Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1- f ][triazin-4-amino] Adenine C -Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses

作者：Dustin S. Siegel, Hon C. Hui, Edward Doerffler, Michael O. Clarke, Kwon Soo Chun, Lijun Zhang, Sean Neville, Ernest Carra, Willard Lew, Bruce S. Ross, Queenie Wang, Lydia Wolfe, Robert Jordan, Veronica Soloveva, John R. Knox, Jason K. Perry, Michel Perron, Kirsten M. Stray, Ona Barauskas, Joy Y. Feng, Yili Xu, Gary Lee, Arnold L. Rheingold, Adrian S. Ray, Roy Bannister, Robert G. Strickley, S. Swaminathan, William A. Lee, Sina Bavari, Tomáš Cihlář, Michael K. Lo, Travis K. Warren, Richard L. Mackman · 发表于：Journal of Medicinal Chemistry · 年份：2017 · DOI：10.1021/acs.jmedchem.6b01594 · 被引用次数：670 · 研究领域：Viral Infections and Outbreaks Research、Hepatitis B Virus Studies、Virus-based gene therapy research

= 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the 1'-CN group and C-linked nucleobase were critical for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclinical efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3-14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals [ Nature 2016 , 531 , 381 - 385 ]. A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of 4b on viral shedding from sanctuary sites in EBOV survivors.