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Modification and Functionalization of the Guanidine Group by Tailor-made Precursors
Published on: April 27, 2017
An Investigation on Linker Modifications of Cyanoguanidine-Based P2X7 Receptor Antagonists
Taylor R Garrett1, Jayson Gilchrist1, Andre D J McKenzie1
1School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
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.
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