Synthesis and anti-acetylcholinesterase activity of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine hydrochloride (E2020) and related compounds

Sugimoto, Hachiro; Iimura, Youichi; Yamanishi, Yoshihiro; Yamatsu, Kiyomi

doi:10.1016/s0960-894x(00)80547-8

Cited by 58 publications

(37 citation statements)

References 5 publications

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“…Male 63 (39) 57 (37) 60 (38) This study demonstrated that the treatment benefits (24) slower rate than that observed in untreated AD patients.…”

Section: A Long-term Open-label Phase II Trialmentioning

confidence: 85%

“…In the cholinergic system, acetylcholine (ACh), synthe-inhibit AChE [23][24][25], without affinity for BuChE. A rationally designed clinical trials program examined sized in presynaptic neurons from choline and acetyl coenzyme A, is released from cells and binds to muscarinic the pharmacokinetics (PK) and pharmacodynamics (PD) of donepezil, its tolerability and its efficacy in treating and nicotinic receptors on both presynaptic and postsynaptic cells, producing either inhibitory or excitatory ac-the cognitive and global symptoms of AD.…”

mentioning

confidence: 99%

“…Indeed, in vitro studies show that it has a much greater relative specificity for AChE compared Other significant areas of research include muscarinic [8] and nicotinic cholinergic agonists [9] and neurotrophic with BuChE than either tacrine [22,28] [22,24]. The ratio of the donepezil IC 50 values for BuChE a number of investigations examined the potential of various drugs and physical conditions to influence the disposiand AChE was 1,252, compared with a ratio of 12 for physostigmine and 1 for tacrine [22,24]. This indicates tion of donepezil.…”

mentioning

confidence: 99%

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Perspectives in the Management of Alzheimer’s Disease: Clinical Profile of Donepezil

Sl¹

1998

Dement Geriatr Cogn Disord

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Donepezil HCl is a piperidine-based reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other cholinesterase (ChE) inhibitors and rationally designed to treat the symptoms of Alzheimer’s disease (AD). It is highly selective for AChE in the central nervous system (CNS), with little or no affinity for butyrylcholinesterase (BuChE). In preclinical studies in animals, donepezil produced increased CNS acetylcholine. The resultant enhancement of cholinergic activity gave rise to improved performance by rats on tests of learning and memory, with no evidence of hepatic or renal toxicity. In subsequent phase I clinical evaluations in healthy volunteers, donepezil demonstrated favorable pharmacokinetic, pharmacodynamic and safety profiles. Its long terminal disposition half-life supported once-daily administration, with no requirement for dose modification in the elderly or in patients with renal or hepatic impairment. A 14-week, phase II dose-finding study in patients with mild to moderate AD (Clinical Dementia Rating [CDR], 1–2; Mini-Mental State Examination [MMSE], 10–26) showed that donepezil at a dose of 5 mg/day produced highly significant improvements in cognition (as measured by the Alzheimer’s Disease Assessment Scale, cognitive subscale [ADAS-cog]). Subsequently, two pivotal parallel-group, placebo-controlled phase III trials (of 15 and 30 weeks’ duration) showed highly statistically significant improvements in ADAS-cog, MMSE, Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC plus) and CDR-SB (Sum of the Boxes) scores, compared with placebo, in mild to moderate AD patients treated with either 5 or 10 mg/day donepezil. Adverse events in the phase II and III trials were mild and transient and resolved with continued donepezil administration. The donepezil clinical trials program has shown that this drug is a clinically effective and well-tolerated once-daily treatment for the symptoms of mild to moderate AD.

