P2X receptor antagonists and their potential as therapeutics: a patent review (2010–2021)

ABSTRACT

Introduction

Purinergic receptors play a critical role in neurotransmission, and modulation of complex physiological functions and thus have implications in numerous disease states. The past decade has seen substantial progress in the design of novel chemical compounds that act on the P2X class of receptors and warrants an updated review of this field.

Areas covered

This review provides a summary of the patent literature describing the discovery and clinical uses of P2X receptor antagonists published between 2010 and September 2021. The reader will gain information on structural claims, representative structures, and biological data of recently reported P2X antagonists.

Expert opinion

Despite continual advancement in both crystallography and chemical biology strengthening our understanding of purinergic signalling, there remains an absence of clinically approved chemotypes. A testament to both the therapeutic potential and academic perseverance in purinergic research is the multitude of research initiatives that maintain active P2X receptor programs that have spanned decades. Very recently, the FDA declined Merck Pharmaceuticals application for Gefapixant, a P2X3 selective inhibitor as a treatment for chronic cough, requesting additional data. This unfortunate setback will ultimately be insignificant considering the long history of P2X investigation and the preclinical and clinical development that will undoubtedly occur over the next decade.

KEYWORDS:

• Drug discovery
• inhibitors
• P2X antagonists
• purinergic
• therapeutic applications

Article highlights

• An overview of the function of purinergic receptors within pathological states is provided.

• P2X antagonists have been preclinically validated in numerous disease models.

• A summary of the patent literature describing the discovery and clinical development of P2X receptor antagonists from 2010 to September 2021, is provided.

• Our evaluation of this area indicates that despite our increased understanding of purinergic signalling and their roles in pathophysiology, there is still a notable lack of clinically approved chemical modalities.

• Further elucidation of the human crystal structures of each purinergic receptor would be largely beneficial for advancement in this area.

• Selectivity data of antagonists against the other P2X subtypes is notably lacking in patent literature and may hinder clinical development.

This box summarises key points contained in this article.

Author’s contributions

C Dane: manuscript preparation, collection of data and preparation of figures and tables.

L Stokes: manuscript preparation and revision. W Jorgensen: manuscript preparation and revision.

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

WT Jorgensen is recipient of a National Health and Medical Research Council Peter Doherty Fellowship (APP1157404).