Discovery of 6-aryl-7-alkoxyisoquinoline inhibitors of IkappaB kinase-beta (IKK-beta).
The identification and progression of a potent and selective series of isoquinoline inhibitors of IkappaB kinase-beta (IKK-beta) are described. Hit-generation chemistry based on IKK-beta active-site knowledge yielded a weakly potent but tractable chemotype that was rapidly progressed into a series with robust enzyme and cellular activity and significant selectivity over IKK-alpha.
Christopher
John A
JA
GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK. john@christopher257.fsnet.co.uk
Bamborough
Paul
P
Alder
Catherine
C
Campbell
Amanda
A
Cutler
Geoffrey J
GJ
Down
Kenneth
K
Hamadi
Ahmed M
AM
Jolly
Adrian M
AM
Kerns
Jeffrey K
JK
Lucas
Fiona S
FS
Mellor
Geoffrey W
GW
Miller
David D
DD
Morse
Mary A
MA
Pancholi
Kiritkant D
KD
Rumsey
William
W
Solanke
Yemisi E
YE
Williamson
Rick
R
D055808:Drug Discovery; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase