SAR studies of 4-acyl-1,6-dialkylpiperazin-2-one arenavirus cell entry inhibitors
SAR studies of 4-acyl-1,6-dialkylpiperazin-2-one arenavirus cell entry inhibitors
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DOI：
10.1016/j.bmcl.2019.08.024
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发表时间：
2019-11-15
影响因子：
2.7
通讯作者：
McCormack, Ken
中科院分区：
文献类型：
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作者：
Plewe, Michael B.;Whitby, Landon R.;McCormack, Ken
旧世界(非洲)和新世界(南美洲)禽流感病毒与人类出血热有关。开发小分子疗法的努力已经产生了几个化学系列，包括4-酰基-1，6-二烷基哌嗪-2-酮。在这里，我们描述了对这种化学类型的广泛探索。在最初的第一阶段研究中，对R-1和R-4扫描文库进行了检测，以确定抗旧大陆(Lassa)病毒的有效取代基。在随后的第二阶段研究中，对R-6取代基和迭代的R-1、R-4和R-6取代基组合进行了评估，以获得具有改进的Lassa和New World(Machupo、Junin和Tacaribe)ARENA病毒抑制活性、体外人肝微粒体代谢稳定性和水溶解性的化合物。
Old World (Africa) and New World (South America) arenaviruses are associated with human hemorrhagic fevers. Efforts to develop small molecule therapeutics have yielded several chemical series including the 4-acyl-1,6-dialkylpiperazin-2-ones. Herein, we describe an extensive exploration of this chemotype. In initial Phase I studies, R-1 and R-4 scanning libraries were assayed to identify potent substituents against Old World (Lassa) virus. In subsequent Phase II studies, R-6 substituents and iterative R-1, R-4 and R-6 substituent combinations were evaluated to obtain compounds with improved Lassa and New World (Machupo, Junin, and Tacaribe) arenavirus inhibitory activity, in vitro human liver microsome metabolic stability and aqueous solubility.