title: 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.
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.
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Dustin
authors.initials: D
authors.lastname: Siegel
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Hon C
authors.initials: HC
authors.lastname: Hui
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Doerffler
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Clarke
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Kwon
authors.initials: K
authors.lastname: Chun
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Sean
authors.initials: S
authors.lastname: Neville
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Ernest
authors.initials: E
authors.lastname: Carra
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Willard
authors.initials: W
authors.lastname: Lew
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Bruce
authors.initials: B
authors.lastname: Ross
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Queenie
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Lydia
authors.initials: L
authors.lastname: Wolfe
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases (USAMRIID) , Frederick, Maryland 21702, United States.
authors.forename: Veronica
authors.initials: V
authors.lastname: Soloveva
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: John
authors.initials: J
authors.lastname: Knox
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Perry
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Michel
authors.initials: M
authors.lastname: Perron
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Stray
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Ona
authors.initials: O
authors.lastname: Barauskas
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Joy Y
authors.initials: JY
authors.lastname: Feng
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Yili
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.affiliation: University of California-San Diego , San Diego, California 92093, United States.
authors.forename: Arnold L
authors.initials: AL
authors.lastname: Rheingold
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Roy
authors.initials: R
authors.lastname: Bannister
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Strickley
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Swami
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: William A
authors.initials: WA
authors.lastname: Lee
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases (USAMRIID) , Frederick, Maryland 21702, United States.
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.affiliation: Centers for Disease Control and Prevention , Atlanta, Georgia 30333, United States.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Lo
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases (USAMRIID) , Frederick, Maryland 21702, United States.
authors.forename: Travis K
authors.initials: TK
authors.lastname: Warren
authors.affiliation: Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Richard L
authors.identifier: 0000-0001-8861-7205
authors.initials: RL
authors.lastname: Mackman
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives; D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry; D000577:Amides / Q000737:chemistry*; D002460:Cell Line; D055808:Drug Discovery; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy*; D006801:Humans; D008826:Microbial Sensitivity Tests; D010756:Phosphoric Acids / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012265:Ribonucleotides / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014777:Virus Diseases / Q000188:drug therapy*
chemical_list: D000577:Amides; D010756:Phosphoric Acids; D011355:Prodrugs; D012265:Ribonucleotides; C000606551:remdesivir; D000249:Adenosine Monophosphate; C011067:phosphoramidic acid; D000409:Alanine