AZ-4217: A High Potency BACE Inhibitor Displaying Acute Central Efficacy in Different In Vivo Models and Reduced Amyloid Deposition in Tg2576 Mice
Number of Authors: 15
2013 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 24, 10075-10084 p.Article in journal (Refereed) Published
A beta, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). beta-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to A beta peptides. Small molecule BACE1 inhibitors are expected to decrease A beta-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC50 160 pM in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of A beta production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.
Place, publisher, year, edition, pages
2013. Vol. 33, no 24, 10075-10084 p.
Other Chemistry Topics
Research subject Neurochemistry with Molecular Neurobiology
IdentifiersURN: urn:nbn:se:su:diva-134887DOI: 10.1523/JNEUROSCI.1165-13.2013ISI: 000320235300023OAI: oai:DiVA.org:su-134887DiVA: diva2:1039430