In Vitro | In vitro activity: AZD3293 is a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. When the potency of AZD3293 with respect to secretion of Aβ40 and sAβPPβ is studied in a range of cellular models, the compound displays pM potency in primary neuron cultures from mice and guinea pigs and in SH-SY5Y cells over-expressing AβPP (IC50 = 610 pM, 310 pM, and 80 pM, respectively). AZD3293 is also tested in a panel of more than 350 in vitro radioligand binding and enzyme activity assays, covering a diverse range of receptors, ion channels, transporters, kinases, and enzymes, up to a concentration of 10μM of AZD3293. A few significant responses are observed, but these had at least a 1,000-fold selectivity against BACE1, thus indicating specificity to BACE1. The off-rate of AZD3293 has an estimated t1/2 of approximately 9 h.
Kinase Assay: Lanabecestat (formerly known as AZD3293 and LY3314814), is a novel potent, orally bioactive, highly permeable, brain-penetreable inhibitor of beta-secretase 1 cleaving enzyme (BACE) with a Ki of 0.4 nM. AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ.
Cell Assay: The cells [SH-SY5Y, SH-SY5Y overexpressing wild type AβPP, HEK293 cells overexpressing AβPP with the Swedish mutation (K595N/M596L), N2A cells, and primary cortical neurons isolated from fetal C57BL/6 mice (E16) or Dunkin-Hartley guinea pigs (E25-27)] are incubated with different AZD3293 concentrations for 5 to 16 h, and the release of sAβPPβ, Aβ1-40, Aβ1-42, or sAβPPα into the medium is analyzed using specific commercial ELISA or kits from Meso Scale Discovery. |
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In Vivo | In vivo in mice, guinea pigs, and dogs, AZD3293 displays significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ. In the dog PK study, the bioavailability of AZD3293 is determined to be 80% (F = 0.8). The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293. |
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