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J Med Chem. 2016 Aug 25;59(16):7410-30. doi: 10.1021/acs.jmedchem.5b01690. Epub 2016 Aug 9.

Potent Suppressive Effects of 1-Piperidinylimidazole Based Novel P2X7 Receptor Antagonists on Cancer Cell Migration and Invasion.

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School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea.
Department of Pharmaceutical Industry, Korea Health Industry Development Institute (KHIDI) , Chungcheongbuk-do 363-700, Republic of Korea.
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
Department of Medical System Engineering, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea.


The P2X7 receptor (P2X7R) has been reported as a key mediator in inflammatory processes and cancer invasion/metastasis. In this study, we report the discovery of novel P2X7R antagonists and their functional activities as potential antimetastatic agents. Modifications of the hydantoin core-skeleton and the side chain substituents of the P2X7R antagonist 7 were performed. The structure-activity relationships (SAR) and optimization demonstrated the importance of the sulfonyl group at the R1 position and the substituted position and overall size of R2 for P2X7R antagonism. The optimized novel analogues displayed potent P2X7 receptor antagonism (IC50 = 0.11-112 nM) along with significant suppressive effects on IL-1β release (IC50 = 0.32-210 nM). Moreover, representative antagonists (12g, 13k, and 17d) with imidazole and uracil core skeletons significantly inhibited the invasion of MDA-MB-231 triple negative breast cancer cells and cancer cell migration in a zebrafish xenograft model, suggesting the potential therapeutic application of these novel P2X7 antagonists to block metastatic cancer.

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