Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists

被引：31

作者：

O'Brien-Brown, James ^{[1
]}

Jackson, Alexander ^{[2
]}

Reekie, Tristan A. ^{[1
]}

Barron, Melissa L. ^{[3
]}

Werry, Eryn L. ^{[3
]}

Schiavini, Paolo ^{[1
]}

McDonnell, Michelle ^{[2
]}

Munoz, Lenka ^{[4
]}

Wilkinson, Shane ^{[1
]}

Noll, Benjamin ^{[5
]}

Wang, Shudong ^{[5
]}

Kassiou, Michael ^{[1
]}

机构：

[1] Univ Sydney, Sch Chem, Sydney, NSW 2006, Australia

[2] Univ Sydney, Sch Med Sci, Sydney, NSW 2006, Australia

[3] Univ Sydney, Fac Hlth Sci, Sydney, NSW 2006, Australia

[4] Univ Sydney, Charles Perkins Ctr, Sydney, NSW 2006, Australia

[5] Univ South Australia, Sch Pharm & Med Sci, Adelaide, SA 5001, Australia

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 130卷

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

P2X(7)R antagonist; P2X receptor; Adamantyl; Adamantane; Inflammation; Neurodegenerative; Alzheimer's; IL-1; beta; ATP; DIRECTED DRUG CARRIER; POORLY ABSORBED DRUG; FORCED SWIM TEST; RHEUMATOID-ARTHRITIS; 1-ADAMANTANE MOIETY; P2X7; ANTAGONISTS; KNOCKOUT MICE; DISEASE; ATP; INFLAMMASOME;

D O I：

10.1016/j.ejmech.2017.02.060

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Here we report adamantyl cyanoguanidine compounds based on hybrids of the adamantyl amide scaffold reported by AstraZeneca and cyanoguanidine scaffold reported by Abbott Laboratories. Compound 27 displayed five-fold greater inhibitory potency than the lead compound 2 in both pore-formation and interleukin-1 beta release assays, while 35-treated mice displayed an antidepressant phenotype in behavioral studies. This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2X(7)R antagonists. (C) 2017 Elsevier Masson SAS. All rights reserved.

引用

页码：433 / 439

页数：7

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