Loughran H Marie, Han Ziying, Wrobel Jay E, Decker Sarah E, Ruthel Gordon, Freedman Bruce D, Harty Ronald N, Reitz Allen B
Fox Chase Chemical Diversity Center, Inc, 3805 Old Easton Road, Doylestown, PA 18902, United States.
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
Bioorg Med Chem Lett. 2016 Aug 1;26(15):3429-35. doi: 10.1016/j.bmcl.2016.06.053. Epub 2016 Jun 23.
We prepared a series of quinoxalin-2-mercapto-acetyl-urea analogs and evaluated them for their ability to inhibit viral egress in our Marburg and Ebola VP40 VLP budding assays in HEK293T cells. We also evaluated selected compounds in our bimolecular complementation assay (BiMC) to detect and visualize a Marburg mVP40-Nedd4 interaction in live mammalian cells. Antiviral activity was assessed for selected compounds using a live recombinant vesicular stomatitis virus (VSV) (M40 virus) that expresses the EBOV VP40 PPxY L-domain. Finally selected compounds were evaluated in several ADME assays to have an early assessment of their drug properties. Our compounds had low nM potency in these assays (e.g., compounds 21, 24, 26, 39), and had good human liver microsome stability, as well as little or no inhibition of P450 3A4.
我们制备了一系列喹喔啉 - 2 - 巯基 - 乙酰 - 脲类似物，并在HEK293T细胞中进行的马尔堡和埃博拉病毒VP40病毒样颗粒出芽试验中评估了它们抑制病毒释放的能力。我们还在双分子互补试验（BiMC）中评估了选定的化合物，以检测和可视化活的哺乳动物细胞中马尔堡病毒mVP40与Nedd4的相互作用。使用表达埃博拉病毒VP40 PPxY L结构域的重组活水疱性口炎病毒（VSV）（M40病毒）对选定的化合物进行抗病毒活性评估。最后，在几种药物代谢及药物动力学（ADME）试验中对选定的化合物进行评估，以早期评估它们的药物特性。我们的化合物在这些试验中具有低纳摩尔效力（例如化合物21、24、26、39），并且具有良好的人肝微粒体稳定性，对P450 3A4的抑制作用很小或没有。
