Butyrylcholinesterase inhibitors as potential anti-Alzheimer’s agents: an updated patent review (2018-present)

ABSTRACT

Introduction

Alzheimer’s disease (AD) constitutes one of the most devastating diseases, with an extraordinarily high increase expected for the next few years. Despite the numerous efforts so far, there is still no cure but just palliative treatments.

Areas covered

The main topic covered herein has been the development of butyrylcholinesterase (BuChE) inhibitors with the aim of increasing the levels of the neurotransmitter acetylcholine (ACh). Two main groups of compounds have been considered: multitarget and non-multitarget ligands, depending on whether the structural design is focused or not on other key targets and pathogenic factors of the disease. Seventeen patents regarding multitarget-directed ligands (MTDLs), twelve for non-multitarget derivatives, and three for miscellaneous use have been covered in the period 2018–2021.

Expert opinion

BuChE is an attractive target in the treatment of AD. It is the most prevalent cholinesterase within more advanced stages of the disease, so drugs inhibiting it would be suitable for the treatment of mid- to severe Alzheimer’s patients. Moreover, BuChE has been proved to be connected with some other key hallmarks of the disease, like amyloidogenesis; hybridization of a BuChE-targeting pharmacophore with other scaffolds designed for other therapeutic targets is quite a promising design for potential anti-Alzheimer’s drugs.

KEYWORDS:

• Alzheimer’s disease
• BuChE inhibitors
• multitarget agents

Article highlights

• An extensive description of AD targets has been included to show the complex and multifactorial nature of the disease.

• Thirty-two patents have been considered herein, divided into three main sections:

  • Multitarget ligands (17)

  • Selective BuChE inhibitors (12)

  • Miscellaneous uses (3)

• Structure-activity relationships have been described for the in vitro assays involving cholinesterases (ChE) of human and non-human origin.

• For multitarget ligands, the relevant Alzheimer’s targets and hallmarks described include the ROS level, amyloidogenesis, hyperphosphorylation of tau protein, cannabinoid receptor subtype 2 (CB₂R), histone deacetylases (HDACs), N-methyl-d-aspartic receptors (NMDAR), secretases, MAO, H3 receptors, and IDO1 (indoleamine 2,3-dioxygenase).

• Some in vivo experiments have been included: scopolamine-induced toxicity, monosodium glutamate (MSG) to reproduce behavioral disorders and brain lesions, Morris water maze test, passive avoidance task, and Barnes maze.

• Relevant BuChE inhibitors from natural origin have been included. Also, the semisynthesis of remarkable derivatives inspired by natural sources has also been reviewed.

• Description of transdermal compositions for donepezil and rivastigmine, together with the use of nano-sized vectors has also been incorporated.

Acknowledgments

The authors thank the Spanish Government for the Grant PID2020-116460RB-I00 funded by MCIN/AEI/10.13039/501100011033 and Junta de Andalucía (FQM-134) for financial support.

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 of this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the Spanish Ministerio de Ciencia e Innovacion (Grant PID2020-116460RB-I00) and Junta de Andalucia (FQM-134).