title: Quinolines as a novel structural class of potent and selective PDE4 inhibitors: optimisation for oral administration.
abstract: Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, England.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lunniss
authors.forename: Anthony W J
authors.initials: AW
authors.lastname: Cooper
authors.forename: Colin D
authors.initials: CD
authors.lastname: Eldred
authors.forename: Michael
authors.initials: M
authors.lastname: Kranz
authors.forename: Mika
authors.initials: M
authors.lastname: Lindvall
authors.forename: Fiona S
authors.initials: FS
authors.lastname: Lucas
authors.forename: Margarete
authors.initials: M
authors.lastname: Neu
authors.forename: Alex G S
authors.initials: AG
authors.lastname: Preston
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Ranshaw
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Redgrave
authors.forename: J
authors.initials: J
authors.lastname: Ed Robinson
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Shipley
authors.forename: Yemisi E
authors.initials: YE
authors.lastname: Solanke
authors.forename: Don O
authors.initials: DO
authors.lastname: Somers
authors.forename: Joanne O
authors.initials: JO
authors.lastname: Wiseman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002417:Cattle; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D006801:Humans; D008297:Male; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000008:administration & dosage* / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4