An investigation on linker modifications of cyanoguanidine-based P2X7 receptor antagonists

Taylor Garrett; Jayson Gilchrist; Andre McKenzie; Fayaz Ali Larik; Jonathan Danon; Eryn Werry; Michael Kassiou

doi:10.1002/cmdc.202400163

An investigation on linker modifications of cyanoguanidine-based P2X7 receptor antagonists

ChemMedChem. 2024 May 23:e202400163. doi: 10.1002/cmdc.202400163. Online ahead of print.

Authors

Taylor Garrett¹, Jayson Gilchrist¹, Andre McKenzie¹, Fayaz Ali Larik¹, Jonathan Danon¹, Eryn Werry¹, Michael Kassiou²

Affiliations

¹ University of Sydney, Chemistry, AUSTRALIA.
² University of Sydney, Sydney, 2006, Sydney, AUSTRALIA.

PMID: 38782733
DOI: 10.1002/cmdc.202400163

Abstract

Despite their acknowledged significance in the inflammatory signalling cascade across a range of disease states, P2X7R antagonists have not yet proven to be effective in clinical trials. In this study, we present findings on P2X7 receptor antagonists that are based on a core adamantyl-cyanoguanidine-quinoline lead. To investigate the specific features of the cyanoguanidine moiety that influence compound potency we carried out a structure-activity relationship (SAR) study. Compound potency was assessed using an in vitro dye-uptake assay measuring P2X7R pore formation. While none of the compounds displayed superior potency to the lead, we established key structural requirements for potent P2X7R antagonism. An additional SAR using different aryl groups was performed based on the promising activity displayed by the squaramide derivative.

Keywords: Inflammation; P2X7R antagonist; cyanoguanidine; squaramide; thiourea.