A Report From the 8th Kuopio Alzheimer Symposium

Haapasalo, Annakaisa; Hiltunen, Mikko

doi:10.2217/nmt-2018-0029

Cited by 14 publications

(14 citation statements)

References 25 publications

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“…Currently, there are several ongoing clinical trials for potential new medications for AD (Table ). However, the latest news from many of these clinical trials indicated a high failure rate of many lead drug candidates, specifically the ones targeting β‐site APP cleaving enzyme 1 (BACE1) . Moreover, the elegant contributions from Cummings et al highlighted several small molecules BACE1 inhibitors that are currently in clinical trials for AD treatment.…”

Section: Introductionmentioning

confidence: 99%

“…However, the latest news from many of these clinical trials indicated a high failure rate of many lead drug candidates, specifically the ones targeting β-site APP cleaving enzyme 1 (BACE1). [7][8][9] Moreover, the elegant contributions from Cummings et al highlighted several small molecules BACE1 inhibitors that are currently in clinical trials for AD treatment. Around 26 candidates were introduced in clinical trials, including agents that target the amyloid-β (Aβ) protein through BACE1 inhibition and others as immunotherapies.…”

mentioning

confidence: 99%

“…125 Consequently, studies over second generation anti-Aβ mAbs have taken place due to the disappointing observations from the first-generation mAbs. Gantenerumab (RG1450/RO4909832, Hoffman-La Roche), is the first fully human IgG1 antibody that targets the fibrillary Aβ form and uniquely binds the epitope that involves both, the N-terminal (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) and mid-region (18)(19)(20)(21)(22)(23)(24)(25)(26)(27) residues. Hence, a folded peptide where the mid domain overlaps with the N-terminus is preferred.…”

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confidence: 99%

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BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

230

175

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Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

230

175

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“…It hasb een shownt hat in patients with AD, the serum levelso fA ChE and BChE are elevated to agreat extent,leadingtoanuncontrolled decreasei nt he levels of ACh, whichc auses an imbalance in motorc oordinationa nd, problems in cognition and memory. [10] Although the number of clinicalc andidates is high, there has also been as ubstantial declinei nn umbers progressing to the next level of evaluation, owing to the rise in toxicityconcerns and efficacy issues. [5] This intensifies the symptomsa ssociated with AD, and therefore AChE is ag ood target against which to develop potentiali nhibitors to bring equilibrium to the induced extreme levels of activity.Atpresent,four AChE inhibitor drugs are approved to treat the symptomatic effects of AD:t acrine, galantamine, donepezil, and rivastigmine.…”

Section: Introductionmentioning

confidence: 99%

“…Around 112d rug candidates were being tested in the clinicalp ipeline as of 2018, out of which,2 6c andidates were in phase III trials. [10] Although the number of clinicalc andidates is high, there has also been as ubstantial declinei nn umbers progressing to the next level of evaluation, owing to the rise in toxicityconcerns and efficacy issues.…”

Section: Introductionmentioning

confidence: 99%

Experimental and Computational Evaluation of Piperonylic Acid Derived Hydrazones Bearing Isatin Moieties as Dual Inhibitors of Cholinesterases and Monoamine Oxidases

et al. 2019

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A set of piperonylic acid derived hydrazones with variable isatin moieties was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO‐A/B). The results of in vitro studies revealed IC50 values in the micromolar range, with the majority of the compounds showing selectivity for the MAO‐B isoform. N‐[2‐Oxo‐1‐(prop‐2‐ynyl)indolin‐3‐ylidene]benzo[d][1,3]dioxole‐5‐carbohydrazide (3) was identified as a lead AChE inhibitor with IC50=0.052±0.006 μm. N‐[(3E)‐5‐chloro‐2‐oxo‐2,3‐dihydro‐1H‐indol‐3‐ylidene]‐2H‐1,3‐benzodioxole‐5‐carbohydrazide (2) was the lead MAO‐B inhibitor with IC50=0.034±0.007 μm, and showed 50 times greater selectivity for MAO‐B over MAO‐A. The kinetic studies revealed that compounds 2 and 3 displayed competitive and reversible inhibition of AChE and MAO‐B, respectively. The molecular docking studies revealed the significance of hydrophobic interactions in the active site pocket of the enzymes under investigation. Further optimization studies might lead to the development of potential neurotherapeutic agents.

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In silico molecular studies of natural compounds as possible anti-Alzheimer’s agents: ligand-based design

Iwaloye

Elekofehinti

Momoh

et al. 2020

Netw Model Anal Health Inform Bioinforma

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Alzheimer disease (AD) is the most common form of dementia contributing to about 60-70% of cases. β-Site amyloid precursor protein cleaving enzyme-1 (BACE1) plays an important role in the onset of AD and has become one of the important drug targets for AD. This approach has led to the development of promising BACE1 inhibitors, many of which are going through different phases of clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new drugs to uncover the mystery behind AD. This study focused on virtual screening of ~ 33,000 natural compounds to find potential BACE1 inhibitors. Multiple ligands pharmacophore model was generated using PHASE to screen retrieved compounds against a four-site (ADDR) hypothesis. Molecular docking was performed to predict the binding status of the natural compounds. Based on binding affinity, the top eight compounds were chosen for further analysis. The docked complexes were analyzed for binding free energy using PRIME MM/GBA calculation. The compounds were filtered for drug-likeness using ADME/TOX (absorption, distribution, metabolism, excretion and toxicity) prediction. AutoQSAR (automated quantitative structure activity relationship) was used to build a model for the prediction of compounds bioactivities. Despite retrieving a large number of compounds with favorable binding affinity, only a few were selected to be promising based on their ADME/TOX proprieties, binding free energy and predicted pIC 50. This study identified four natural compounds (NPC469686, NPC262328, NPC29763 and NPC86744) as novel BACE1 inhibitors. The insights obtained from this study could be employed to produce next-generation drug for AD.

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A Report From the 8th Kuopio Alzheimer Symposium

Cited by 14 publications

References 25 publications

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Experimental and Computational Evaluation of Piperonylic Acid Derived Hydrazones Bearing Isatin Moieties as Dual Inhibitors of Cholinesterases and Monoamine Oxidases

In silico molecular studies of natural compounds as possible anti-Alzheimer’s agents: ligand-based design

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