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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

PubMedBMC cardiovascular disorders2026-11-11

Amantadine, donepezil and memantine associated arrhythmia in an elderly patient.

Atmaca Hasan H, Gürbüz Doğaç Çağlar DÇ, Erol Mustafa Kemal MK, Yetkin Ertan E

CASE İNFORMATION: A 78-year-old male patient was referred to the cardiology clinic for mild dyspnea. Initial electrocardiography (ECG) showed sinus bradycardia at a rate of 59 beats/min, a right bundle branch block (RBBB), a first-degree atrioventricular (AV) block, and a normal QTc duration. One month later, the patient was readmitted because of worsening dyspnea and an arrhythmia detected by a neurologist. The patient stated that the neurologist had prescribed donepezil (5 mg) and memantine (10 mg) combined, along with amantadine (100 mg) for dementia. His control ECG revealed interpolated ventricular premature contractions (VPCs) in a trigeminy pattern, in addition to the first-degree AV block and RBBB. After consultation with the neurologist, the anti-dementia medications were discontinued. We believe the combination of amantadine, donepezil, and memantine caused the interpolated VPCs, as the arrhythmia disappeared after drug cessation.

PMID 43009756
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PubMedFrontiers in aging neuroscience2026-11-11

Gastrodin combined with donepezil alleviates cognitive dysfunction in Alzheimer's disease mice by improving mitochondrial function through AMPK/PGC-1α/SIRT3 axis.

Wang Junwen J, Wu Jing J, Liang Fenrong F, Huang Shulei S et al.

This study aims to explore whether gastrodin (Gas) combined with donepezil (Don) has a neuroprotective effect on Alzheimer's disease (AD) mice by regulating the AMPK/PGC-1α/SIRT3 signaling axis. HT22 cells were transfected with SIRT3 siRNA or control siRNA. Cells were then treated with the AMPK inhibitor, Don, Gas, or their combination. Subsequently, HT22 cells were treated with Amyloid beta 1-42 (Aβ 1-42) to induce an in vitro AD model. Cell viability was detected by CCK8 assay. DCFH-DA fluorescent probe was used to evaluate cell reactive oxygen species (ROS). Adenosine triphosphate (ATP) content was detected by luciferase chemiluminescence method. Cell membrane potential was measured by flow cytometry. For in vivo experiments, WT mice and APP/PS1 mice were treated with Don, Gas or a combination of drugs. Morris water maze test, Y-maze test and novel object recognition test were used to evaluate the cognitive impairment of mice. The pathological changes of hippocampus were detected by HE staining, and the expression of Aβ protein in hippocampus and cortex was detected by IHC. In addition, the protein and mRNA expressions of APP, Tau, and AMPK/PGC-1α/SIRT3 signaling axis were determined by Western blot and RT-QPCR. Gas combined with Don significantly improved cognitive dysfunction, reduced Aβ plaque deposition in the cortex and hippocampus, up-regulated AMPK/PGC-1α/SIRT3 axis, and inhibited the abnormal phosphorylation of Tau and APP in APP/PS1 mice compared with the model group and the Don group (p < 0.05). In vitro cell experiments confirmed that the combination of the two drugs could improve cell viability, inhibit cell apoptosis, restore ATP level, reduce ROS accumulation, stabilize mitochondrial membrane potential, and improve mitochondrial function (p < 0.05). Molecular experiments and complementary experiments showed that Gas combined with Don activated AMPK/PGC-1α/SIRT3 signaling axis (p < 0.05). Silencing SIRT3 or inhibiting AMPK could reverse the protective effect of the combined regimen (p < 0.05). Gas combined with Don can maintain mitochondrial homeostasis through AMPK/PGC-1α/SIRT3 pathway, alleviate AD-relaated pathological damage, and exert neuroprotection.

PMID 43011657
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PubMedJournal of molecular histology2026-11-06

Mechanism of Tongqiao Huashuan decoction regulating neuroinflammation and its effect on intestinal flora in vascular dementia rats.

