AZ-4217: A High Potency BACE Inhibitor Displaying Acute Central Efficacy in Different In Vivo Models and Reduced Amyloid Deposition in Tg2576 Mice

作者：Eketjall Susanna^*; Janson Juliette; Jeppsson Fredrik; Svanhagen Alexander; Kolmodin Karin; Gustavsson Susanne; Radesater Ann Cathrin; Eliason Kristina; Briem Sveinn; Appelkvist Paulina; Niva Camilla; Berg Anna Lena; Karlstrom Sofia; Swahn Britt Marie; Falting Johanna

来源：Journal of Neuroscience, 2013, 33(24): 10075-10084.

DOI：10.1523/JNEUROSCI.1165-13.2013

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.

• 出版日期2013-6-12