Update on novel purinergic P2X3 and P2X2/3 receptor antagonists and their potential therapeutic applications

ABSTRACT

Introduction: Purinergic P2X3-P2X2/3 receptors are placed in nociceptive neurons’ strategic location and show unique desensitization properties; hence, they represent an attractive target for many pain-related diseases. Therefore, a broad interest from academic and pharmaceutical scientists has focused on the search for P2X3 and P2X2/3 receptor ligands and has led to the discovery of numerous new selective antagonists. Some of them have been studied in clinical trials for the treatment of pathological conditions such as bladder disorders, gastrointestinal and chronic obstructive pulmonary diseases.

Areas covered: This review provides a summary of the patents concerning the discovery of P2X3 and/or P2X2/3 receptor antagonists published between 2015 and 2019 and their potential clinical use. Thus, the structures and biological data of the most representative molecules are reported.

Expert opinion: The 2016 publication of the crystallographic structure of the human P2X3 receptor subtype gave an improvement of published patents in 2017. Hence, a great number of small molecules with dual antagonist activity on P2X3-P2X2/3 receptors, a favorable pharmacokinetic profile, and reasonable oral bioavailability was discovered. The most promising compounds are the phenoxy-diaminopyrimidines including gefapixant (AF-219), and the imidazo-pyridines like BLU-5937, which are in phase III and phase II clinical trials, respectively, for refractory chronic cough.

KEYWORDS:

• P2X3 and P2X2/3 receptors
• P2X3 receptor antagonists
• patents on P2X3 receptor antagonists
• AF-219

Article highlights

• P2X3 and P2X2/3 receptor antagonists are a promising target to treat many pathological conditions like refractory chronic cough and pain.

• The discovery of new classes of molecules able of antagonize these receptors are able to reduce cough and avoid central nervous system side effects such as sedation, characteristic of many current antitussive drugs.

• A new class of potential antitussive drugs, the P2X3R selective antagonists imidazo-pyridines, has the advantage of not altering the taste function, a typical side effect of P2X3 and P2X2/3 receptor unselective antagonists.

• The use of P2X3R selective antagonists could represent an excellent strategy in pain management reducing the probability of adverse effects in brain, gastrointestinal, or cardiovascular tissues, effects that remain deterring aspects for many current pain drugs.

This box summarizes key points contained in the article.

Author contributions

G Marucci: manuscript preparation. D Dal Ben: collection of the data. M Buccioni: collection of the data. A Martí Navia: preparation of figures and tables. A Spinaci: preparation of figures and tables. R Volpini: manuscript preparation and revision. C Lambertucci contributed to the English language 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

This work was supported by Fondo di Ricerca di Ateneo [FAR FPI00004, University of Camerino].