AAlzheimer’s disease (AD)  is a neurodegenerative disease, characterized by progressive memory loss. In AD patients’ brain, the Aβ-containing plaques and tau-containing neurofibrillary tangles exhibit significant accumulation. Aβ is primarily generated by neurons, also by astrocytes and glial cells in some case. The first step of Aβ peptide production is BACE-1 cleavage of amyloid precursor protein. BACE-1, also known as the β-secretase enzyme, is a prime target to block the pathogenic amyloid cascade leading to AD.  Furthermore, This approach leads to the development of potent BACE-1 inhibitors which can reduce the accumulation of Aβ.

Elenbecestat (E2609) is a potent, orally active, and CNS-penetrant BACE-1 inhibitor.

Besides, it acts by interfering with the amyloid cascade upstream of Aβ peptide generation. Animal researches have shown that, this orally active drug can reduce cerebral Aβ levels.

In rats and guinea pigs, oral administration of Elenbecestat (0.3-30 mg/kg) showed a robust, dose-dependent decrease in levels of Aβx-40 and Aβx-42 in cerebrospinal fluid and brain. In cynomolgus monkeys, a single oral administration of Elenbecestat (0.3-30 mg/kg) could significantly reduce plasma Aβ1-40 and Aβ1-42 levels, with an estimated plasma IC₅₀ (unbound) of 1.3 nmol/L. It exhibited a moderate to high CNS penetration. In addition, Elenbecestat’s peak reduction of up to ~90% in CSF could sustain for 24 hours or more at effective doses.

In conclusion, Elenbecestat is a potent, orally active and CNS-penetrant BACE-1 inhibitor, reducing the accumulation of Aβ in the brain. Additionally, This inhibitor has the potential for alzheimer’s disease (AD) research

Reference:

[1] Kumar D, et al. Eur J Med Chem. 2018;148:436-452.

[2] Fukushima, T., et al. Alzheimer’s & Dementia, 8: P223-P224.

[3] Angelica Quartino, et al. Alzheimer’s & Dementia, 8: P224-P224