A patent review of butyrylcholinesterase inhibitors and reactivators 2010–2017

ABSTRACT

Introduction: Butyrylcholinesterase (BuChE) has obtained a renewed interest as therapeutic target in Alzheimer’s disease (AD), when changes in BuChE activity and expression along disease progression were highlighted as well as correlation between BuChE levels and cognitive function.

Areas covered: During the last eight years, fourteen patents on BuChE inhibitors (BuChEI) have been submitted. Only three of them relate to BuChE selective inhibitors, while four of them focus on multitarget inhibitors which address different key pathological factors other than BuChE. Two patents report on non-selective acetylcholinesterase (AChE)/BuChE inhibitors, while four patents deal with natural compounds and their derivatives. One patent relates to antitoxic agents to treat exposure to ChEI pesticides and nerve agents.

Expert opinion: Increasing evidence supports BuChE as a more beneficial target in moderate-to-severe forms of AD in comparison to the well-known AChE. However, hitting a single pathological target is likely not sufficient to halt the disease progression. Therefore, patented BuChE inhibitors with a multifunctional profile may open new therapeutic avenues, since the additional activities could reinforce the therapeutic effects. Unfortunately, in vivo studies are limited and key parameters, such as ADMET data, are missing. This lack of information makes difficult to forecast the development of patented BuChEIs into effective drug candidates.

KEYWORDS:

• Butyrylcholinesterase inhibitors
• acetylcholinesterase selectivity
• multitarget inhibitors
• natural compounds
• oxime reactivators

Article highlights

• Increasing evidence supports BuChE as more beneficial target in moderate-to-severe forms of AD in comparison to AChE. Animal studies have highlighted BuChE selective inhibitors may affect other hallmarks than the cholinergic system, e.g. amyloid production and aggregation.

• Fourteen patents embracing different BuChEI structures, inhibition mechanism, selectivity, origin (synthetic or natural) and therapeutic indications have been submitted in the last eight years. Thirteen out of fourteen patents claim application in the treatment of Alzheimer-type dementia.

• All patents include preliminary in vitro data to confirm claimed activities/selectivities while in vivo data are limited and generally refer to the assessment of the CNS activity using scopolamine-induced memory impairment.

• Among patented drugs, combination of BuChE inhibition with further activities towards other targets involved in AD progression may be more beneficial. Thus, patented multitarget BuChE inhibitors could deserve further studies in view of a development as drugs. The administration of selective BuChE reactivators as detoxification agents for terroristic attacks or accidental poisoning by ChE irreversible inhibitors is likely to be less efficient than administration of AChE selective or non-selective ChE oximes.

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

Additional information

Funding

This paper was not funded.