Background:

Description:

IC50: 16.7 nM for BACE1

β-Site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processes of the amyloid precursor protein (APP) and formation of amyloid β peptide (Aβ) species. Because cerebral deposition of Aβ species is possibly critical for the pathogenesis of Alzheimer disease, BACE1 has emerged as a key target for the treatment of this disease. AZD3839 is a potent and selective BACE1 inhibitor.

In vitro: AZD3839 concentration-dependently inhibited BACE1 activity in a biochemical fluorescence resonance energy transfer assay, Aβ and sAPPβ release from modified and wild-type human SH-SY5Y cells and mouse N2A cells as well as from guinea pig and mouse primary cortical neurons. Selectivity against BACE2 and cathepsin D was 14 and >1000-fold, respectively [1].

In vivo: AZD3839 exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aβ levels in mouse, guinea pig, and non-human primate. PK/PD analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects [1].

Clinical trial: Based on the pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man [2].

Reference:
[1] Jeppsson F, Eketj?ll S, Janson J, Karlstr?m S, Gustavsson S, Olsson LL, Rades?ter AC, Ploeger B, Cebers G, Kolmodin K, Swahn BM, von Berg S, Bueters T, F?lting J.  Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem. 2012 Nov 30;287(49):41245-57.
[2] https://clinicaltrials. gov/ct2/show/NCT01348737?term=AZD3839&rank=1