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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

PubMedACS omega2026-08-02

Benzoxazolinone-Based Propionyl Thiosemicarbazides as Multi-Target-Directed Ligands for Alzheimer's Disease: Cholinesterase and MAO Inhibition, Docking, and Molecular Dynamics.

Taşci Hayrünnisa H, Avcı Ahmet A, Özenver Nadire N, Sağlık Özkan Begüm Nurpelin BN et al.

Alzheimer's disease (AD) benefits from multitarget-directed ligands (MTDLs) that can enhance cholinergic transmission while attenuating monoamine-oxidase-linked oxidative stress. Here, we report a benzoxazolinone-based propionyl thiosemicarbazide series, synthesized and fully characterized by infrared (IR) spectroscopy, 1H nuclear magnetic resonance (NMR), and high-resolution mass spectra (HRMS). The compounds showed consistent submicromolar inhibitory activity across AChE, BChE, MAO-A, and MAO-B in vitro. Several AChE potencies approached the reference donepezil, and selected BChE activities were within an order of magnitude of tacrine. Notably, 4bk' (5-Me/benzyl) inhibited three targets (IC50: 0.029 ± 0.001 μM for AChE, IC50: 0.071 ± 0.003 μM for BChE, IC50: 0.048 ± 0.002 μM for MAO-B), and 4af' (5-Cl/phenyl) showed a balanced profile (IC50: 0.025 ± 0.001 μM for AChE, IC50: 0.056 ± 0.002 μM for BChE, IC50: 0.095 ± 0.003 μM for MAO-A), 4ac' (5-Cl/propyl) combined potent AChE and MAO-B inhibition (IC50: 0.035 ± 0.001 μM for AChE, IC50: 0.045 ± 0.002 μM for MAO-B), whereas 4ag' (5-Cl/4'-Cl-phenyl) was strongly MAO-B-selective (IC50: 0.041 ± 0.001 μM for MAO-B). Antioxidant capacity was pronounced for para-substituted analogues. The efficient compounds 4bk', 4af', 4ac', and 4ag' presented quite low toxicity on healthy cells (cell survival % was above %70 for 4bk', 4af', and 4ac', while it was around 64% for 4ag') even when they were applied at 100 times higher concentrations than their IC50 values, which indicates that they are safe at effective doses. Moreover, assessment of the compounds at a concentration of 10 μM demonstrated no cytotoxic effects on either healthy BV-2 microglial cells or H9c2 rat myoblastoma cells. Docking and 100 ns molecular dynamics (MD) simulations (AChE: 4EY7; MAO-B: 2V5Z) supported stable binding for dual-active representatives (RMSD ∼1.5-2.8 Å). In silico ADME (QikProp) indicated compliance with Lipinski's Rule of Five and Jorgensen's Rule of Three. Collectively, this scaffold is tunable from MAO-B-selective to balanced MTDL profiles suitable for further AD-relevant optimization.

PMID 42540265
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PubMedInflammopharmacology2026-08-02

Valorization of 2-aminoethoxydiphenyl borate as a neurotherapeutic agent: modulation of calcineurin, TRPC1 and MARK2/GSK-3β signaling in scopolamine-triggered tauopathy.

Kewal Akash A, Rajput Mithun Singh MS, Shah Jigna J, Gandhi Dipal D

In Alzheimer's disease (AD), amyloid beta (Aβ) plaques and hyperphosphorylated tau tangles drive neurodegeneration and cognitive decline. Disrupted calcium homeostasis-particularly via transient receptor potential canonical-1 (TRPC1) channels-contributes to tauopathy and disease progression. This study investigated the therapeutic potential of 2-aminoethoxydiphenyl borate (2-APB), a modulator of TRP channels, in a scopolamine-induced rat model of AD. Adult Wistar rats were assigned to six groups: normal control, disease control (scopolamine 2.5 mg/kg), three 2-APB treatment groups (2.5, 5.0 and 10.0 mg/kg) and a donepezil group (5.0 mg/kg), each with six animals. Treatments lasted three weeks. Cognitive performance was assessed using the Morris water maze, memory consolidation and open field tests. Biochemical assays measured acetylcholinesterase (AChE), calcineurin, oxidative stress markers (GSH, MDA) and inflammatory cytokines (TNF-α, IL-6, IL-1β). Protein and gene expression analyses (Western blot, qRT-PCR) evaluated tau, GSK-3β, TRPC1, MARK2, and calcineurin A/PPP3CA, alongside histopathological and immunohistochemical studies. 2-APB treatment significantly reduced pro-inflammatory cytokines, alleviated neuroinflammation, and decreased oxidative stress. Cognitive function improved, correlating with normalized AChE activity and preserved neuronal structure. At the molecular level, 2-APB reduced tau hyperphosphorylation at Ser396 and Thr231, likely through suppression of TRPC1-associated calcium entry and consequent modulation of calcium-dependent kinases (MARK2) and phosphatases (calcineurin), as well as the GSK-3β pathway. However, given that 2-APB is a broad-spectrum calcium signaling modulator - known to act on IP₃ receptors, SOCE/ORAI pathways, and multiple TRPC subtypes in addition to TRPC1-the present findings provide supportive evidence linking TRPC1 modulation to the observed neuroprotective effects. Although, the involvement of additional interconnected signaling mechanisms cannot be excluded and these findings should be interpreted within the context of 2-APB's pleiotropic pharmacological profile. Downregulation of TRPC1 and calcineurin A/PPP3CA gene expression supported 2-APB's role in restoring calcium balance and mitigating tau pathology. These results highlight 2-APB's potential in addressing key AD features-tauopathy, oxidative stress, neuroinflammation and cognitive impairment-warranting further preclinical and clinical research as a potential therapeutic for AD and related tauopathies.

PMID 42541674
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PubMedAmerican journal of physiology. Lung cellular and molecular physiology2026-08-01

Central Cholinergic Modulation of the Cough Reflex: Suppressive Effects of Donepezil in rabbits.

Vitale Claudia C, Cinelli Elenia E, Sorano Alessandra A, Fabietti Giulia G et al.

Cough is a purposeful airway defensive reflex, but in chronic cough it no longer provides a clear physiological benefit and markedly impairs patient's quality of life. Currently available antitussive drugs have limited efficacy and may cause severe side effects. Thus, further research is needed to find reliable treatments. It has been shown that acetylcholine (ACh) downregulates cough via muscarinic ACh receptor (mAChRs) in the rabbit caudal portion of the nucleus tractus solitarii (cNTS), with a major involvement of the M4 receptor subtype. The identification of cholinergic agents modulating ACh depressant effects on coughing could be of considerable interest for the development of novel therapeutic strategies. Here we tested the hypothesis that increasing synaptic ACh levels by inhibiting acetylcholinesterase activity may downregulate the cough reflex. In anesthetized, spontaneously breathing rabbits, we investigated the effect of donepezil, a brain-penetrant, potent and selective acetylcholinesterase inhibitor, on the modulation of the cough reflex induced by mechanical and chemical stimulation of the tracheobronchial tree and on the sneeze reflex. Efferent respiratory and electromyographic activities were recorded from phrenic nerves and abdominal muscles, respectively. Donepezil, either systemically administered (5 mg/kg; subcutaneously) or bilaterally microinjected (5 mM; 30-50 nl) into the cNTS, induced strong depressant effects up to the complete abolition of the mechanically-induced cough, without affecting sneezing. Donepezil also decreased expiratory activity even to complete suppression, while transient increases in respiratory frequency were observed only after local application. These findings support further investigation on donepezil and related centrally acting cholinergic agents as candidate antitussive therapies.

PMID 42537636
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PubMedComputational biology and chemistry2026-07-31

Integrative computational discovery of a lichen-derived acetylcholinesterase inhibitor candidate for Alzheimer's disease.

Larico-Ramirez Leslie Pamela LP, Paco-Chipana Margot M, Herrera María Isabel MI, Goyzueta-Mamani Daniel D et al.

Alzheimer's disease (AD), the leading cause of dementia worldwide, is a progressive neurodegenerative disorder for which current pharmacological treatments provide only limited symptomatic relief. Human acetylcholinesterase (hAChE) remains one of the most extensively validated therapeutic targets because its inhibition enhances cholinergic neurotransmission and temporarily improves cognitive function. Motivated by the remarkable structural diversity of lichen secondary metabolites, we investigated their potential as novel hAChE inhibitors using an integrated multiscale computational strategy that combined structure-based virtual screening, ADME/Tox profiling, density functional theory (DFT) calculations, molecular dynamics (MD) simulations, and MM/GBSA binding free-energy analysis, with donepezil employed as the reference inhibitor. Among the screened compounds, calycin emerged as the most promising candidate. It displayed high predicted binding affinity together with favorable pharmacokinetic characteristics, including high gastrointestinal absorption and blood-brain barrier permeability. Electronic structure analysis revealed greater chemical reactivity and electronic adaptability than donepezil, indicating an enhanced ability to establish stabilizing interactions within the hAChE active site. Molecular electrostatic potential and local reactivity descriptors further identified chemically active regions responsible for favorable non-covalent interactions along the active-site gorge. Long-timescale MD simulations confirmed the structural stability of the hAChE-calycin complex, while MM/GBSA calculations demonstrated a thermodynamically favorable binding process predominantly driven by van der Waals and hydrophobic interactions with key aromatic residues. Collectively, these findings identify calycin as a promising lead scaffold for the development of next-generation hAChE inhibitors and demonstrate the potential of lichen-derived natural products as an underexplored source of chemically diverse candidates for Alzheimer's disease drug discovery.

