May Barnaby C H, Zorn Julie A, Witkop Juanita, Sherrill John, Wallace Andrew C, Legname Giuseppe, Prusiner Stanley B, Cohen Fred E
Institute for Neurodegenerative Diseases, University of California-San Francisco, San Francisco, California 94158, USA.
J Med Chem. 2007 Jan 11;50(1):65-73. doi: 10.1021/jm061045z.
2-Aminopyridine-3,5-dicarbonitrile compounds were previously identified as mimetics of dominant-negative prion protein mutants and inhibit prion replication in cultured cells. Here, we report findings from a comprehensive structure-activity relationship study of the 6-aminopyridine-3,5-dicarbonitrile scaffold. We identify compounds with significantly improved bioactivity (approximately 40-fold) against replication of the infectious prion isoform (PrPSc) and suitable pharmacokinetic profiles to warrant evaluation in animal models of prion disease.
2-氨基吡啶-3,5-二腈化合物先前被鉴定为显性负性朊病毒蛋白突变体的模拟物，并能抑制培养细胞中的朊病毒复制。在此，我们报告了对6-氨基吡啶-3,5-二腈支架进行全面构效关系研究的结果。我们鉴定出了对感染性朊病毒异构体（PrPSc）复制具有显著提高的生物活性（约40倍）且具有合适药代动力学特征的化合物，值得在朊病毒病动物模型中进行评估。
