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
Top Cited Papers
- 26 January 2017
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 60 (5), 1648-1661
- https://doi.org/10.1021/acs.jmedchem.6b01594
Abstract
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 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.Keywords
Funding Information
- Centers for Disease Control and Prevention
- Defense Threat Reduction Agency (CB10218)
This publication has 33 references indexed in Scilit:
- Ebola Virus Shedding and Transmission: Review of Current EvidenceThe Journal of Infectious Diseases, 2016
- The lipid moiety of brincidofovir is required for in vitro antiviral activity against Ebola virusAntiviral Research, 2016
- Molecular Evidence of Sexual Transmission of Ebola VirusThe New England Journal of Medicine, 2015
- Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primatesNature, 2015
- Ebola and Marburg haemorrhagic feverJournal of Clinical Virology, 2015
- Reversion of advanced Ebola virus disease in nonhuman primates with ZMappNature, 2014
- Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal modelAntiviral Research, 2014
- Post-exposure efficacy of Oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse modelAntiviral Research, 2014
- Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430Nature, 2014
- Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus InfectionsViruses, 2012