Development of BACE1 Inhibitors for Alzheimers Disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. The production and accumulation of beta-amyloid peptides (Abeta) from the beta-amyloid precursor protein (APP) are believed to play a key role in the onset and progression of AD. BACE1 (beta-site APP cleaving enzyme 1) is the protease responsible for the N-terminal cleavage of APP leading to the production of Abeta peptides and the development of BACE1 inhibitors as potential therapeutic agents for AD has generated tremendous interests from both academia and the pharmaceutical industry. A wide variety of BACE1 inhibitors have been reported, several of which have demonstrated highly promising efficacy in animal models of AD. This review focuses on recent disclosures of BACE1 inhibitors in the patent and scientific literature, covering the period from approximately May 2004 to November 2005.

The Expression of MicroRNA miR-107 Decreases Early in Alzheimer's Disease and May Accelerate Disease Progression through Regulation of β-Site Amyloid Precursor Protein-Cleaving Enzyme 1

“…The dysregulation of BACE1 appears to directly contribute to the pathogenesis of AD (Dominguez et al, 2004;Durham and Shepherd, 2006;Guo and Hobbs, 2006;John, 2006). Our ISH show that miR-107, like BACE1 (Bigl et al, 2000;Fukumoto et al, 2002), is enriched in neurons.…”

“…BACE1 protein is an endopeptidase that cleaves the ␤-amyloid precursor protein to generate neurotoxic ␤-amyloid peptide A␤ (Vassar et al, 1999;Haniu et al, 2000). The dysregulation of BACE1 may play a major role in the pathogenesis of AD (Dominguez et al, 2004;Durham and Shepherd, 2006;Guo and Hobbs, 2006;John, 2006). BACE1 is enriched in neurons (Bigl et al, 2000;Fukumoto et al, 2002) and its expression is regulated posttranscriptionally (Marambaud et al, 1998;Rossner et al, 2006).…”

Computational pharmaceutical analysis of anti-Alzheimer's Chinese medicine Coptidis Rhizoma alkaloids

“…According to statistics, the number of patients suffering from AD is likely to double in the next 20 years. AD has become a disease that causes heavy social and financial burden to both society and the families involved (2). Until recently, two major hypotheses were proposed regarding the molecular mechanism of pathogenesis: the cholinergic hypothesis and the amyloid cascade hypothesis (3).…”

Structure and modeling in the design of β‐ and γ‐secretase inhibitors

“…Other recent reviews on this topic include Avram et al [2006], McGaughey and Holloway [2007], and Villaverde et al [2007]. There are also recent reviews of the development of BACE-1 inhibitors [Cumming et al, 2004;Durham and Shepherd, 2006;Guo and Hobbs, 2006;Hills and Vacca, 2007] and g-secretase inhibitors [Churcher and Beher, 2005;Marjaux and de Strooper, 2004].…”