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Structure–Activity Relationships and Optimization of 3,5-Dichloropyridine Derivatives As Novel P2X7 Receptor Antagonists
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2012-04-06 00:00:00 , DOI: 10.1021/jm2012326 Won-Gil Lee 1 , So-Deok Lee 1 , Joong-Heui Cho 1 , Younghwan Jung 1 , Jeong-hyun Kim 1 , Tran T. Hien 2 , Keon-Wook Kang 2 , Hyojin Ko 3 , Yong-Chul Kim 1, 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2012-04-06 00:00:00 , DOI: 10.1021/jm2012326 Won-Gil Lee 1 , So-Deok Lee 1 , Joong-Heui Cho 1 , Younghwan Jung 1 , Jeong-hyun Kim 1 , Tran T. Hien 2 , Keon-Wook Kang 2 , Hyojin Ko 3 , Yong-Chul Kim 1, 3
Affiliation
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–activity 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-1β, by LPS/IFN-γ/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.
中文翻译:
新型P2X 7受体拮抗剂3,5-二氯吡啶衍生物的结构-活性关系和优化
化合物库的筛选显示,基于二氯吡啶的类似物9是新型P2X 7受体拮抗剂。为了优化其活性,我们评估了9的结构-活性关系(SAR),重点是酰肼连接基,二氯吡啶骨架和疏水性酰基(R 2)基团。我们发现,酰肼连接基和吡啶骨架中的3,5-二取代的氯化物对于P2X 7拮抗活性至关重要,并且疏水多环烷基在R 2位置的存在优化了拮抗活性。在hP2X 7中的EtBr摄取测定中表达HEK293细胞的优化拮抗剂51和52的IC 50值分别为4.9和13 nM。51和52的拮抗作用与其通过TPS-1细胞的LPS /IFN-γ/ BzATP刺激抑制促炎性细胞因子IL-1β释放的能力平行(IC 50 = 1.3和9.2 nM,分别)。另外,有52种药物强烈抑制了THP-1细胞中iNOS / COX-2的表达和NO的产生,进一步表明该化合物阻断了炎症信号传导,并表明二氯吡啶类似物可用于开发靶向P2X 7受体的抗炎剂。
更新日期:2012-04-06
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
新型P2X 7受体拮抗剂3,5-二氯吡啶衍生物的结构-活性关系和优化
化合物库的筛选显示,基于二氯吡啶的类似物9是新型P2X 7受体拮抗剂。为了优化其活性,我们评估了9的结构-活性关系(SAR),重点是酰肼连接基,二氯吡啶骨架和疏水性酰基(R 2)基团。我们发现,酰肼连接基和吡啶骨架中的3,5-二取代的氯化物对于P2X 7拮抗活性至关重要,并且疏水多环烷基在R 2位置的存在优化了拮抗活性。在hP2X 7中的EtBr摄取测定中表达HEK293细胞的优化拮抗剂51和52的IC 50值分别为4.9和13 nM。51和52的拮抗作用与其通过TPS-1细胞的LPS /IFN-γ/ BzATP刺激抑制促炎性细胞因子IL-1β释放的能力平行(IC 50 = 1.3和9.2 nM,分别)。另外,有52种药物强烈抑制了THP-1细胞中iNOS / COX-2的表达和NO的产生,进一步表明该化合物阻断了炎症信号传导,并表明二氯吡啶类似物可用于开发靶向P2X 7受体的抗炎剂。