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donepezil (IPI301 / donepezil, iCure / Donerion)

✓ Approved

Icure Pharmaceutical Incorporation · ACHE · 小分子

什么是 donepezil？

donepezil 是一种小分子，由Icure Pharmaceutical Incorporation研发。该药已获批，用于治疗相关适应症，给药途径：Transdermal。

药物档案

商品名IPI301, donepezil, iCure, Donerion
公司Icure Pharmaceutical Incorporation
药物类别小分子
分子靶点ACHE
给药途径Transdermal
状态Approved
来源： ClinicalTrials.gov, Icure Pharmaceutical Incorporation

作用机制

分子靶点

donepezil 作用于 1 个分子靶点：

ACHEacetylcholinesterase (Cartwright blood group) (N-ACHE, ACEE)
需要更深入的分析？Noah AI 可解释复杂机制并与同类药物比较。

治疗适应症

donepezil 针对 1 个适应症，涉及 1 个治疗领域。

治疗领域疾病/病症分期
Nervous system disordersDementia Alzheimer's type✓ Approved

相关研究文献

PubMedJournal of tropical medicine2026-10-26

Green-Synthesized Silver Nanoparticles Improve Cognitive Function and Modulate Nrf2/HO-1-BDNF-Related Gene Expression in Experimental Chronic Toxoplasmosis.

Khaksarian Mojtaba M, Khalaf Amal Khudair AK, Shojaee Saeedeh S, Shakib Pegah P et al.

This study aimed to evaluate the neuroprotective effects of silver nanoparticles (AgNPs) green-synthesized using the ethanolic extract of Muscari neglectum against Toxoplasma gondii-induced cognitive impairment and to explore the underlying Nrf2/BDNF and oxidative stress-related mechanisms. Chronic toxoplasmosis was experimentally induced in mice using the Tehran strain of T. gondii. Forty-eight mice were randomly allocated into six experimental groups, including a noninfected control group, an infected untreated control group, and four treatment groups receiving pyrimethamine (PYM, 20 mg/kg), donepezil (DON, 2 mg/kg), AgNPs (10 mg/kg), or AgNPs (20 mg/kg). Spatial learning and memory capabilities were assessed using the Morris water maze test. Post-treatment, brain cyst number and size were determined via microscopic examination. Additionally, quantitative real-time PCR was employed to evaluate the expression levels of genes associated with oxidative stress and neuroprotection, including brain-derived neurotrophic factor (Bdnf), NADPH oxidase 2 (Nox2), superoxide dismutase 2 (Sod2), catalase (Cat), glutathione peroxidase 1 (Gpx1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (Hmox1). Treatment with AgNP resulted in a significant, dose-dependent improvement in behavioral performance, evidenced by reduced escape latency and enhanced exploration of the target quadrant (p < 0.001). Moreover, AgNP administration markedly decreased both the number and size of brain Toxoplasma cysts, with the 20 mg/kg dose demonstrating superior efficacy compared to PYM (p < 0.01). Molecular analyses indicated significant upregulation of Nrf2, Hmox1, Bdnf, Sod2, Cat, and Gpx1, accompanied by downregulation of Nox2 expression in mice treated with AgNP (p < 0.001). These findings suggest that green-synthesized AgNP exert significant, dose-dependent antiparasitic and neuroprotective effects in the context of chronic toxoplasmosis. AgNP notably reduced brain cyst burden, enhanced spatial learning and memory, and normalized oxidative stress-related gene expression. Importantly, AgNP exhibited greater efficacy than both PYM and DON, indicating their potential as a promising therapeutic approach for neurotoxoplasmosis.

PMID 42928771
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PubMedAmerican journal of translational research2026-10-25

Effects of butylphthalide plus donepezil on symptoms, cognitive function, and oxidative stress in patients with cognitive impairment in Parkinson's disease.

Li Ni N, Li Yuqin Y, He Xuebing X, Huang Shungui S

To investigate the effects of butylphthalide combined with donepezil on clinical symptoms, cognitive function, and oxidative stress in patients with cognitive impairment associated with Parkinson's disease (PD). A total of 119 patients with PD-associated cognitive impairment who were admitted to Chengdu Sixth People's Hospital (Donghong Branch) were retrospectively included and divided into two groups. Both groups received levodopa and benserazide hydrochloride as basic treatment. In addition, patients in the control group (n = 55) received donepezil, and those in the research group (n = 64) received butylphthalide combined with donepezil. The two groups were compared in terms of therapeutic efficacy, clinical symptoms (assessed by the Unified Parkinson's Disease Rating Scale [UPDRS]), cognitive function (Montreal Cognitive Assessment [MoCA]), activities of daily living (ADLs; ADL scale), neurotransmitter levels (dopamine [DA], gamma-aminobutyric acid [GABA], 5-hydroxytryptamine [5-HT]), neurotrophic factors (neurotrophin-3 [NT-3], nerve growth factor [NGF]), oxidative stress (superoxide dismutase [SOD], malondialdehyde [MDA]), adverse events, and quality of life (QoL; the 36-Item Short Form Health Survey [SF-36]). Furthermore, exploratory subgroup analyses were performed according to Hoehn-Yahr staging (H-Y staging) and baseline MoCA scores. Compared to the control group, patients in the research group exhibited much higher overall response rate, lower post-treatment UPDRSII, UPDRSIII, and MDA levels, and higher MoCA scores, ADL scores, DA, GABA, 5-HT, NT-3, NGF, SOD levels, and SF-36 scores. The overall incidence of adverse events was comparable between groups. Neither H-Y staging nor baseline MoCA scores significantly affected the efficacy of the combination therapy. Butylphthalide combined with donepezil may exert beneficial effects on symptom improvement, cognitive function enhancement, and oxidative stress regulation in patients with PD-associated cognitive impairment.

PMID 42923556
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PubMedACS omega2026-10-25

Rapid HPLC-Based ADME Profiling of Novel Donepezil and Rivastigmine Analogues for Potential Application in Alzheimer's Disease.

Simić Stefan S, Leuci Rosalba R, Pirker Marianne M, Kalaba Predrag P et al.

Multitarget ligands derived from established cholinesterase inhibitors offer a strategy for addressing the multifactorial pathology of Alzheimer's disease, but biological potency must be considered together with developability. In this study, a rapid biomimetic high-performance liquid chromatography-based workflow was used to characterize key absorption, distribution, metabolism and excretion-related properties of 26 donepezil- and rivastigmine-derived hybrid compounds, including plasma stability, plasma protein binding, membrane affinity, biomimetic distribution parameters, blood-brain barrier permeability, intestinal absorption, experimental log P and aqueous solubility. Plasma stability was reassessed using first-order regression across seven time points with 95% confidence intervals. Most profiles showed limited degradation during the 24 h experiment; accordingly, many apparent half-lives required extrapolation and are interpreted as comparative stability parameters rather than estimates of in vivo persistence. Human serum albumin and α1-acid glycoprotein binding was generally high, emphasizing the need to balance protein binding with the unbound fraction, while immobilized artificial membrane-based models predicted central nervous system-positive classification and high intestinal absorption across the series. Importantly, the blood brain barrier permeability and CNS-distribution estimates are derived from biomimetic models and should be regarded as predictive descriptors that require confirmation in dedicated in vivo pharmacokinetic studies. Solubility was more variable and emerged as an important differentiating property, with compound (26) showing the most favorable profile. An exploratory desirability-based ADME score placed compounds (15), (8), (26), (4), (10) and (24) in the highest tier. Integration with previously reported cholinesterase, fatty acid amide hydrolase and monoamine oxidase activities, which were not remeasured in the present study, further refined lead selection: (24) provided the clearest potency-developability compromise and was prioritized as the principal lead, whereas (26) emerged as a developability-oriented colead. (3) and (18) remained potency-driven secondary candidates. Overall, combining biomimetic ADME profiling with existing pharmacological evidence provides a transparent framework for early lead prioritization and supports confirmatory pharmacokinetic, exposure and in vivo efficacy studies.

PMID 42923404
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PubMedMolecular neurobiology2026-10-24

Association of Cholinergic Stimulation with Improved Functional Performance and Neurotrophic Markers in Mild Cognitive Impairment.

