donepezil one-month depot (GB-5001) / G2GBIO - LARVOL DELTA

Isatin derivatives as potent cholinesterase inhibitors: recent developments and future challenges. (PubMed, RSC Adv) - "However, the currently approved small molecules, including tacrine, donepezil, rivastigmine, and galantamine, are limited by their modest efficacy, poor selectivity, and adverse effects, necessitating the development of improved therapeutic agents. Structure-activity relationship studies have revealed the critical influence of electronic effects, linker optimization, N-substitution, and molecular hybridization on inhibitory potency and selectivity. This review summarizes the most promising isatin-based cholinesterase inhibitors reported from 2020 to the present, highlighting their biological activities, structure-activity relationships, and potential for the development of next-generation anti-Alzheimer therapeutics."

Journal • Review • Alzheimer's Disease • CNS Disorders • Pain

A Switching from Oral Donepezil to a Twice-Weekly Korean Transdermal Donepezil Patch in Patients with Dementia with PD (MDS Congress 2026) - No abstract available

Clinical • Alzheimer's Disease • CNS Disorders • Dementia

Crystal structure, intermolecular interactions, Hirshfeld surface analysis, theoretical studies and biological evaluation of (E)-5-(benzyloxy)-2-{[(2,5-dimethoxyphenyl)imino]methyl}phenol, a new Schiff base. (PubMed, Acta Crystallogr C Struct Chem) - "Compared with the corresponding reference inhibitors, BDIMPh showed a slightly higher IC50 value than donepezil for AChE, a slightly lower IC50 value than ethacrynic acid for GST and a higher IC50 value than acarbose for α-glucosidase. These results indicate an enzyme-dependent inhibitory profile rather than uniformly superior activity relative to the reference inhibitors."

Journal • Pain • Tyrosinase

Formoterol attenuates lipopolysaccharide-induced mnemonic impairment in the delayed nonmatch to position task in rats. (PubMed, Behav Pharmacol) - "By means of validation, the effect of treatment with the muscarinic receptor antagonist scopolamine [0.02 mg/kg, subcutaneously (s.c.)], known to disrupt performance in the task, and its reversal by coadministration of the cognitive-enhancing agent and acetylcholinesterase inhibitor donepezil (0.3 mg/kg, s.c.) were confirmed. Coadministration of Formoterol (0.5 mg/kg, s.c.) attenuated LPS-driven mnemonic impairments in males but not females. Overall, the results show the DNMTP task is a paradigm sensitive to acute systemic inflammation and indicate that Formoterol may have useful anti-inflammatory properties in mitigating inflammatory-associated cognitive impairment."

Journal • Preclinical • Cognitive Disorders • Inflammation

Transcriptomic integration reveals immune heterogeneity in vascular dementia and identifies ELF2 as a candidate therapeutic target. (PubMed, Medicine (Baltimore)) - "Molecular docking analysis suggested strong binding affinities between ELF2 and nicergoline (-7.23 kcal/mol), nimodipine (-6.92 kcal/mol), and donepezil (-6.29 kcal/mol). This integrative transcriptomic study reveals disrupted immune balance and neuroglial-vascular cell homeostasis in vascular dementia, and prioritizes ELF2 as a candidate regulator associated with immune heterogeneity in VaD."

Heterogeneity • Journal • CNS Disorders • Dementia • Solid Tumor • CD4

Design, Synthesis and Molecular Docking Studies of Some Novel Hydrazone Derivatives Based on Trimetazidine as Selective and Potent AChE Inhibitors. (PubMed, Drug Dev Res) - "The compounds were evaluated for in vitro inhibition of AChE and butyrylcholinesterase (BChE) using donepezil and tacrine as reference inhibitors, respectively. To rationalize the observed activity trends, molecular docking studies were performed, suggesting that the most active ligands adopt donepezil-like binding modes spanning the catalytic and peripheral anionic sites and are further stabilized by π-π/π-cation contacts and hydrogen-bonding interactions within the active gorge. Overall, these findings identify trimetazidine-derived hydrazide-hydrazones as a promising chemotype for the development of selective AChE inhibitors and provide a basis for further optimization and advanced biological validation."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Multi-functional bionic nanoparticles for precise neuronal targeting and synergistic therapy in Alzheimer's disease. (PubMed, Mater Today Bio) - "The nanoparticles (NPs) core was fabricated using safe, biocompatible poly (lactic-co-glycolic acid) (PLGA) to co-deliver natural product genistein and mature marketed donepezil, which act synergistically to enhance therapeutic efficacy. Collectively, BTRN treats AD through multiple mechanisms, including reducing Aβ production, regulating cholinergic function, and inhibiting neuronal apoptosis. This biomimetic system presents a promising therapeutic strategy and offers valuable insights for the clinical translation of combination therapies in AD."

