ACS Chemical Neuroscience Molecule Spotlight on Begacestat (GSI-953)

Hopkins, Corey R.

doi:10.1021/cn200124u

Cited by 32 publications

(14 citation statements)

References 10 publications

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“…During the semagacestat treatment, side effects were shown to increase the risk of skin cancer. Begacestat (GSI-953) decreased Aβ levels in plasma, brain, and cerebrospinal fluid in Tg2576 mice, but it failed to reduce Aβ concentration in the AD patient brain [ 141 ]. It was discontinued in the phase 1 trial in 2010.…”

Section: What Is the Role Of Small Molecules In Inhibition Mechanism Of Aβ Aggregation?mentioning

confidence: 99%

An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

Boopathi

Poma

Garduño‐Juárez

2021

IJMS

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Amyloid beta (Aβ) oligomers are the most neurotoxic aggregates causing neuronal death and cognitive damage. A detailed elucidation of the aggregation pathways from oligomers to fibril formation is crucial to develop therapeutic strategies for Alzheimer’s disease (AD). Although experimental techniques rely on the measure of time- and space-average properties, they face severe difficulties in the investigation of Aβ peptide aggregation due to their intrinsically disorder character. Computer simulation is a tool that allows tracing the molecular motion of molecules; hence it complements Aβ experiments, as it allows to explore the binding mechanism between metal ions and Aβ oligomers close to the cellular membrane at the atomic resolution. In this context, integrated studies of experiments and computer simulations can assist in mapping the complete pathways of aggregation and toxicity of Aβ peptides. Aβ oligomers are disordered proteins, and due to a rapid exploration of their intrinsic conformational space in real-time, they are challenging therapeutic targets. Therefore, no good drug candidate could have been identified for clinical use. Our previous investigations identified two small molecules, M30 (2-Ohydroisoquinolin-2(1H)-ylethanamine) and Gabapentin, capable of Aβ binding and inhibiting molecular aggregation, synaptotoxicity, intracellular calcium signaling, cellular toxicity and memory losses induced by Aβ. Thus, we recommend these molecules as novel candidates to assist anti-AD drug discovery in the near future. This review discusses the most recent research investigations about the Aβ dynamics in water, close contact with cell membranes, and several therapeutic strategies to remove plaque formation.

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Section: What Is the Role Of Small Molecules In Inhibition Mechanism Of Aβ Aggregation?mentioning

confidence: 99%

An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

Boopathi

Poma

Garduño‐Juárez

2021

IJMS

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“…Furthermore, in Tg2576 transgenic mice studies, high doses of GSI-953 reduced Aβ41 levels in the brain ( 120 , 121 ). A clinical study was performed using GSI-953 for AD treatment ( 119 , 122 ), and the results demonstrated that GSI-953 does not exhibit a positive effect on the reduction of Aβ40 levels in the CSF of patients with AD ( 120 ).…”

Section: The Use Of Receptor-based Pharmaceutical Agents To Treat Admentioning

confidence: 99%

Computational modeling and biomarker studies of pharmacological treatment of Alzheimer's disease (Review)

et al. 2018

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Alzheimer's disease (AD) is a complex and multifactorial disease. In order to understand the genetic influence in the progression of AD, and to identify novel pharmaceutical agents and their associated targets, the present study discusses computational modeling and biomarker evaluation approaches. Based on mechanistic signaling pathway approaches, various computational models, including biochemical and morphological models, are discussed to explore the strategies that may be used to target AD treatment. Different biomarkers are interpreted on the basis of morphological and functional features of amyloid β plaques and unstable microtubule-associated tau protein, which is involved in neurodegeneration. Furthermore, imaging and cerebrospinal fluids are also considered to be key methods in the identification of novel markers for AD. In conclusion, the present study reviews various biochemical and morphological computational models and biomarkers to interpret novel targets and agonists for the treatment of AD. This review also highlights several therapeutic targets and their associated signaling pathways in AD, which may have potential to be used in the development of novel pharmacological agents for the treatment of patients with AD. Computational modeling approaches may aid the quest for the development of AD treatments with enhanced therapeutic efficacy and reduced toxicity.

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“…90 The compound has shown promise in recent Phase I clinical trials. 91 NIC5-15 is a natural compound acted as a Notch-sparing gsecretase inhibitor and an insulin sensitizer. The compound can improve cognitive function through multiple mechanisms including reduce Ab production by modulating g-secretase.…”

Section: Cholinergic Drugsmentioning

confidence: 99%