Qaisar Rizwan R, Iqbal M Shahid MS, Ahmad Firdos F, Karim Asima A

Mild cognitive impairment (MCI) is frequently accompanied by early impairment in gait and postural control. Whether commonly prescribed cognitive therapies differentially influence physical function and neurotrophic signaling remains unclear. We followed 99 older adults with MCI for six months while receiving either the cholinergic agent Donepezil (n = 47, age = 68.3 ± 4.1 years) or the glutamatergic modulator Memantine (n = 52, age = 70.1 ± 3.9 years). Postural balance and gait speed were assessed using the Short Physical Performance Battery. Plasma brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) were measured. Donepezil treatment improved postural balance (Cohen's d = 0.30) and gait speed (d = 0.45), whereas Memantine produced no meaningful changes (d < 0.20 for both outcomes). Repeated-measures ANOVA demonstrated significant Time × Treatment interactions for balance (F(1,97) = 5.9, p < 0.05) and gait speed (F(1,97) = 6.4, p < 0.05). Plasma BDNF increased by approximately 22% (d = 0.46) and GDNF by 19% (d = 0.42) following Donepezil, with no significant biomarker changes in the Memantine group. In the Donepezil group, changes in BDNF correlated with improvements in balance (r2 = 0.13, p = 0.012) and gait speed (r2 = 0.12, p = 0.018), while GDNF changes correlated with balance (r2 = 0.10, p = 0.032) and gait speed (r2 = 0.19, p = 0.002). Multivariate regression analyses demonstrated independent associations of BDNF and GDNF with balance and selected functional outcomes after adjustment for confounders. Donepezil is associated with clinically meaningful improvements in mobility in MCI, accompanied by enhanced neurotrophic support. These findings are consistent with a relationship between cholinergic stimulation, motor function, and neurotrophic pathways in MCI.

PMID 42920027
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PubMedJournal of neurology2026-10-23

Dynamic long-term modulation of cognition, brain structure and covariance networks in mild cognitive impairment due to AD by donepezil: A 36-month longitudinal study.

Chen Yingxin Y, Tong Zhichao Z, Wang Haocheng H, Xu Xinru X et al.

Whether donepezil exerts long-term efficacy in mitigating cognitive decline, preserving brain structure, and restoring impaired structural covariance networks in patients with mild cognitive impairment due to Alzheimer's disease (AD-MCI) remains controversial. This study aimed to characterize the longitudinal dynamic alterations in cognition, brain morphology, and structural covariance network topology in AD-MCI patients receiving continuous 36-month donepezil treatment, thereby elucidating the long-term modulatory effects of donepezil on AD progression. Cross-sectional analysis included 92 normal controls (NC) and 107 AD-MCI patients to identify baseline abnormalitiesin cognitive performance, brain morphological parameters, global topological features, and nodal metrics of individual gray matter covariance networks. Subsequently, 35 AD-MCI patients who completed 36-month continuous donepezil treatment were retrospectively enrolled to explore the therapeutic modulation of donepezil on the aforementioned abnormal indicators. Linear and piecewise linear mixed-effects models were employed to quantify longitudinal changes. AD-MCI patients showed left hippocampus (including subfields) atrophy and widespread structural covariance network impairment at baseline. During treatment, significant time main effects were observed in MMSE scores and the volume of the left hippocampus and multiple subfields, both of which continued to show progressive decline, with accelerated deterioration between 12 and 18 months. Global topological metrics stabilized after initial short-term improvement, while right hippocampus nodal metrics were significantly enhanced. Donepezil treatment in AD-MCI patients represents a dynamic therapeutic process: it elicits transient short-term improvement of global brain network topology but confers only modest long-term benefits, with insufficient evidence supporting sustained, impactful neuroprotective effects. This study provides novel multi-level longitudinal evidence describing the neuroimaging changes underlying donepezil's modulation of AD progression.

PMID 42911381
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PubMedJournal of medicinal chemistry2026-10-23

Design, Synthesis and Evaluation Donepezil-Based Dual BuChE/FAAH Inhibitors for Alzheimer's Disease Therapy.

Liu Xiaodan X, Wu Yinxin Y, Ding Yulu Y, Hu Shilin S et al.

Alzheimer's disease (AD) is multifactorial, prompting multi-target therapy. A series of donepezil-based derivatives were designed, synthesized, and evaluated as dual inhibitors of human butyrylcholinesterase (hBuChE) and fatty acid amide hydrolase (hFAAH). Among them, lead G15 displayed potent and balanced inhibition with IC50 values of 2.44 μM and 0.17 μM, respectively, and favorable selectivity over carboxylesterases CES1/2 (SI 14.4 and 8.4). G15 not only acted as a time-dependent, mixed-type hFAAH inhibitor and a pseudo-irreversible hBuChE inhibitor, but also exhibited good drug-like properties, including high BBB permeability and oral bioavailability (108%). Moreover, G15 chelated Zn2+, protected PC12 cells from oxidative stress, and promoted microglial M1 → M2 polarization. In an Aβ1-42-induced mouse model, G15 significantly reversed cognitive deficits, outperforming donepezil. Therefore, G15 is poised for further development as a promising multi-target candidate for AD therapy.

PMID 42911745
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