Journal • Alzheimer's Disease • CNS Disorders

Topical Donepezil for Cholinergic Modulation in Chronic Wound Repair. (PubMed, Wound Repair Regen) - "This approach may complement metabolic therapies that support arginine-NO coupling and redox balance. Controlled pilot studies should assess local cutaneous pharmacodynamics, perfusion responses, and wound-closure outcomes."

Journal • Review • Pain • NOS3

Efficacy of donepezil in patients with chronic tinnitus. (PubMed, Clinics (Sao Paulo)) - "In the present double-blind, randomized, placebo-controlled clinical trial, no statistically significant difference was identified between the groups regarding the primary outcome. However, the donepezil-treated group demonstrated better performance than the placebo group, and a possible indication of greater clinical benefit was observed in the treatment group in those using amplification, suggesting a potential therapeutic relevance, but larger, more in-depth studies are needed to confirm our findings."

Clinical • Journal • CNS Disorders • Dementia • Otorhinolaryngology

Bushen-Yizhi formula promotes neurogenesis and ameliorates cognitive impairment by activating ST8Sia Ⅱ/Ⅳ-PSA-NCAM pathway in ibotenic acid induced mice. (PubMed, J Ethnopharmacol) - "Our study demonstrates BSYZ promotes hippocampal neurogenesis to ameliorate cognitive impairment by activating ST8Sia II/IV-PSA-NCAM pathway. These findings provide mechanistic evidence supporting the therapeutic potential of BSYZ for AD treatment."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • NCAM1 • NES

Psychotropic Polypharmacy in Alzheimer's Disease: A Potentially Inappropriate Medication Perspective in Older Adults. (PubMed, Curr Alzheimer Res) - "This review specifically examines anticholinergic drugs, antipsychotics, benzodiazepines and Z-drugs, tricyclic antidepressants, and select newer antidepressants-including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine, trazodone, and paroxetine-guided by the 2023 American Geriatrics Society (AGS) Beers Criteria®. Current evidence indicates that these medications may contribute to cognitive decline through anticholinergic burden, sedation, and pharmacodynamic interactions with cholinesterase inhibitors, such as donepezil and memantine...This study also summarizes current nonpharmacological strategies and proposes a structured clinical medication review framework. Overall, this review highlights the importance of minimizing inappropriate psychotropic use in AD, prioritizing non-pharmacological interventions, and conducting individualized risk-benefit assessments in clinical practice."

Journal • Alzheimer's Disease • Anesthesia • CNS Disorders • Dementia • Psychiatry

Longitudinal Multi-tracer PET/CT for Monitoring the Progression of Diabetic Cardiac Autonomic Neuropathy: A Preclinical Study. (PubMed, Acad Radiol) - "This multi-tracer longitudinal investigation establishes that parasympathetic denervation precedes sympathetic impairment during DCAN development, with both deficits predating microvascular and metabolic crises. These insights offer a critical, noninvasive diagnostic window for early DCAN detection and clinical monitoring."

Journal • Preclinical • Diabetes • Diabetic Neuropathy • Inflammation • Metabolic Disorders • Pain • Type 2 Diabetes Mellitus

Improvement in Delusional Jealousy and Caregiver Distress After Switching From Oral Galantamine to a Donepezil Transdermal Patch in Alzheimer's Disease: A Case Report. (PubMed, Psychogeriatrics) - "This case suggests that switching from oral galantamine to a donepezil transdermal patch may be associated with improvement in delusional jealousy, selected caregiver-rated NPS domains and caregiver distress in some patients, although causal inference is not possible in a single case and responses may vary."

Journal • Alzheimer's Disease • CNS Disorders • Psychiatry

Phase 1 Study And Population Pharmacokinetic Characterization Of GB-5001, A Long-acting Intramuscular Donepezil (AAIC 2026) - No abstract available

Clinical • P1 data • PK/PD data

Pharmacokinetic Evaluation of GB-5001, a Long-Acting Injectable Formulation of Donepezil, in Healthy Korean Participants: Population Pharmacokinetics with Phase 1 Study. (PubMed, Pharmaceutics) - "It achieved a 3-4-fold longer half-life than oral donepezil. These findings, supported by modeling, highlight GB-5001A's potential as a once-monthly IM alternative for Alzheimer's disease treatment."

