title: Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors.
abstract: VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species.
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA. Electronic address: Michael_Boyd@vrtx.com.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Boyd
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Upul K
authors.initials: UK
authors.lastname: Bandarage
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Hamilton
authors.initials: H
authors.lastname: Bennett
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Randal R
authors.initials: RR
authors.lastname: Byrn
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Ioana
authors.initials: I
authors.lastname: Davies
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Gu
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Jacobs
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Ledeboer
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Ledford
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Leeman
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Perola
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Tiansheng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Bennani
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clark
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D001372:Aza Compounds; D002264:Carboxylic Acids; D007211:Indoles; C502893:PB2 protein, influenza virus; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D014764:Viral Proteins; C000605010:pimodivir
keywords: Influenza; Isostere; VX-787