Non-oxime inhibitors of B-Raf(V600E) kinase.
The development of inhibitors of B-Raf(V600E) serine-threonine kinase is described. Various head-groups were examined to optimize inhibitor activity and ADME properties. Several of the head-groups explored, including naphthol, phenol and hydroxyamidine, possessed good activity but had poor pharmacokinetic exposure in mice. Exposure was improved by incorporating more metabolically stable groups such as indazole and tricyclic pyrazole, while indazole could also be optimized for good cellular activity.
Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, USA.
Li
L
Ren
Steve
S
Wenglowsky
Greg
G
Miknis
Bryson
B
Rast
Alex J
AJ
Buckmelter
Robert J
RJ
Ely
Stephen
S
Schlachter
Ellen R
ER
Laird
Nikole
N
Randolph
Michele
M
Callejo
Matthew
M
Martinson
Sarah
S
Galbraith
Barbara J
BJ
Brandhuber
Guy
G
Vigers
Tony
T
Morales
Walter C
WC
Voegtli
Joseph
J
Lyssikatos
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D007191:Indazoles / Q000737:chemistry; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009154:Mutation; D010091:Oximes / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry; D013329:Structure-Activity Relationship
D007191:Indazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D048493:Proto-Oncogene Proteins B-raf