4-Phenyl-7-azaindoles as potent, selective and bioavailable IKK2 inhibitors demonstrating good in vivo efficacy.
The lead optimization of a series of potent azaindole IKK2 inhibitors is described. Optimization of the human whole blood activity and selectivity over IKK1 in parallel led to the discovery of 16, a potent and selective IKK2 inhibitor showing good efficacy in a rat model of neutrophil activation.
GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. john.2.liddle@gsk.com
John
J
Liddle
Paul
P
Bamborough
Michael D
MD
Barker
Sebastien
S
Campos
Chun-Wa
CW
Chung
Rick P C
RP
Cousins
Paul
P
Faulder
Michelle L
ML
Heathcote
Heather
H
Hobbs
Duncan S
DS
Holmes
Chris
C
Ioannou
Cesar
C
Ramirez-Molina
Mary A
MA
Morse
Ruth
R
Osborn
Jeremy J
JJ
Payne
John M
JM
Pritchard
William L
WL
Rumsey
Daniel T
DT
Tape
Giorgia
G
Vicentini
Caroline
C
Whitworth
Rick A
RA
Williamson
D000818:Animals; D001682:Biological Availability; D004195:Disease Models, Animal; D006207:Half-Life; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008168:Lung / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
C023422:7-azaindole dimer; D007211:Indoles; D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase