title: Discovery of an oral respiratory syncytial virus (RSV) fusion inhibitor (GS-5806) and clinical proof of concept in a human RSV challenge study.
abstract: GS-5806 is a novel, orally bioavailable RSV fusion inhibitor discovered following a lead optimization campaign on a screening hit. The oral absorption properties were optimized by converting to the pyrazolo[1,5-a]-pyrimidine heterocycle, while potency, metabolic, and physicochemical properties were optimized by introducing the para-chloro and aminopyrrolidine groups. A mean EC50 = 0.43 nM was found toward a panel of 75 RSV A and B clinical isolates and dose-dependent antiviral efficacy in the cotton rat model of RSV infection. Oral bioavailability in preclinical species ranged from 46 to 100%, with evidence of efficient penetration into lung tissue. In healthy human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a mean 4.2 log10 reduction in peak viral load and a significant reduction in disease severity compared to placebo. In conclusion, a potent, once daily, oral RSV fusion inhibitor with the potential to treat RSV infection in infants and adults is reported.
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Mackman
authors.forename: Michael
authors.initials: M
authors.lastname: Sangi
authors.forename: David
authors.initials: D
authors.lastname: Sperandio
authors.forename: Jay P
authors.initials: JP
authors.lastname: Parrish
authors.forename: Eugene
authors.initials: E
authors.lastname: Eisenberg
authors.forename: Michel
authors.initials: M
authors.lastname: Perron
authors.forename: Hon
authors.initials: H
authors.lastname: Hui
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.forename: Dustin
authors.initials: D
authors.lastname: Siegel
authors.forename: Hai
authors.initials: H
authors.lastname: Yang
authors.forename: Oliver
authors.initials: O
authors.lastname: Saunders
authors.forename: Constantine
authors.initials: C
authors.lastname: Boojamra
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: Dharmaraj
authors.initials: D
authors.lastname: Samuel
authors.forename: Kerim
authors.initials: K
authors.lastname: Babaoglu
authors.forename: Anne
authors.initials: A
authors.lastname: Carey
authors.forename: Brian E
authors.initials: BE
authors.lastname: Gilbert
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Piedra
authors.forename: Robert
authors.initials: R
authors.lastname: Strickley
authors.forename: Quynh
authors.initials: Q
authors.lastname: Iwata
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Hayes
authors.forename: Kirsten
authors.initials: K
authors.lastname: Stray
authors.forename: April
authors.initials: A
authors.lastname: Kinkade
authors.forename: Dorothy
authors.initials: D
authors.lastname: Theodore
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.forename: Manoj
authors.initials: M
authors.lastname: Desai
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007191:Indazoles; D008252:Macaca fascicularis; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control* / Q000821:virology*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D007191:Indazoles; D011720:Pyrazoles; D013449:Sulfonamides; C000591241:presatovir