新型N-芳基哌嗪类CXCR4拮抗剂的发现
Discovery of novel N-aryl piperazine CXCR4 antagonists.
作者信息
Zhao Huanyu, Prosser Anthony R, Liotta Dennis C, Wilson Lawrence J
机构信息
Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, GA 30329, United States.
Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, GA 30322, United States.
出版信息
Bioorg Med Chem Lett. 2015 Nov 1;25(21):4950-4955. doi: 10.1016/j.bmcl.2015.04.036. Epub 2015 Apr 17.
A novel series of CXCR4 antagonists with substituted piperazines as benzimidazole replacements is described. These compounds showed micromolar to nanomolar potency in CXCR4-mediated functional and HIV assays, namely inhibition of X4 HIV-1(IIIB) virus in MAGI-CCR5/CXCR4 cells and inhibition of SDF-1 induced calcium release in Chem-1 cells. Preliminary SAR investigations led to the identification of a series of N-aryl piperazines as the most potent compounds. Results show SAR that indicates type and position of the aromatic ring, as well as type of linker and stereochemistry are significant for activity. Profiling of several lead compounds showed that one (49b) reduced susceptibility towards CYP450 and hERG, and the best overall profile when considering both SDF-1 and HIV potencies (6-20 nM).
描述了一系列以取代哌嗪作为苯并咪唑替代物的新型CXCR4拮抗剂。这些化合物在CXCR4介导的功能和HIV检测中表现出微摩尔至纳摩尔的效力，即在MAGI-CCR5/CXCR4细胞中抑制X4 HIV-1(IIIB)病毒以及在Chem-1细胞中抑制SDF-1诱导的钙释放。初步的构效关系研究确定了一系列N-芳基哌嗪为最有效的化合物。结果显示的构效关系表明，芳环的类型和位置、连接基的类型以及立体化学对活性都很重要。对几种先导化合物的分析表明，其中一种（49b）对CYP450和hERG的敏感性降低，并且在同时考虑SDF-1和HIV效力（6 - 20 nM）时具有最佳的总体特征。
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