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
By D. Siegel, H. Hui, Edward M. Doerffler, M. Clarke, K. Chun, Lijun Zhang, Sean Neville, Ernest A. Carra, W. Lew, B. Ross and 23 more. Journal of Medicinal Chemistry, 2017
623 citations recorded by the source corpus.
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 [Nature2016, 531, 381−38526934220]. 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.
Subfields: Epidemiology, Genetics, Infectious Diseases
View Paper: https://www.semanticscholar.org/paper/7e4528a7703d4884e94176c53b14fafe32918424
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In Infectious Diseases
Citations in the corpus
- Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency (2020, background): “Ebola virus (EBOV))(5,8) and Paramyxoviridae (e.”
- The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus (2020, neutral): “RDV was originally developed for the treatment of Ebola virus disease (2).”
- Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase (2020, neutral): “RDV is a phosphoramidate prodrug of a 10-cyano-substituted adenosine nucleotide analog that shows broad-spectrum antiviral activity against several RNA viruses (Siegel et al., 2017).”