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.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1002/med.21622 | DOI Listing |
Brain Sci
November 2024
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia.
Background/objectives: Diabetes mellitus (DM), a widespread endocrine disorder characterized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer's disease (AD). Effective blood glucose management is essential, and sitagliptin (SITG), a dipeptidyl peptidase-4 () inhibitor, may offer neuroprotective benefits in type 2 diabetes mellitus (T2DM).
Methods: T2DM was induced in rats using nicotinamide (NICO) and streptozotocin (STZ), and biomarkers of AD and DM-linked enzymes, inflammation, oxidative stress, and apoptosis were evaluated in the brain.
Curr Alzheimer Res
January 2025
Silicon Script Sciences Private Limited, Bharatpur, Gorahi, Dang, 22400, Nepal.
Background: Alzheimer's disease (AD) is marked by cognitive decline, amyloid plaques, neurofibrillary tangles, and cholinergic loss. Due to the limited success of amyloid-targeted therapies, attention has shifted to new non-amyloid targets like phosphodiesterases (PDE). This study investigates the potential of phytomolecules and derivatives, particularly 8-Prenyldaidzein, in AD treatment.
View Article and Find Full Text PDFFront Pharmacol
December 2024
Department of Health and Pharmaceutical Sciences, Faculty of Pharmacy, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, Spain.
Alzheimer's disease (AD) is a major neurodegenerative disorder that courses with chronic neuroinflammation. Pleiotrophin (PTN) is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ which is upregulated in different neuroinflammatory disorders of diverse origin, including AD. To investigate the role of RPTPβ/ζ in neuroinflammation and neurodegeneration, we used eight-to ten-month-old APP/PS1 AD mouse model.
View Article and Find Full Text PDFSAR QSAR Environ Res
December 2024
Department of Pharmacognosy, Faculty of Pharmacognosy and Traditional Medicine, Hanoi University of Pharmacy, Hanoi, Vietnam.
A comprehensive computational strategy that combined QSAR modelling, molecular docking, and ADMET analysis was used to discover potential inhibitors for β-secretase 1 (BACE-1). A dataset of 1,138 compounds with established BACE-1 inhibitory activities was used to build a QSAR model using mol2vec descriptors and support vector regression. The obtained model demonstrated strong predictive performance (training set: = 0.
View Article and Find Full Text PDFACS Nano
January 2025
Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR 999078, China.
More than the sparse infiltration in glioblastoma, cytotoxic T lymphocytes (CTLs) also function inefficiently and overexpress the inhibitory markers, especially the identified NK cell receptor (NK1.1). However, most studies solely focus on how to augment tumor-infiltrating CTLs and overlook their killing maintenance.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!