Lanabecestat (AZD3293) is a highly permeable, orally active and blood-brain barrier penetrating BACE1 inhibitor (Ki: 0.4 nM).

Lanabecestat displays a very high target affinity and a markedly slow target off-rate. The off-rate of Lanabecestat has an estimated t1/2 of approximately 9?h. Lanabecestat 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).

In mice, guinea pigs, and dogs, Lanabecestat displays significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ.

Cells are incubated with different Lanabecestat concentrations for 5 to 16?h, and the release of sAβPPβ, Aβ1-40, Aβ1-42, or sAβPPα into the medium is analyzed using kits. Cytotoxic effect of Lanabecestat is evaluated in the cell plates using cell proliferation/cytotoxicity kit.

Female 7- to 14-week-old C57BL/6 mice (n=6 per treatment group and time point) receive a vehicle or Lanabecestat solution at 50, 100, or 200 μmol/kg (20, 41, or 82?mg/kg) as a single dose via oral gavage. Mice and guinea pigs are anesthetized 1.5, 2, 3, 4, 6, 8, 16, 24, or 48?h after the (last) administration of vehicle or drug and are then kept under isoflurane anesthesia. Cerebrospinal fluid (CSF) is aspirated from the cisterna magna, and plasma is isolated from blood collected by cardiac puncture into EDTA tubes. The animals are then sacrificed by decapitation, and the brains are dissected into hemispheres.

1383982-64-6

C26H28N4O

412.53

LY3314814;AZD3293

DMSO:100 mg/mL (242.41 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years