Lanabecestat

Research use only, not for human use.

Lanabecestat (AZD-3293, LY-3314814) is a potent, orally active and brain-permeable BACE1 inhibitor with Ki of 0.4 nM.

Lanabecestat (AZD-3293, LY-3314814) is a potent, orally active and brain-permeable BACE1 inhibitor with Ki of 0.4 nM; shows equipotency against hBACE2 (Ki=0.8 nM), >25,000- and >41,000-fold selectivity against cathepsin D and γ-secretase; significantly reduces Aβ40, Aβ42, and sAβPPβ in mouse, guinea pig and dog, also shows in vitro potency in mouse and guinea pig primary cortical neuronal cells (IC50<1 nM); reduces cerebrospinal fluid (CSF) Aβ1-40 and Aβ1-42 in clinical trails.Alzheimer's Disease Phase 3 Clinical.

Lanabecestat acts as a full inhibitor of BACE1 in vitro, with a competitive and reversible mechanism of action towards the hBACE1 active site. 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). The in vitro plasma protein binding of lanabecestat is determined by equilibrium dialysis using mouse, rat, guinea pig, dog, and human plasma. The compound is stable in the plasma of these species for at least the duration of the in vitro incubation period. The unbound fractions are 1.3% to 1.8% for mice, 4.2% to 5.9% for rats, 8.3% to 10.3% for guinea pigs, 9.4% to 10.3% for dogs, and 7.7% to 9.4% for human plasma. The mean blood:plasma ratio of 0.7 in human blood indicates no significant association with red blood cells. The free fraction in the brain tissue binding assay is 4.5%.

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.

AZD-3293 | LY-3314814 | LY3314814 | AZD3293

Metabolic Enzyme/Protease

BACE

BACE

Neurological Disease

Alzheimer Disease

1383982-64-6

412.537

C26H28N4O

>98% (HPLC)

10 mM in DMSO

CC#CC1=CC(=CN=C1)C2=CC3=C(CC4(C35N=C(C(=N5)N)C)CCC(CC4)OC)C=C2

(1r,4r)-4-methoxy-5''-methyl-6'-(5-(prop-1-yn-1-yl)pyridin-3-yl)-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amine

(-20℃)

With Ice Pack

≥ 2 years