Journal • P1 data • PK/PD data • Alzheimer's Disease • CNS Disorders • Pain

Population Pharmacokinetic Modeling and Simulation for Dose Optimization of GB-5001, a Long-Acting Intramuscular Injection of Donepezil, in Healthy Participants. (PubMed, Neurol Ther) - P1 | "The population PK model well explained the PKs of donepezil following administration of both the IM and oral formulations. This model could be applied for the design and dose selection of future BE trials."

Journal • PK/PD data • Alzheimer's Disease • CNS Disorders

Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics From Single Dose of Intramuscular (IM) and Subcutaneous (SC) Donepezil (GB-5001) Injections Versus Donepezil Oral Tablet (Aricept®) in Healthy Male Volunteers (clinicaltrials.gov) - P1 | N=56 | Recruiting | Sponsor: G2GBio, Inc.

New P1 trial • Alzheimer's Disease • CNS Disorders

Comparative Pharmacokinetic Studies of One-Month Donepezil IM Depot and Once Daily Oral Tablet in Healthy Male Volunteers (AAIC 2023) - "A single dose of 70mg donepezil IM depot was found to be safe and well tolerated in healthy male volunteers. The pharmacokinetic results of 70mg donepezil IM depot showed stable donepezil blood concentration for more than one month without burst drug release, and showed comparable unit dose drug exposure not lower than that of once daily 10mg oral formulation. Through the PK results for additional higher doses and multiple PK simulations, optimal once monthly dose of donepezil IM depot could be suggested which will be bioequivalent to 10mg once daily tablet."

Clinical • PK/PD data • Alzheimer's Disease

Novel High-Donepezil Loaded One-Month Release Microspheres for Alzheimer’s Disease Treatment (AAIC 2023) - "We have developed novel donepezil microspheres with high drug contents and without initial burst release. These high donepezil-loaded microspheres can improve patient compliance and medication convenience by lowering dosage volume at the injection site. Currently, this novel donepezil formulation is planned for commercialization after clinical trials."

Alzheimer's Disease • CNS Disorders • Pain

Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of Donepezil From Single Dose of GB-5001 IM Depot and Aricept® Oral Tablets in Healthy Male Volunteers (clinicaltrials.gov) - P1 | N=48 | Completed | Sponsor: G2GBio, Inc. | Recruiting ➔ Completed | Trial completion date: Sep 2023 ➔ Jun 2023

Trial completion • Trial completion date • Alzheimer's Disease • CNS Disorders

Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of Donepezil From Single Dose of GB-5001 IM Depot and Aricept® Oral Tablets in Healthy Male Volunteers (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: G2GBio, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Alzheimer's Disease • CNS Disorders

Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of Donepezil From Single Dose of GB-5001 IM Depot and Aricept® Oral Tablets in Healthy Male Volunteers (clinicaltrials.gov) - P1 | N=48 | Not yet recruiting | Sponsor: G2GBio, Inc.

New P1 trial • Alzheimer's Disease • CNS Disorders

Donepezil ameliorates Aβ pathology but not tau pathology in 5xFAD mice. (PubMed, Mol Brain) - "However, neither intraperitoneal/oral injection of donepezil nor oral injection of rivastigmine altered tau phosphorylation at Thr212/Ser214 (AT100), Thr396, and Thr231 in 5xFAD mice. Surprisingly, we observed that intraperitoneal/oral injection of donepezil treatment significantly increased tau phosphorylation at Thr212 in 5xFAD mice. Taken together, these data suggest that intraperitoneal injection of donepezil suppresses Aβ pathology but not tau pathology in 5xFAD mice."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders

Donepezil Regulates LPS and Aβ-Stimulated Neuroinflammation through MAPK/NLRP3 Inflammasome/STAT3 Signaling. (PubMed, Int J Mol Sci) - "The acetylcholinesterase inhibitors donepezil and rivastigmine have been used as therapeutic drugs for Alzheimer's disease (AD), but their effects on LPS- and Aβ-induced neuroinflammatory responses and the underlying molecular pathways have not been studied in detail in vitro and in vivo. In a mouse model of AD (5xFAD mice), donepezil significantly reduced Aβ-induced microglial and astrocytic activation, density, and morphology. Taken together, our findings indicate that donepezil significantly downregulates LPS- and Aβ-evoked neuroinflammatory responses in vitro and in vivo and may be a therapeutic agent for neuroinflammation-associated diseases such as AD."

Journal • Alzheimer's Disease • CNS Disorders • Immunology • Inflammation • IL6