Mechanism of action: AZD3839 is a brain-permeable oral inhibitor of human beta-site amyloid (Aβ) precursor protein-cleaving enzyme1 (BACE1)
AZD3839 was able to completely abolish Aβ40 and sAPPβ production in vitro. In preclinical animal models, however, the concentration-effect relationship of Aβ40 reduction revealed that AZD3839 achieved a maximal inhibition of ∼60–70%, with the exception of the brain compartment in guinea pig. Repeated dosing of AZD3839 in mouse did not alter this relationship.
The selectivity for AZD3839 was evaluated against the two aspartyl proteases hBACE2 and Cathepsin D as well as Notch processing and resulted in 14, > 960 and > 10,000 times selectivity respectively.
Safety and Tolerability
Following evaluation of AZD3839 in healthy volunteers (single ascending dose range of 1-300 mg), a dose-related effect on QTcF was observed, with a mean QTcF prolongation of 5 to 6 ms at the 60 mg dose, 9 to 10 ms at the 100 mg dose, and 16 ms at the 300 mg dose. Clinical development was discontinued based on this observation.
Following a single oral dose (dose range 1-300 mg), the increase of AUC, AUC(0-t), and Cmax was non-linear and greater than proportional. Visual inspection of the pharmacokinetic/pharmacodynamic relationship indicated that there is a trend towards a decrease in plasma amyloid-beta (for both amyloid-beta 1-40 and 1-42) with increasing plasma AZD3839 concentrations.
Suitable for and exclusions
Suitable for preclinical experiments.
One clinical trial has been conducted with AZD3839. In healthy volunteers, a single ascending dose (SAD) study (NCT01348737) has completed. The clinical study report synopsis is available as an attachment on AstraZeneca Clinical Trials (https://astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=1737)
Jeppsson F, Eketjäll S, Janson J, Karlström S, Gustavsson S, Olsson LL, Radesäter AC, Ploeger B, Cebers G, Kolmodin K, Swahn BM, von Berg S, Bueters T, Fälting J (2012) Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem 287, 41245-41257.