Available online 16 June 2022, 108228

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.

P2X7R

P2X7R antagonist

Inflammation

Coronary Artery Disease

Clinical translation

Drug discovery

reactive oxygen species

colchicine cardiovascular outcome trial

cardiovascular disease

major adverse cardiovascular event

cardiovascular outcome trial

coronary artery disease

high-sensitivity C-reactive protein

low-dose colchicine

adenosine triphosphate

damage-associated molecular patterns, GSDMD, gasdermin-d

central nervous system

vascular cell adhesion molecule-1

intercellular adhesion molecule-1

oxygenised low-density lipoprotein

nuclear factor kappa-light chain enhancer of activated B cells

small interfering RNA

2(3)-O-(4-Benzylbenzoyl) adenosine 5’-triphosphate

pattern recognition receptors

heart failure with preserved ejection fraction

heart failure with reduced ejection fraction

matrix metalloproteinase 9

tumour necrosis factor

vascular smooth muscle cells

ST-elevation myocardial infarction

extracellular matrix metalloproteinase inducer

positron emission tomography

pyridoxalphosphate-6-azophenyl-2’,4’-disulfonic acid.

© 2022 Published by Elsevier Inc.