Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California.
J Pharmacol Exp Ther. 2013 Nov;347(2):325-38. doi: 10.1124/jpet.113.205799. Epub 2013 Aug 21.
The only small-molecule compound demonstrated to substantially extend survival in prion-infected mice is a biaryl hydrazone termed "Compd B" (4-pyridinecarboxaldehyde,2-[4-(5-oxazolyl)phenyl]hydrazone). However, the hydrazone moiety of Compd B results in toxic metabolites, making it a poor candidate for further drug development. We developed a pharmacophore model based on diverse antiprion compounds identified by high-throughput screening; based on this model, we generated biaryl amide analogs of Compd B. Medicinal chemistry optimization led to multiple compounds with increased potency, increased brain concentrations, and greater metabolic stability, indicating that they could be promising candidates for antiprion therapy. Replacing the pyridyl ring of Compd B with a phenyl group containing an electron-donating substituent increased potency, while adding an aryl group to the oxazole moiety increased metabolic stability. To test the efficacy of Compd B, we applied bioluminescence imaging (BLI), which was previously shown to detect prion disease onset in live mice earlier than clinical signs. In our studies, Compd B showed good efficacy in two lines of transgenic mice infected with the mouse-adapted Rocky Mountain Laboratory (RML) strain of prions, but not in transgenic mice infected with human prions. The BLI system successfully predicted the efficacies in all cases long before extension in survival could be observed. Our studies suggest that this BLI system has good potential to be applied in future antiprion drug efficacy studies.
唯一被证明能显著延长朊病毒感染小鼠存活时间的小分子化合物是一种联苯腙，称为“化合物 B”（4-吡啶甲醛，2-[4-（5-恶唑基）苯基]腙）。然而，化合物 B 的腙部分会产生有毒代谢物，使其不太适合进一步开发药物。我们基于高通量筛选鉴定的多种抗朊病毒化合物开发了一个药效团模型；基于该模型，我们生成了化合物 B 的联苯酰胺类似物。药物化学优化导致多个化合物的效力、脑浓度和代谢稳定性增加，表明它们可能是抗朊病毒治疗的有前途的候选药物。用含供电子取代基的苯基取代化合物 B 的吡啶环增加了效力，而在恶唑部分添加芳基增加了代谢稳定性。为了测试化合物 B 的疗效，我们应用了生物发光成像（BLI），先前的研究表明，BLI 可以比临床症状更早地检测到活鼠中的朊病毒病发病。在我们的研究中，化合物 B 在感染了经过改造的 Rocky Mountain Laboratory（RML）株朊病毒的两种转基因小鼠中表现出良好的疗效，但在感染了人类朊病毒的转基因小鼠中则没有。BLI 系统成功地预测了所有情况下的疗效，远远早于观察到生存时间的延长。我们的研究表明，该 BLI 系统具有良好的潜力，可应用于未来的抗朊病毒药物疗效研究。
