BACE1 Inhibitors Under Development for Alzheimer’s Disease

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the beta-secratase enzyme required for the production of beta-amyloid, the neurotoxic peptide implicated in Alzheimer’s disease (AD). The extracellular aggregation of amyloid beta represents one of the two pathognomonic features AD, the other being tau hyperphosphorylation. Others scientists, have speculated that beta-amyloid may be an epiphenomenon of AD, since beta amyloid burden does not always correlate with severity of cognitive deficits.

BACE1 is widely believed to play a crucial role in the etiological of AD, and the clinical development of BACE1 inhibitors is being vigorously pursued.

Since the discovery of Abeta and the amyloid processing protein (APP) mutations that resulted in familiar alzheimer’s disease (FAD), beta and gamma secratase inhibitors have emerged as prime candidates for the treatment of AD.

The endogenous substrates of BACE1 are, like amyloid processing protein (APP), Type I membrane proteins.

BACE1 Inhibitors For The Treatment of AD

The first generation of BACE1 inhibitors consisted mostly of polypeptides which bound BACE1 with high affinity. It was soon recognized that these peptides possessed unfavorable pharmacokinetic and pharmacodynamic features, such as poor oral bioavailability, excessively long serum half-life, and poor CNS penetration. More recently, potent third-generation small molecule BACE1 inhibitors have been developed that possess acceptable blood brain barrier permeability and robust amyloid-beta reduction in experimental paradigms.

E2609 Eisai Woodcliff Lake, NJ Alzheimer’s disease Phase I completed
HPP854 Transtech Pharma High Point, NC Alzheimer’s disease Phase I
MK-8931 Merck Whitehouse Station, NJ Alzheimer’s disease Phase II/III


Vassar R. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res Ther. 2014;6(9):89.