1. Academic Validation
  2. AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice

AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice

  • J Neurosci. 2013 Jun 12;33(24):10075-84. doi: 10.1523/JNEUROSCI.1165-13.2013.
Susanna Eketjäll 1 Juliette Janson Fredrik Jeppsson Alexander Svanhagen Karin Kolmodin Susanne Gustavsson Ann-Cathrin Radesäter Kristina Eliason Sveinn Briem Paulina Appelkvist Camilla Niva Anna-Lena Berg Sofia Karlström Britt-Marie Swahn Johanna Fälting
Affiliations

Affiliation

  • 1 Innovative Medicines AstraZeneca, CNS & Pain, S-151 85 Södertälje, Sweden. Susanna.Eketjall@astrazeneca.com
Abstract

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.

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