AZD3839
Preclinical pharmacology
AZD3839 is a brain-permeable inhibitor of human BACE1 (nonselective for BACE1 vs BACE2) that has been shown to reduce levels of Aβ1-40 and Aβ1-42 in in vitro models. 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 5-6ms at the 60 mg dose, 9-10ms at the 100 mg dose, and 16ms at the 300mg dose. Clinical development was discontinued based on this observation.
Clinical pharmacology
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.
Mechanism of Action
Beta-site amyloid (Aβ) precursor protein-cleaving enzyme1 (BACE1)
Original Therapeutic Area
Neuroscience
CNS Penetrant
Yes
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Jeppsson F., et al. (2012).
Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem. 2012;287(49):41245-41257. doi:10.1074/jbc.M112.409110.