Therapeutic modulators of the serotonin 5-HT₄ receptor: a patent review (2014-present)

ABSTRACT

Introduction

Numerous chemotypes have been described over time in order to generate potent and selective 5-HT₄R ligands. Both agonists and antagonists have demonstrated their interest in several disease models. This culminates with the FDA approval of tegaserod and prucalopride in the recent years.

Areas covered

This review summarizes the patent applications from 2014 to present, dedicated to the use or the description of novel 5-HT₄R modulators. Several novel ligands and scaffolds have been industrially protected mainly in the field of central nervous system (CNS) pathologies as well as gastrointestinal disorders, including the combination with other drugs or for veterinary uses.

Expert opinion

The therapeutic potential of 5-HT₄R modulators has been explored for several years in animal models, but also linked to potential safety issues with initial ligands. The current use of prucalopride in humans demonstrates that its toxicity is not linked to the target and that 5-HT₄R modulators are safe in humans. Therefore, an important number of studies and patents has continued in the recent years to expand the use of 5-HT₄R modulators, not only to treat gastrointestinal disorders, but also for CNS pathologies. This article details current efforts in this development.

KEYWORDS:

• Serotonin
• 5-HT₄ receptor
• central nervous system
• Alzheimer
• depression
• gastrointestinal disorders

Article highlights

• The interest of 5-HT₄R modulators have been explored in several pathologies and approved by the FDA.

• The progress in the development of 5-HT₄R modulators patented between 2014 and 2019 is reviewed.

• The exploration of multiple chemical scaffolds has led to the discovery of several potent and selective 5-HT₄R modulators.

• Several 5-HT₄R modulators are currently being evaluated in clinical trials.

• The potential therapeutic interest of 5-HT₄R modulators in combination with other drugs could lead to synergistic combined therapies.

This box summarizes key points contained in the article.

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

Additional information

Funding

This work was supported by funding from Normandie Valorisation; the French Agence Nationale de la Recherche [project MALAD ANR-12-JS007-0012-01, project ADAMGUARD ANR-12-BSV4-008-01]; the Fondation Plan Alzheimer [AAP2015 Project TRIAD 016]. The authors gratefully acknowledge the Conseil Régional de Normandie, as well as the European Community (FEDER).