Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration.
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.
Woodrow
Michael D
MD
Immuno-Inflammation CEDD Medicinal Chemistry Dept, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK. michael.d.woodrow@gsk.com
Ballantine
Stuart P
SP
Barker
Michael D
MD
Clarke
Beth J
BJ
Dawson
John
J
Dean
Tony W
TW
Delves
Christopher J
CJ
Evans
Brian
B
Gough
Sharon L
SL
Guntrip
Steven B
SB
Holman
Stuart
S
Holmes
Duncan S
DS
Kranz
Michael
M
Lindvaal
Mika K
MK
Lucas
Fiona S
FS
Neu
Margarete
M
Ranshaw
Lisa E
LE
Solanke
Yemisi E
YE
Somers
Don O
DO
Ward
Peter
P
Wiseman
Joanne O
JO
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
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