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

被引：504

作者：

Siegel, Dustin ^{[1
]}

Hui, Hon C. ^{[1
]}

Doerffler, Edward ^{[1
]}

Clarke, Michael O. ^{[1
]}

Chun, Kwon ^{[1
]}

Zhang, Lijun ^{[1
]}

Neville, Sean ^{[1
]}

Carra, Ernest ^{[1
]}

Lew, Willard ^{[1
]}

Ross, Bruce ^{[1
]}

Wang, Queenie ^{[1
]}

Wolfe, Lydia ^{[1
]}

Jordan, Robert ^{[1
]}

Soloveva, Veronica ^{[2
]}

Knox, John ^{[1
]}

Perry, Jason ^{[1
]}

Perron, Michel ^{[1
]}

Stray, Kirsten M. ^{[1
]}

Barauskas, Ona ^{[1
]}

Feng, Joy Y. ^{[1
]}

Xu, Yili ^{[1
]}

Lee, Gary ^{[1
]}

Rheingold, Arnold L. ^{[3
]}

Ray, Adrian S. ^{[1
]}

Bannister, Roy ^{[1
]}

Strickley, Robert ^{[1
]}

Swaminathan, Swami ^{[1
]}

Lee, William A. ^{[1
]}

Bavari, Sina ^{[1
,2
]}

Cihlar, Tomas ^{[1
]}

Lo, Michael K. ^{[4
]}

Warren, Travis K. ^{[2
]}

Mackman, Richard L. ^{[1
]}

机构：

[1] Inc, Gilead Sci, Foster City, CA 94404 USA

[2] United States Army Med Res Inst Infect Dis USAMR, Frederick, MD 21702 USA

[3] Univ Calif San Diego, San Diego, CA 92093 USA

[4] Centers Dis Control & Prevent, Atlanta, GA 30333 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 05期

关键词：

ANTIVIRAL ACTIVITY; MITOCHONDRIAL RNA; T-705; FAVIPIRAVIR; 4-AZA-7,9-DIDEAZAADENOSINE; TRANSMISSION; REPLICATION; POLYMERASE; INHIBITOR; INFECTION; EFFICACY;

D O I：

10.1021/acs.jmedchem.6b01594

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1648 / 1661

页数：14

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