Development and clinical translation of P2X7 receptor antagonists: A potential therapeutic target in coronary artery disease?

Elijah Genetzakis; Jayson Gilchrist; Michael Kassiou; Gemma A Figtree

doi:10.1016/j.pharmthera.2022.108228

Development and clinical translation of P2X7 receptor antagonists: A potential therapeutic target in coronary artery disease?

Pharmacol Ther. 2022 Sep:237:108228. doi: 10.1016/j.pharmthera.2022.108228. Epub 2022 Jun 16.

Authors

Elijah Genetzakis¹, Jayson Gilchrist², Michael Kassiou², Gemma A Figtree³

Affiliations

¹ Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, Australia.
² The University of Sydney, School of Chemistry, Sydney, Australia.
³ Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, Australia; Department of Cardiology, Royal North Shore Hospital, Sydney, Australia. Electronic address: gemma.figtree@sydney.edu.au.

PMID: 35716953
DOI: 10.1016/j.pharmthera.2022.108228

Abstract

The purinoceptor 7 receptor (P2X₇R) plays an important role in promoting inflammation in response to accumulating damage-associated molecular patterns (DAMPs) released from stressed or apoptotic cells and has been connected to various pathological conditions. The initial investment by large pharmaceutical companies such as AstraZeneca and Pfizer led to the development of several classes of P2X₇R antagonists for the treatment of rheumatoid arthritis and Crohn's disease. While these compounds showed early promise as therapeutic agents and were found to potently inhibit adenosine triphosphate (ATP)-induced release of interleukin 1 beta (IL-1β) in patient-derived monocytes primed with lipopolysaccharide (LPS), they failed to elicit a therapeutic benefit in phase II clinical trials. Within the last 10 years, a wealth of strong preclinical and clinical evidence has implicated IL-1β as an aggressor in the development and progression of cardiovascular diseases, a cytokine modulated by the P2X₇R. On account of the immune-mediated events that regulate atherosclerosis, antagonism of the P2X₇R has been proposed as a therapeutic strategy due to the unique functionality of the receptor as an instigator of sterile inflammation. Here, we review the success and failures in P2X₇R drug development to evaluate the major barriers to successful clinical translation of P2X₇R antagonists. These avenues should be addressed by researchers and pharmaceutical companies to ensure future clinical success in the treatment of CAD.

Keywords: Clinical translation; Coronary Artery Disease; Drug discovery; Inflammation; P2X(7)R; P2X(7)R antagonist.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate
Coronary Artery Disease* / drug therapy
Humans
Inflammation / drug therapy
Lipopolysaccharides
Pharmaceutical Preparations
Purinergic P2X Receptor Antagonists* / pharmacology
Purinergic P2X Receptor Antagonists* / therapeutic use
Receptors, Purinergic P2X7 / therapeutic use

Substances

Lipopolysaccharides
Pharmaceutical Preparations
Purinergic P2X Receptor Antagonists
Receptors, Purinergic P2X7
Adenosine Triphosphate