AZD3839 (free base)

AZD3839 is an orally available, selective, reversible inhibitor of the β-site amyloid precursor protein cleaving enzyme BACE1 that can cross the blood-brain barrier. AZD3839 inhibits recombinant human BACE1 with a K_i=26.1 nM. AZD3839 inhibits A40 production in SH-SY5Y cells with an IC₅₀ of 4.8 nM. AZD3839 binds to BACE1 and reduces the Aβ amyloid produced by the cleavage of amyloid precursor protein (APP) by BACE1 and γ-secretase. AZD3839 can be used in the field of Alzheimer's disease research^[1][2][3]. In Vitro:In the hBACE1 and hBACE2 time-resolved fluorescence resonance energy transfer (TR-FRET) experiment, AZD3839 free base can inhibit the cleavage of APP sequence by recombinant human BACE1 in a concentration-dependent manner and inhibit the activity of BACE2. The inhibitory effect on BACE1 is 14 times stronger than that on BACE2^[1].
AZD3839 free base can effectively reduce the levels of A40 or sAPP_β secreted by the corresponding cells or neurons in the SH-SY5Y sAPP_β release assay, SH-SY5Y A40 release assay, N2A A40 release assay, mouse primary neuron A40 release assay, and guinea pig primary neuron A40 release assay, and the IC₅₀ values in different cells are different. For example, the IC₅₀ for inhibiting A40 levels in SH-SY5Y cells is 4.8 nM, and that in mouse primary neurons is 50.9 nM^[1].
In Vivo:In the female C57BL/6 mouse model, the brain concentration of AZD3839 free base (80 μmol/kg, 160 μmol/kg; oral gavage; single dose) increases rapidly and reaches a peak at 0.5 h. The levels of Aβ40, Aβ42 and sAPP in the brain decreased in a dose- and time-dependent manner. The plasma Aβ40 level is also significantly reduced, and the high dose (160 μmol/kg) had a more significant effect and lasted longer^[1].
AZD3839 free base (100 μmol/kg; oral gavage; twice a day; 7 days) inhibits the level and accumulation of Aβ40 in the mouse brain and plasma in the female C57BL/6 mouse model^[1].
AZD3839 free base (100 μmol/kg, 200 μmol/kg; oral gavage; single dose) reduces the levels of Aβ40 and Aβ42 in plasma, brain and cerebrospinal fluid of guinea pigs in a concentration- and time-dependent manner in the male Dunkin-Hartley guinea pig model^[1].
AZD3839 free base (5.5 μmol/kg, 20 μmol/kg; intravenous injection; single dose) significantly reduces the levels of Aβ40, Aβ42 and sAPP in the cerebrospinal fluid of 3-5 year old female cynomolgus monkeys^[1].