Small-molecule BACE1 inhibitors: a patent literature review (2011 to 2020)

ABSTRACT

Introduction

Inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) has been extensively pursued as potential disease-modifying treatment for Alzheimer’s disease (AD). Clinical failures with BACE inhibitors have progressively raised the bar forever cleaner candidates with reduced cardiovascular liability, toxicity risk, and increased selectivity over cathepsin D (CatD) and BACE2.

Areas covered

This review provides an overview of patented BACE1 inhibitors between 2011 and 2020 per pharmaceutical company or research group and highlights the progress that was made in dialing out toxicity liabilities.

Expert opinion

Despite an increasingly crowded IP situation, significant progress was made using highly complex chemistry in avoiding toxicity liabilities, with BACE1/BACE2 selectivity being the most remarkable achievement. However, clinical trial data suggest on-target toxicity is likely a contributing factor, which implies the only potential future of BACE1 inhibitors lies in careful titration of highly selective compounds in early populations where the amyloid burden is still minimal as prophylactic therapy, or as an affordable oral maintenance therapy following amyloid-clearing therapies.

KEYWORDS:

• Alzheimer’s
• BACE1, BACE2
• β-secretase
• amyloid
• neurodegenerative diseases

Article highlights

• Challenges for BACE1 inhibitors, notably achieving central penetration and avoiding toxicity, been progressively overcome in the past 10 years.

• The most recent progress was made in getting high BACE1/BACE2 selectivity, which further reduces the toxicity risk.

• The BACE1 field has been marked by a succession of clinical failures, and no clinical program remains active to date.

• Further elucidation of the role of BACE1 and BACE2 in brain and identifying biomarkers for undesired side effects of BACE inhibitors will be key in determining whether a therapeutic index can be found.

• If there remains a future for targeting amyloid beta production with BACE1 inhibitors, it will likely be for a BACE1 selective inhibitor titrated carefully in a preclinical population.

This box summarizes the key points contained in the article.

Declaration of interest

F Rombouts, CC Hsiao and HJM Gijsen are employees of Janssen Pharmaceutica N. V; KI Kusakabe is an employee of Shionogi & Co., Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are an employee of Novartis Pharma AG. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.