Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs.

Riqiang Yan

doi:10.1186/s40035-016-0061-5

Abstract

Alzheimer’s disease (AD) is the most common age-dependent neurodegenerative disease which impairs cognitive function and gradually causes patients to be unable to lead normal daily lives. While the etiology of AD remains an enigma, excessive accumulation of β-amyloid peptide (Aβ) is widely believed to induce pathological changes and cause dementia in brains of AD patients. BACE1 was discovered to initiate the cleavage of amyloid precursor protein (APP) at the β-secretase site. Only after this cleavage does γ-secretase further cleave the BACE1-cleaved C-terminal APP fragment to release Aβ. Hence, blocking BACE1 proteolytic activity will suppress Aβ generation. Due to the linkage of Aβ to the potential cause of AD, extensive discovery and development efforts have been directed towards potent BACE1 inhibitors for AD therapy. With the recent breakthrough in developing brain-penetrable BACE1 inhibitors, targeting amyloid deposition-mediated pathology for AD therapy has now become more practical. This review will summarize various strategies that have successfully led to the discovery of BACE1 drugs, such as MK8931, AZD-3293, JNJ-54861911, E2609 and CNP520. These drugs are currently in clinical trials and their updated states will be discussed. With the promise of reducing Aβ generation and deposition with no alarming safety concerns, the amyloid cascade hypothesis in AD therapy may finally become validated.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is the third leading cause of death in the elderly behind heart disease and cancer
The crystal structure of BACE1, first solved by the Jordan Tang laboratory, indicates that the proteolytic site of BACE1 is largely similar to most human aspartic proteases, it is more open and less hydrophobic [33]. These findings suggest potential cross-inhibition of BACE1 inhibitors, with other crucial aspartic proteases that are important to normal human functions, will need to be considered
Over the past decade, substantial research efforts have been directed toward understanding BACE1 as a critical target for AD therapy

Summary

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is the third leading cause of death in the elderly behind heart disease and cancer. These preclinical results were clearly encouraging and this compound became the first BACE1 inhibitor to pass a Phase I clinical trial in 2008.

Results

Conclusion