2. Academic Validation
  3. 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

  • J Med Chem. 2017 Mar 9;60(5):1648-1661. doi: 10.1021/acs.jmedchem.6b01594.
Dustin Siegel 1,  Hon C Hui 1,  Edward Doerffler 1,  Michael O Clarke 1,  Kwon Chun 1,  Lijun Zhang 1,  Sean Neville 1,  Ernest Carra 1,  Willard Lew 1,  Bruce Ross 1,  Queenie Wang 1,  Lydia Wolfe 1,  Robert Jordan 1,  Veronica Soloveva 2,  John Knox 1,  Jason Perry 1,  Michel Perron 1,  Kirsten M Stray 1,  Ona Barauskas 1,  Joy Y Feng 1,  Yili Xu 1,  Gary Lee 1,  Arnold L Rheingold 3,  Adrian S Ray 1,  Roy Bannister 1,  Robert Strickley 1,  Swami Swaminathan 1,  William A Lee 1,  Sina Bavari 2,  Tomas Cihlar 1,  Michael K Lo 4,  Travis K Warren 2,  Richard L Mackman 1
Affiliations

Affiliations

  • 1 Gilead Sciences, Inc. , Foster City, California 94404, United States.
  • 2 United States Army Medical Research Institute of Infectious Diseases (USAMRIID) , Frederick, Maryland 21702, United States.
  • 3 University of California-San Diego , San Diego, California 92093, United States.
  • 4 Centers for Disease Control and Prevention , Atlanta, Georgia 30333, United States.
PMID: 28124907 DOI: 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.

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