PT  - JOURNAL ARTICLE
AU  - Eketjäll, Susanna
AU  - Janson, Juliette
AU  - Jeppsson, Fredrik
AU  - Svanhagen, Alexander
AU  - Kolmodin, Karin
AU  - Gustavsson, Susanne
AU  - Radesäter, Ann-Cathrin
AU  - Eliason, Kristina
AU  - Briem, Sveinn
AU  - Appelkvist, Paulina
AU  - Niva, Camilla
AU  - Berg, Anna-Lena
AU  - Karlström, Sofia
AU  - Swahn, Britt-Marie
AU  - Fälting, Johanna
TI  - AZ-4217: A High Potency BACE Inhibitor Displaying Acute Central Efficacy in Different <em>In Vivo</em> Models and Reduced Amyloid Deposition in Tg2576 Mice
AID  - 10.1523/JNEUROSCI.1165-13.2013
DP  - 2013 Jun 12
TA  - The Journal of Neuroscience
PG  - 10075--10084
VI  - 33
IP  - 24
4099  - http://www.jneurosci.org/content/33/24/10075.short
4100  - http://www.jneurosci.org/content/33/24/10075.full
SO  - J. Neurosci.2013 Jun 12; 33
AB  - Aβ, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). β-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to Aβ peptides. Small molecule BACE1 inhibitors are expected to decrease Aβ-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 Aβ 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.