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
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
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DOI：
10.1021/acs.jmedchem.6b01594
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发表时间：
2017-03-09
影响因子：
7.3
通讯作者：
Mackman, Richard L.
中科院分区：
文献类型：
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作者：
Siegel, Dustin;Hui, Hon C.;Mackman, Richard L.
最近在西非爆发的埃博拉病毒（EBOV）是有史以来最大的一次，有超过28，000例病例，导致超过11，000人死亡，其中包括超过500名医护人员。一项集中的筛选和先导优化工作将巨噬细胞中抗EBOV EC 50 = 86 nM的4 b（GS-5734）确定为临床候选药物。结构活性关系确定了1 '-CN基团和C-连接的核碱基对于最佳抗EBOV效力和对宿主聚合酶的选择性是关键的。稳健的非对映选择性合成提供了足够量的4 b，以在非人灵长类EBOV攻击模型中实现临床前功效。在感染后第3-14天每天一次10 mg/kg iv给药对病毒血症和死亡率具有显著影响，导致感染给药动物的存活率为100%[Nature 2016，531，381-385]。一项2期研究（PREVAIL IV）目前正在招募，并将评估4 b对EBOV幸存者从避难所网站病毒脱落的影响。
The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC50 = 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the l'-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.