Quinolines as a novel structural class of potent and selective PDE4 inhibitors: optimisation for oral administration.
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.
Lunniss
Christopher J
CJ
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, England.
Cooper
Anthony W J
AW
Eldred
Colin D
CD
Kranz
Michael
M
Lindvall
Mika
M
Lucas
Fiona S
FS
Neu
Margarete
M
Preston
Alex G S
AG
Ranshaw
Lisa E
LE
Redgrave
Alison J
AJ
Ed Robinson
J
J
Shipley
Tracy J
TJ
Solanke
Yemisi E
YE
Somers
Don O
DO
Wiseman
Joanne O
JO
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
D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4