Discovery of aryl aminoquinazoline pyridones as potent, selective, and orally efficacious inhibitors of receptor tyrosine kinase c-Kit.
Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.
Hu
Essa
E
Department of Medicinal Chemistry, Amgen Inc, Thousand Oaks, CA 91320-1799, USA. ehu@amgen.com
Tasker
Andrew
A
White
Ryan D
RD
Kunz
Roxanne K
RK
Human
Jason
J
Chen
Ning
N
Bürli
Roland
R
Hungate
Randall
R
Novak
Perry
P
Itano
Andrea
A
Zhang
Xuxia
X
Yu
Violeta
V
Nguyen
Yen
Y
Tudor
Yanyan
Y
Plant
Matthew
M
Flynn
Shaun
S
Xu
Yang
Y
Meagher
Kristin L
KL
Whittington
Douglas A
DA
Ng
Gordon Y
GY
D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D006636:Histamine Release / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011799:Quinazolines; D019009:Proto-Oncogene Proteins c-kit