BACE is a type I integrated membrane protein that contains two D (T/S) G (T/S) motifs in its extracellular domain. Importantly, BACE1 starts the production of β-amyloid peptides which are associated with cognitive impairment caused by abnormal oligomerization and aggregation in Alzheimer’s disease (AD). The 501 amino acid sequences of BACE1 have the characteristic features of the eukaryotic aspartate protease of the pepsin family. Particularly, BACE1 gene knockout mice will not produce β-Amyloid protein, and there will be no Alzheimer’s disease related symptoms. Obviously, BACE1 and γ-secreting enzymes sequentially cleave to produce Aβ-40 and Aβ-42 Peptides. Aβ-42 generated by BACE1 is related to memory regulation, synaptic function, myelin repair, and AD. Interestingly, BACE1 also has “starch like decomposition” activity, which can decompose longer Aβ Peptide degradation to non-toxic Aβ34 intermediates. Additionally, BACE1 is a type I transmembrane aspartate protease, and its optimal activity requires an acidic environment in both endosomes and lysosomes. Now, we will introduce an orally active BACE1/2 inhibitor, Verubecestat.
Verubecestat is an Orally Active BACE1/2 Inhibitor for Alzheimer’s Disease Research.
Firstly, Verubecestat (MK-8931) is an orally active, high-affinity BACE1 and BACE2 inhibitor with Ki values of 2.2 nM and 0.38 nM. Meanwhile, Verubecestat effectively reduces Aβ40 and has the potential for Alzheimer’s Disease.
Secondly, Verubecestat has IC50s of 2.1 nM, 0.7 nM, 4.4 nM for Aβ1-40, Aβ1-42, sAPPβ in HEK293 APPSwe/Lon cells. Nonetheless, Verubecestat does not significantly inhibit human CYP isoforms 1A2, 2C9, 2C19, 2D6, and 3A4 (all IC50>40 μM).
Again, Verubecestat dose-dependently reduces CSF and cortex Aβ40 with ED50 values of 5 and 8 mg/kg, respectively. By the way, Verubecestat reduces profound, sustained of CSF Aβ40 levels and has peak effects on CSF Aβ lowering (72 and 81% reduction at 3 and 10 mg/kg, respectively) 12 h after dosing.
Finally, Verubecestat is an orally active BACE1/2 inhibitor for Alzheimer’s disease research.
References:
【Scott JD, et al. Med Chem. 2016 Dec 8;59(23):10435-10450.