Acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease – a patent review (2016–present)

ABSTRACT

Introduction – AD, the most common form of dementia, has a multifactorial etiology, and the current therapy (AChEIs and memantine) is unable to interrupt its progress and fatal outcome. This is reflected in the research programs that are oriented toward the development of new therapeutics able to operate on multiple targets involved in the disease progression.

Areas covered – The patents from 2016 to present regarding the use of AChEIs in AD, concerns the development of new AChEIs, multitarget or multifunctional ligands, or the associations of currently used AChEIs with other compounds acting on different targets involved in the AD.

Expert opinion – The development of new multitarget AChEIs promises to identify compounds with great therapeutic potential but requires more time and effort in order to obtain drugs with the optimal pharmacodynamic profile. Otherwise, the research on new combinations of existing drugs, with known pharmacodynamic and ADME profile, could shorten the time and reduce the costs to develop a new therapeutic treatment for AD. From the analyzed data, it seems more likely that a response to the urgent need to develop effective treatments for AD therapy could come more quickly from studies on drug combinations than from the development of new AChEIs.

KEYWORDS:

• Acetylcholinesterase inhibitors
• alzheimer’s disease
• drug combinations
• learning and memory test
• multifunctional ligands
• multitarget directed ligands

Article highlights

• Alzheimer’s disease (AD) has a multifactorial etiology that requires drugs able to act on multiple targets and processes.

• The 2016-2020 patents report acetylcholinesterase inhibitors (AChEIs) for potential use in the treatment of AD and concern new AChEIs or combinations of currently used AChEIs and other drugs or bioactive compounds.

• Some MTDL AChEIs interfere with amyloid deposition (inhibition of BACE1 or Aβ aggregation) or act on Tau aggregation (inhibition of GSK-3β).

• Some MTDL AChEIs derivatives act on the second neurotransmission, such as MAO-B inhibitors or 5-HT₄ receptor agonists.

• Some associations are designed to ameliorate cognitive deficit associated with AD (M₁ PAMs, H₃R inverse agonists, H₃R antagonists, 5-HT₆ antagonists, 5-HT₄ agonists).

• Some associations are designed to ameliorate noncholinergic symptoms of AD, such as depression, insomnia, apathy (SSRIs, modafinil, 5-HT₆ antagonists).

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no 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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by Sapienza funding (RP11916B6ECA91C1).