Structure鈥揂ctivity Relationships and Optimization of 3,5-Dichloropyridine Derivatives As Novel P2X7 Receptor Antagonists

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• 作者：Won-Gil Lee ; So-Deok Lee ; Joong-Heui Cho ; Younghwan Jung ; Jeong-hyun Kim ; Tran T. Hien ; Keon-Wook Kang ; Hyojin Ko ; Yong-Chul Kim
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 26, 2012
• 年：2012
• 卷：55
• 期：8
• 页码：3687-3698
• 全文大小：416K
• 年卷期：v.55,no.8(April 26, 2012)
• ISSN：1520-4804

文摘

Screening of a library of chemical compounds showed that the dichloropyridine-based analogue 9 was a novel P2X₇ receptor antagonist. To optimize its activity, we assessed the structure鈥揳ctivity relationships (SAR) of 9, focusing on the hydrazide linker, the dichloropyridine skeleton, and the hydrophobic acyl (R₂) group. We found that the hydrazide linker and the 3,5-disubstituted chlorides in the pyridine skeleton were critical for P2X₇ antagonistic activity and that the presence of hydrophobic polycycloalkyl groups at the R₂ position optimized antagonistic activity. In the EtBr uptake assay in hP2X₇-expressing HEK293 cells, the optimized antagonists, 51 and 52, had IC₅₀ values of 4.9 and 13 nM, respectively. The antagonistic effects of 51 and 52 were paralleled by their ability to inhibit the release of the pro-inflammatory cytokine, IL-1尾, by LPS/IFN-纬/BzATP stimulation of THP-1 cells (IC₅₀ = 1.3 and 9.2 nM, respectively). In addition, 52 strongly inhibited iNOS/COX-2 expression and NO production in THP-1 cells, further indicating that this compound blocks inflammatory signaling and suggesting that the dichloropyridine analogues may be useful in developing P2X₇ receptor targeted anti-inflammatory agents.