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“…Male 63 (39) 57 (37) 60 (38) This study demonstrated that the treatment benefits (24) slower rate than that observed in untreated AD patients.…”

Section: A Long-term Open-label Phase II Trialmentioning

confidence: 85%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Perspectives in the Management of Alzheimer’s Disease: Clinical Profile of Donepezil

Sl¹

1998

Dement Geriatr Cogn Disord

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“…Donepezil is a specifically designed piperidine derivative with reversible acetylcholinesterase inhibitor activity. It has a much higher specificity for AChE inhibition compared with tacrine [17] and its CNS selectivity is highlighted by the lack of activity in peripheral tissue such as cardiac tissue or gut smooth muscle.…”

Section: Synthetic Inhibitors Of Achementioning

confidence: 99%

In Silico Comparison of Synthetic and Natural Molecules Bindings with Acetylcholinesterase Enzyme using Molecular Docking

Mesli¹,

Bouchentouf²,

Ghomri³

et al. 2018

JAMB

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Abstract. Inhibition of Acetylcholinesterase (AChE) is an important approach for Alzheimer's disease (AD) treatment. Different synthetic and natural inhibitors are used for Acetylcholinesterase inhibition. Synthetic inhibitors Polyphenols (Tacrine, Donepezil, Rivastigmine, Galantamine) and Natural molecules from Green tea which mainly contains catechins (Epicatechin, Epicatechin Gallate, Epigallocatechin, Epigallocatechin Gallate) are used to inhibit Acetylcholinesterase. In this work we use molecular docking methods to identify the ligand which has the best interaction energy with AChE among synthetic and natural products, and also descript binding affinity in purpose to design new inhibitor ligands. Obtained results from Docking and analyze of complexes parameters showed that the best affinity binding was observed for both (Galantamie and Epicatechin Gallete).This latter leads to same conclusion with experimentation inhibition study. We observed also that bulky group causes conformational rearrangement in the active pocket, which will probably give better interactions.

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“…Through extensive chemical structure-activity relationship and molecular modelling studies, donepezil was specifically designed for the symptomatic treatment of AD [24][25][26][27][28][29][30][31][32]. Donepezil is a reversible and specific inhibitor of AChE, as opposed to butyrylcholinesterase [28,33,34], which is found extensively in the periphery (table 1). This characteristic was predicted to minimize cholinergic side effects, particularly those that are gastrointestinal in nature (e.g.…”

Section: Chemical Characteristicsmentioning

confidence: 99%

Clinical Profile of Donepezil in the Treatment of Alzheimer’s Disease

Doody

1999

Gerontology

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Although the underlying pathogenesis of Alzheimer’s disease (AD) is not fully understood, one of its key features is the widespread loss of central cholinergic innervation, known to be fundamental for cognitive processes. This finding led to the hypothesis that pharmacological enhancement of acetylcholine (ACh) neurotransmission may alleviate the symptoms of AD. Currently, cholinergic therapy, particularly cholinesterase (ChE) inhibition, represents the most realistic approach to the symptomatic treatment of AD. Donepezil HCl, for example, is a piperidine-based, reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other ChE inhibitors and rationally designed for the symptomatic treatment of AD. It is highly selective for centrally acting AChE, with little or no affinity for butyrylcholinesterase, present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil’s favourable pharmacokinetic, pharmacodynamic and safety profile with no requirement for dose modification in the elderly or in patients with renal or hepatic impairment. Furthermore, its long half-life supports a simple and convenient once-daily dosing regimen. Subsequent to encouraging phase II clinical trial results, two pivotal, randomized, double-blind phase III trials (of 15 and 30 weeks’ duration) demonstrated highly significant improvements in cognition and global function in mild to moderately severe AD patients treated with either 5 or 10 mg/day donepezil compared with placebo. Adverse events in the phase II and III trials, primarily cholinergic in nature, were transient and generally mild in severity and resolved during continued donepezil administration. Thus, the donepezil clinical trials programme has shown that this drug is a clinically effective and well-tolerated, once-daily treatment for the symptoms of mild to moderately severe AD.

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Synthesis and anti-acetylcholinesterase activity of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine hydrochloride (E2020) and related compounds

Cited by 58 publications

References 5 publications

Perspectives in the Management of Alzheimer’s Disease: Clinical Profile of Donepezil

Perspectives in the Management of Alzheimer’s Disease: Clinical Profile of Donepezil

In Silico Comparison of Synthetic and Natural Molecules Bindings with Acetylcholinesterase Enzyme using Molecular Docking

Clinical Profile of Donepezil in the Treatment of Alzheimer’s Disease

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