Adsorption, Distribution, Metabolism, Excretion (ADME), Efficacy, and Toxicology for BACE Inhibitors

Hussain, Ishrut; Demont, Emmanuel H.

doi:10.1002/9780470594087.ch8

Cited by 1 publication

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“…9 Although this approach was successful in generating potent BACE-1 inhibitors, these compounds exhibited poor pharmacokinetic properties, including low brain penetration and cytochrome P450 liabilities, which hindered their subsequent development. 22 More recently, fragment-based drug discovery has been applied for the identification of BACE-1 inhibitors. 23,24 Because of the limited success with BACE-1 inhibitor development, the availability of alternative screening assays for BACE-1 could be advantageous.…”

Section: Introductionmentioning

confidence: 99%

Development and Characterization of a Novel Membrane Assay for Full-Length BACE-1 at pH 6.0

et al. 2013

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β-Site amyloid precursor protein cleaving enzyme-1 (BACE-1) is a transmembrane aspartic protease that mediates the initial cleavage of the amyloid precursor protein (APP), leading to the generation of amyloid-β (Aβ) peptides that are thought to be causative of Alzheimer's disease (AD). Consequently, inhibition of BACE-1 is an attractive therapeutic approach for the treatment of AD. In general, in vitro biochemical assays to monitor BACE-1 activity have used the extracellular domain of the protein that contains the catalytic active site. This form of BACE-1 is catalytically active at acidic pH and cleaves APPbased peptide substrates at the β-site. However, this form of BACE-1 does not mimic the natural physiology of BACE-1 and shows minimal activity at pH 6.0, which is more representative of the pH within the intracellular compartments where BACE-1 resides. Moreover, high-throughput screens with recombinant BACE-1 at pH 4.5 have failed to identify tractable leads for drug discovery, and hence, BACE-1 inhibitor development has adopted a rational drug design approach. Here we describe the development and validation of a novel membrane assay comprising full-length BACE-1 with measurable activity at pH 6.0, which could be used for the identification of novel inhibitors of BACE-1.

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