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
  • 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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