Developments with multi-target drugs for Alzheimer’s disease: an overview of the current discovery approaches

ABSTRACT

Introduction: Alzheimer’s disease (AD), the most common type of dementia among older adults, is a chronic neurodegenerative pathology that causes a progressive loss of cognitive functioning with a decline of rational skills. It is well known that AD is multifactorial, so there are many different pharmacological targets that can be pursued.

Areas covered: The authors highlight the strategic value of privileged scaffolds in a multi-target lead compound generation against AD, exploring the concept of multi-target design, with a special emphasis on hybrid compounds. Hence, the most promising building blocks for designing and synthesizing hybrid anti-AD drugs are shown, while also presenting the more advanced hybrid compounds.

Expert opinion: The available therapeutic arsenal for AD, designed under the traditional paradigm of ‘one-drug/one target/one-disease’, is based on the inhibition of brain acetylcholinesterase (AChE) to increase acetylcholine (ACh) levels. However, this classical approach has not been sufficiently effective when used to treat any multifactor-depending pathology (cancer, diabetes or AD). The multi-target drug concept has been quickly adopted by medicinal chemists. The basic research developments reported in recent years are a solid foundation that will pave the way for the construction of future AD therapeutics.

KEYWORDS:

• Alzheimer’s disease
• current hypotheses
• multi-target direct ligand
• privileged building blocks

Article Highlights

• The paradigm shift from one target to a multi-target drug is a promising approach to combat multifactorial Alzheimer´s disease (AD).

• Target identification and rational design are the cornerstones of the multi-target drug discovery project in AD.

• The knowledge around AD has led to the identification of a small number of structures, which can be considered as ‘privileged building blocks’ for the development of new hits in MTDL.

• A few hybrid compounds show promising features for the treatment of AD.

• Detection of AD at the pre-symptomatic stages is another aspect which requires much attention.

This box summarizes key points contained in the article.

Declaration of interest

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 apart from those disclosed.

Reviewer Disclosures

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

Additional information

Funding

The authors gratefully acknowledge the financial support of Ministerio de Ciencia, Innovación y Universidades (MICINN) CTQ2017-86170. The Project PR26/16-16B has been funded by the Complutense University of Madrid (UCM), in cooperation with the Banco de Santander.