P2X7 receptor antagonists for the treatment of systemic inflammatory disorders.

P2X7 has continued to be a target of immense interest since it is implicated in several peripheral and central nervous system disorders that result from inflammation. This review primarily describes new P2X7 receptor antagonists that have been investigated and disclosed in patent applications or primary literature since 2015. While a crystal structure of the receptor to aid in the design of novel chemical structures remains elusive, many of the chemotypes that have been disclosed contain similarities, with an amide motif present in all series that have been explored to date. Several of the recent antagonists described are brain penetrant, and two compounds are currently in clinical trials for CNS indications. Additionally, brain penetrant PET ligands have been developed that aid in measuring target engagement and these ligands can potentially be used as biomarkers.