BACE Inhibitors as Potential Drugs for the Treatment of Alzheimers Disease: Focus on Bioactivity

Abstract

Current drug development for the treatment of Alzheimer's Disease is principally based on the amyloid cascade theory, and aims to reduce the levels of Aβ amyloid peptide in the brain. This can be achieved, either by decreasing peptide production through inhibition of β-secretase (also known as BACE-1) or γ-secretase, or by interfering with Aβ aggregation, or by promoting Aβ clearance. Targeting BACE-1, the proteolytic enzyme that initiates Aβ formation, has generated a lot of research interest recently and is currently thought to be one of the most promising therapeutic approaches. In this review, we summarize and discuss the latest patents and publications describing BACE-1 inhibitors, principally focussing on their drug properties and performance in preclinical trials.

Targeting the β secretase BACE1 for Alzheimer's disease therapy

“…61 Soon thereafter, new classes of small-molecule BACE1 inhibitors were designed that possessed improved drug-like properties, including low molecular weight, plasma membrane permeability, and enhanced pharmacokinetics. 62,63 Unfortunately, these second-generation BACE1 inhibitors were unable to achieve sufficiently high brain concentrations, because most were substrates of P-glycoprotein, the ATP-dependent drug efflux pump for xenobiotics in the blood–brain barrier.…”

Synthesis, biological activity, and biopharmaceutical characterization of tacrine dimers as acetylcholinesterase inhibitors

“…In addition to targeting cholinergic deficiency, reducing glutamate induced excitotoxicity by N-methyl-D-aspartate receptor antagonists (e.g., FDA approved memantine) (Reisberg et al, 2003), and preventing the build-up of Ab by b-secretase 1 (BACE 1) inhibitors (e.g., MK-8931, LY2886721 in clinical trials) also severed two kinds of treatments of AD. However, none of above strategies could completely prevent the neurodegeneration and cure the AD till now (Evin et al, 2011;Robinson and Keating, 2006;Terry and Buccafusco, 2003), which may be due to that they only focused on one targeting site of drug action. As a consequence, drug discovery in AD is gradually moving from the development of molecules with a single target to the "multi-target-directed ligands" (MTDLs), which is capable to simultaneously address several key pathophysiological processes as described above (Bajda et al, 2011;Cavalli et al, 2008).…”

Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

“…90,98 In addition, a variety of classes of molecules capable of inhibiting BACE1 with a high potency were discovered through screening of drug libraries, particularly of aspartyl protease inhibitors prepared for drug-discovery programs targeting renin or human immunodeficiency virus protease, as well as through a fragment-based drug-discovery approach guided by X-ray and nuclear magnetic resonance structure analyses. 88,99 Obtaining compounds with a selectivity of several orders of magnitude for BACE1 towards BACE2 and other aspartyl proteases, such as cathepsin D, remains a major challenge. Cathepsin D is a major lysosomal protease, and decreasing its activity would compromise the overall cellular degradation machinery.…”