamine-induced animal model of AD and the related molecular mechanisms regarding GABRA5α, GSK-3β, and pERK pathways. SAGE was characterized using phytochemical profiling and antioxidant assays. IC50 values were determined in vitro for inhibitor activity against GABRA5α and GSK-3β. In vivo experiments included assessment of behavior (Morris water maze), assays for oxidative stress and inflammation, gene expression studies by qPCR, and histopathology of hippocampal tissue. Efficacy versus donepezil was compared. Statistical significance was based on one-way ANOVA followed by Tukey's post-hoc test (p < 0.05) for robust comparisons between all treatment groups. The SAGE had strong antioxidant abilities and was able to inhibit GABRA5α and GSK-3β in a target-specific way. SAGE treatment greatly enhanced spatial learning and memory, retained the redox equilibrium, decreased neuroinflammatory markers, and normalized AChE activity. Gene expression was found to modulate favourably for GABRA5α, GSK-3β and pERK. Histological findings confirmed neuronal preservation. In all parameters, SAGE was more effective than donepezil. The present findings demonstrated the therapeutic potential of SAGE's phenolics to mitigate oxidative cascades, including those suggested as contributing factors to AD pathology. The superior multi-modal efficacy of SAGE over donepezil due to its phenolic-rich phytochemical profile and capacity to modulate oxidative, inflammatory, and neuronal pathways is demonstrated. This is encouraging, and additional studies should be conducted to investigate pharmacokinetics, mechanistic and clinical significance. S. officinalis AE strongly protects the brain against scopolamine-induced AD-like neuropathology in a superior way over standard treatment via altered multi-targets. Its characteristics promote its further development as a natural therapeutic candidate for AD treatment. There are however constraints, such as nodescription of the pharmacokinetic profiling and no tau/Aβ quantification. Prospective studies with these endpoints and chronic dosing schedules should now address the issue of long-term effectiveness and safety.

PMID 42163745
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