PMID 42537334
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PubMedChinese journal of integrative medicine2026-07-31

Therapeutic Potential of Jiedu Yizhi Formula for Alzheimer's Disease: A Randomized Controlled Trial.

Li Yun-Qiang YQ, Chen Dong-Xue DX, Zhu Xiao-Ting XT, Li Wei W et al.

To observe the clinical effect and safety of Jiedu Yizhi Formula (JYF) in Alzheimer's disease (AD) patients. Eligible patients with mild to moderate AD and Chinese medicine (CM) syndrome of Pi (Spleen)-Shen (Kidney) deficiency with phlegm-turbidity obscuring orifices were collected from the Third Affiliated Hospital of Changchun University of Chinese Medicine between December 2022 and December 2023. Patients were randomly assigned to JYF and donepezil groups at a 1:1 ratio by using a random number table and received a total of 24 weeks of continuous treatment. Both groups were given AD cognitive behavior training and health education at the same time. The Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), AD Assessment Scale-Cognitive (ADAS-cog), Activity of Daily Living (ADL), and Hamilton Depression (HAMD) scale scores were measured before treatment, 12 and 24 weeks after treatment. The cognitive domain scores and the total effective rates were also compared between groups. During the study period, any adverse reactions were recorded and compared between groups. Totally 62 participants completed the study, with 31 in each group. The MMSE, MoCA, ADAS-cog, ADL, and HAMD scores significantly improved after 12 and 24 weeks of treatment in both groups (P<0.05 or P<0.01). Moreover, significant improvements in the ADL and HAMD scores were observed in the JYF group at 12 or 24 weeks than in the donepezil group (P<0.05 or P<0.01). Meanwhile, the cognitive domain scores of orientational and abstraction abilities and the total effective rate (64.52% vs. 45.16%) in the JYF group were significantly higher (P<0.05). No significant difference was found in the incidence of adverse reactions between groups (9.68% vs. 6.45%, P>0.05). JYF can improve the cognitive dysfunction of mild to moderate AD patients with CM syndrome of Pi-Shen deficiency with phlegm-turbidity obscuring orifices, and its safety is good. (Trial registration No. NCT06393413).

PMID 42536296
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PubMedBioorganic & medicinal chemistry2026-07-31

Lead optimization of rivastigmine-like hybrids: Impact of nitro group and halogen substitution on multi-target anti-Alzheimer's activity.

Leuci Rosalba R, Paparella Marco M, Cerini Marco M, Simic Stefan S et al.

The multifactorial profile of Alzheimer's disease has led researchers to adopt a multi-target strategy for the design of new small molecules. In this context, starting from the structure of ROS151, a novel series of seventeen rivastigmine-like hybrids was developed. Structural modification involved the aryloxy-methylene portion, with the substitution of the nitro group with other groups and the variation of type and position of the halogen atom. The nitro group was confirmed to be essential for high anti-ChE activity, with compound 3 showing the most balanced profile, superior to that of the lead compound (IC50 = 0.827 ± 0.012 μM and 4.58 ± 0.01 μM against hAChE and eqBChE, respectively). Hybrid 2 showed inhibitory activity against hAChE close to that of donepezil (IC50 = 0.029 ± 0.005 μM), while 7 had better activity against eqBChE than the parent drug rivastigmine (IC50 = 0.45 ± 0.02 μM). In silico experiments were performed to corroborate these results. When the nitro group was reduced to amine, as for compound 10, relevant antioxidant activity (ABTS, IC50 = 25.2 ± 1.2 μM) and remarkable chelating properties toward Fe3+ (pM = 15.6) and Cu2+ (pM = 11.4), with a good selectivity over Zn2+ (pM = 6.0) were observed. Inhibition of fatty acid amide hydrolase (hFAAH) resulted less relevant but still appreciable. Cyano-derivative 8 appears to be the only compound with preserved multi-enzymatic inhibitory potential, even without nitro-group in its structure and can be used as starting point for further series. Finally, many hybrids demonstrated interesting experimental pharmacokinetic properties, evaluated using bioanalytical methods.

PMID 42531673
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