title: Discovery of Novel, Orally Bioavailable β-Amino Acid Azaindole Inhibitors of Influenza PB2.
abstract: In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic β-amino acid inhibitors, highlighted by compound4. Compound4showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound4offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Farmer
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clark
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Boyd
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Perola
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jones
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Alice
authors.initials: A
authors.lastname: Tsai
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Jacobs
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Upul K
authors.initials: UK
authors.lastname: Bandarage
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Ledeboer
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Tiansheng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Deng
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Ledford
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Gu
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Duffy
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Randy S
authors.initials: RS
authors.lastname: Bethiel
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Dean
authors.initials: D
authors.lastname: Shannon
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Randal A
authors.initials: RA
authors.lastname: Byrn
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Leeman
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Rene
authors.initials: R
authors.lastname: Rijnbrand
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Hamilton B
authors.initials: HB
authors.lastname: Bennett
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Colleen
authors.initials: C
authors.lastname: O'Brien
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Memmott
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Kwame
authors.initials: K
authors.lastname: Nti-Addae
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
keywords: PB2 inhibitor; azaindole; influenza