Cai Jing J, Jiang Xiaoqu X, Yu Shuyao S, Tang Zhongsheng Z et al.

To investigate molecular changes associated with the protective effect of Tongqiao Huashuan Decoction (THD) in vascular dementia (VD), focusing on the NF‑κB‑related inflammatory response, and to observe its influence on intestinal flora. The components of THD were identified using Liquid chromatography‑quadrupole time‑of‑flight tandem mass spectrometry (LC‑Q‑TOF‑MS/MS) with electrospray ionization in positive/negative modes, a methanol‑0.1% formic acid gradient mobile phase, and a C18 column (1.7 μm, 2.1 × 100 mm). Sprague‑Dawley rats were divided into four groups: Sham, VD, VD + TCM (THD), and VD+Donepezil (donepezil hydrochloride). Spatial learning and memory were assessed using the Morris Water Maze. Transmission electron microscopy (TEM) analyzed the ultrastructure of hippocampal CA1 neurons. Enzyme‑linked immunosorbent assay (ELISA) detected interleukin‑1β (IL‑1β), tumor necrosis factor‑α (TNF‑α), macrophage inflammatory protein‑2 (MIP‑2), and IL‑6 in the hippocampus and serum. Immunohistochemistry (IHC) and Western blotting (WB) measured the expression of sirtuin 1 (SIRT1), NF‑κB, caspase‑1, and NOD‑like receptor protein 3 (NLRP3). Fecal flora was analyzed via 16S rRNA sequencing. LC‑Q‑TOF‑MS/MS detected 998 chemical constituents in THD extract. Among them, 24 high‑signal‑intensity constituents with mass‑spectrometry response values > 100 000 were tentatively annotated based on exact‑mass and MS/MS fragmentation matching against public databases and published literature. Compared with the Sham group, VD rats exhibited longer escape latency, hippocampal neuronal damage, elevated proinflammatory factors, upregulated caspase‑1/NLRP3/NF‑κB, and downregulated SIRT1/IκBα. THD treatment reversed these VD‑induced pathological abnormalities. In addition, THD restored intestinal flora dysbiosis observed in VD model rats. THD ameliorates VD‑related cognitive dysfunction, accompanied by altered expression of SIRT1/IκBα/NF‑κB‑related proteins and reduced pro‑inflammatory cytokines. Meanwhile, THD can restore disturbed gut microbiota in VD rats. Changes in the SIRT1/IκBα/NF‑κB signaling cascade are therefore associated with THD‑mediated protective outcomes.

PMID 42993338
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PubMedIn silico pharmacology2026-11-06

In silico methods of Molecular Docking, ADMET, DFT and MD simulations reveal the potential of cis-hydroxycinnamic acid derivatives as potent Acetylcholinesterase Inhibitors.

Lone Shabir H SH, Qayoom Basit B, Khanday Waheed Ahmad WA, Farooq Saleem S et al.

Acetylcholinesterase (AChE) remains one of the important targets for treating patients with Alzheimer's disease (AD). Currently there are no complete treatments available for the disease. This study is aimed to virtually identify novel cis-hydroxycinnamic acid with potential to inhibit AChE enzyme. A series of 21 alkyl/aryl derivatives of cis-o-hydroxycinnamic acid was hypothesized. The compounds were subjected to molecular docking using Auto Dock tools to find the binding interactions of the compounds with the target protein, acetylcholinesterase. About 14 compounds displayed predicted binding affinity ranging from - 9.83 to - 13.88 kcal/mol in comparison to standard Donepezil displaying ΔG of - 11.46 kcal/mol. Swiss ADME and Deep PK deduced their drug likeness and ADMET profile. The results of binding interactions were validated through DFT calculations using ORCA that helped to calculate various electronic parameters, frontier molecular orbitals and molecular electrostatic potential maps. Compounds 8, 9, 10, 11, 12, 13, 14 15, 16, 17, 18, 19, 20, 21 displayed appreciable binding interactions, majority of drug likeness parameters, optimal pharmacokinetic and electronic profile. However, the most balanced and favourable profile was observed for compounds 14 and 19 which demonstrated the need for evaluating the flexibility and structural rigidity of the docked complexes using Cabs-flex and IMODS. The docked complexes of both the compounds 14 and 19 revealed the optimal flexibility and physical movement. The findings in this study thus reveal that these derivatives of cis-o-hydroxycinnamic acid have the potential to act as promising acetylcholinesterase inhibitors. However, experimental studies need to be carried out to further validate this in silico study.

PMID 42991934
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PubMedCombinatorial chemistry & high throughput screening2026-11-05

Integrating DCE-MRI and Network Pharmacology to Elucidate the Therapeutic Mechanism of Tongnaoyizhi Formula in Vascular Cognitive Impairment.

Jiang Zhida Z, Luo Shouzhen S, Jin Tonglong T, Pei Yi Y et al.

To investigate the therapeutic efficacy and underlying mechanisms of Tongnaoyizhi Formula (TNYZ) in treating vascular cognitive impairment (VCI). A 2VO-induced VCI rat model was treated with TNYZ or donepezil. Cognitive function, DCE-MRI-derived parameters, network pharmacology, and molecular docking were assessed. TNYZ-high improved spatial memory and was associated with higher whole-brain and regional Ktrans/V values. Network pharmacology and docking predicted involvement of HSP90AA1/TP53/NTRK1 and MAPK/PI3K-Akt. These exploratory findings suggest that high-dose TNYZ may improve VCI-related cognitive impairment and is associated with DCE-MRI parameter changes. However, Ktrans is a composite parameter, and Vp reflects plasma volume fraction, not cerebral perfusion or vascular density; the imaging results therefore cannot be equated with restored perfusion or vascular density. Network pharmacology and docking predictions are hypothesis-generating and require experimental validation. High-dose TNYZ improved cognitive function in VCI rats and was associated with higher DCE-MRI-derived Ktrans and Vp values in cognition-related brain regions; however, these exploratory imaging findings cannot be equated with restored cerebral perfusion or vascular density. Network pharmacology and molecular docking predicted the potential involvement of HSP90AA1/TP53/NTRK1-related targets and MAPK/PI3K-Akt pathways, which require further experimental validation.

PMID 42983934
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PubMedRSC medicinal chemistry2026-11-03

Novel triazolo[1,5]benzodiazepines as potent dual AChE/BChE inhibitors for Alzheimer's disease: synthesis, characterization, in vitro and in silico studies.

Ait Lahcen Marouane M, Şenol Halil H, Zekri Saad S, Sadeghian Nastaran N et al.

In this current work we report the synthesis of new diastereoisomer derivatives of triazolo[1,5]benzodiazepine by the 1,3-dipolar cycloaddition reaction of diarylnitrilimines with 1,5-benzodiazepine derivatives. The structures of the new compounds 3(a-d) and 4(a-d) were determined by nuclear magnetic resonance (NMR) (1H and 13C) and high-resolution mass spectrometry (HRMS) methods. Then, X-ray crystallography analysis of compounds 3a and 4a confirmed the stereochemistry of the cycloadducts. Density functional theory (DFT) calculations were carried out to optimize the molecular geometries and examine electronic descriptors, including the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), and molecular electrostatic potential maps. These descriptors provided insight into the electronic stability, reactivity, and charge distribution of the compounds. The synthesized compounds were evaluated for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing potent enzyme inhibition with IC50 and K i values in the nanomolar range. Among the tested molecules, compound 3c (SS) exhibited the strongest dual inhibitory activity, showing lower IC50 and K i values against both enzymes compared to the reference drugs donepezil and galantamine. Overall, the compounds demonstrated a stronger inhibitory tendency toward BChE, suggesting potential relevance for late-stage Alzheimer's disease (AD). Stereochemical configuration influenced enzyme inhibition, with SS isomers generally displaying higher potency than their SR counterparts. These results highlight the synthesized compounds as promising dual AChE/BChE inhibitors for further pharmacological investigation.

PMID 42974392
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