Advances in prodrug design for Alzheimer’s disease: the state of the art

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. 

KEYWORDS:

• Alzheimer’s disease
• central nervous system
• prodrug
• polypharmacology

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

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

This work was supported by funding from French Agence Nationale de la Recherche (project DOWNALZ ANR-20-CE18-0036). The authors gratefully acknowledge support from the Conseil Régional de Normandie, as well as via the European Regional Development Fund (FEDER).