P2X7 receptor antagonists: a patent review (2010–2015)

ABSTRACT

Introduction: The P2X7 receptor (P2X7R) is a unique subtype among the family of seven purinergic P2X receptors, which are ATP-gated non-selective cation channels. P2X7R has been reported to have pathological roles in various diseases, including autoimmune diseases such as arthritis and inflammatory bowel disease, neurodegenerative diseases, chronic pain, mood disorders and cancers. Therefore, many pharmaceutical companies have endeavored to develop a clinical candidate targeting P2X7R.

Areas covered: This review provides a summary of various patents on chemicals and biologics and their clinical use published between 2010 and 2015. The reader will gain information on structural claims, representative structures and biological activities of recently developed P2X7R antagonists.

Expert opinion: P2X7R is a fascinating therapeutic target and potential biomarker for inflammation, pain disorders and cancers. Research on the development of P2X7R antagonists has continually increased despite the failure of AstraZeneca and Merck’s compounds in phase II clinical trials. Various scaffolds have been disclosed by several pharmaceutical industries, and some compounds are currently under investigation in clinical trials.

KEYWORDS:

• Purinergic receptor
• P2X7 receptor
• IL-1β
• ion channel

Article highlights

• In the past six years, more than 70 patents claiming novel P2X7R antagonists have been filed. They are reported in this article.

• Many pharmaceutical companies have continually filed patents that explicitly claim P2X7R antagonists, including Glaxo, AstraZeneca, Roche, Janssen, Lundbeck, Renovis, and Abbott.

• These applications indicate that P2X7R antagonists have potential in the treatment of a broad spectrum of diseases, including chronic pain, neuroinflammation, and cancer but not rheumatoid arthritis.

• Janssen have developed JNJ-47965567, JNJ-42253432 and JNJ-54232334 as high affinity P2X7R antagonists for novel CNS drug. [³H] JNJ-54232334 is under study as a good radioligand tracer.

• The crystal structure of zP2X4R could be usefully applied in the design or discovery of new P2X7R ligands.

This box summarizes key points contained in the article.

Acknowledgments

American Journal Experts provided editorial assistance.

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.

Additional information

Funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2014R1A2A1A11052300) and by the GIST Research Institute (GRI) in 2016.