title: Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration.
abstract: Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-alpha from isolated human peripheral blood mononuclear cells with a pIC(50) of 11.1. GSK256066 also has a suitable profile for inhaled dosing.
authors: Immuno-Inflammation CEDD Medicinal Chemistry Dept, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK. michael.d.woodrow@gsk.com
authors: Michael D
authors: MD
authors: Woodrow
authors: Stuart P
authors: SP
authors: Ballantine
authors: Michael D
authors: MD
authors: Barker
authors: Beth J
authors: BJ
authors: Clarke
authors: John
authors: J
authors: Dawson
authors: Tony W
authors: TW
authors: Dean
authors: Christopher J
authors: CJ
authors: Delves
authors: Brian
authors: B
authors: Evans
authors: Sharon L
authors: SL
authors: Gough
authors: Steven B
authors: SB
authors: Guntrip
authors: Stuart
authors: S
authors: Holman
authors: Duncan S
authors: DS
authors: Holmes
authors: Michael
authors: M
authors: Kranz
authors: Mika K
authors: MK
authors: Lindvaal
authors: Fiona S
authors: FS
authors: Lucas
authors: Margarete
authors: M
authors: Neu
authors: Lisa E
authors: LE
authors: Ranshaw
authors: Yemisi E
authors: YE
authors: Solanke
authors: Don O
authors: DO
authors: Somers
authors: Peter
authors: P
authors: Ward
authors: Joanne O
authors: JO
authors: Wiseman
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4