title: Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2.
abstract: In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Ave, Boston, Massachusetts 02210, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clark
authors.forename: Mark W
authors.initials: MW
authors.lastname: Ledeboer
authors.forename: Ioana
authors.initials: I
authors.lastname: Davies
authors.forename: Randal A
authors.initials: RA
authors.lastname: Byrn
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jones
authors.forename: Emanuele
authors.initials: E
authors.lastname: Perola
authors.forename: Alice
authors.initials: A
authors.lastname: Tsai
authors.forename: Marc
authors.initials: M
authors.lastname: Jacobs
authors.forename: Kwame
authors.initials: K
authors.lastname: Nti-Addae
authors.forename: Upul K
authors.initials: UK
authors.lastname: Bandarage
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Boyd
authors.forename: Randy S
authors.initials: RS
authors.lastname: Bethiel
authors.forename: John J
authors.initials: JJ
authors.lastname: Court
authors.forename: Hongbo
authors.initials: H
authors.lastname: Deng
authors.forename: John P
authors.initials: JP
authors.lastname: Duffy
authors.forename: Warren A
authors.initials: WA
authors.lastname: Dorsch
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Farmer
authors.forename: Huai
authors.initials: H
authors.lastname: Gao
authors.forename: Wenxin
authors.initials: W
authors.lastname: Gu
authors.forename: Katrina
authors.initials: K
authors.lastname: Jackson
authors.forename: Dylan H
authors.initials: DH
authors.lastname: Jacobs
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Kennedy
authors.forename: Brian
authors.initials: B
authors.lastname: Ledford
authors.forename: Jianglin
authors.initials: J
authors.lastname: Liang
authors.forename: François
authors.initials: F
authors.lastname: Maltais
authors.forename: Mark
authors.initials: M
authors.lastname: Murcko
authors.forename: Tiansheng
authors.initials: T
authors.lastname: Wang
authors.forename: M Woods
authors.initials: MW
authors.lastname: Wannamaker
authors.forename: Hamilton B
authors.initials: HB
authors.lastname: Bennett
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Leeman
authors.forename: Colleen
authors.initials: C
authors.lastname: McNeil
authors.forename: William P
authors.initials: WP
authors.lastname: Taylor
authors.forename: Christine
authors.initials: C
authors.lastname: Memmott
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Rene
authors.initials: R
authors.lastname: Rijnbrand
authors.forename: Christopher
authors.initials: C
authors.lastname: Bral
authors.forename: Ursula
authors.initials: U
authors.lastname: Germann
authors.forename: Azin
authors.initials: A
authors.lastname: Nezami
authors.forename: Yuegang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Francesco G
authors.initials: FG
authors.lastname: Salituro
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001682:Biological Availability; D004285:Dogs; D024882:Drug Resistance, Viral; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009980:Influenza A virus / Q000187:drug effects / Q000502:physiology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D009976:Orthomyxoviridae Infections / Q000188:drug therapy; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001372:Aza Compounds; D007211:Indoles; C057027:PB2 protein, Influenzavirus A; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase