ABSTRACT
Introduction
Alzheimer’s disease (AD) is a complex and multifactorial neurodegenerative disease that remains today a challenge for drug discovery. Like many pathologies of the central nervous system, one of the first hurdle is the development of a compound with a sufficient brain exposure to ensure a potential therapeutic benefit. In this direction, the development of prodrugs has been an intense field of research in the last years.
Areas covered
Two main strategies of prodrugs development are analyzed in this review. First, the application of the classical modulation of an active compound to incorporate a promoiety has been exemplified in the field of AD. In a second chapter, a series of innovative prodrugs based on a polypharmacological approach is described to take into account the complexity of AD.
Expert opinion
In the past 10 years, prodrugs have been approved by the FDA for the treatment of CNS pathologies. Most of them have been developed in order to improve membrane permeability of the parent drugs. Facing the limitation of AD drug discovery, the development of prodrugs will likely play a central role in the next years with the rise of innovative pleiotropic prodrugs.
Article highlights
The interest of prodrugs in the context of Alzheimer’s disease has been studied
Prodrugs possessing promoiety and bioprecursors could increase the central distribution of neuroprotective agents
Prodrug strategy has been used to limit peripheral toxicity of Alzheimer’s disease drugs
Several prodrugs are currently evaluated in clinical trials for the treatment of Alzheimer’s disease
Mutual prodrugs and pleiotropic prodrugs could tackle the multifactorial origin of Alzheimer’s disease
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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.