Discovery of a potent and selective c-Kit inhibitor for the treatment of inflammatory diseases.
A potent and selective c-Kit inhibitor 20 was identified through a structure-activity relationship study. In an in vivo mouse model of mast cell activation, 20 blocked the SCF-induced histamine release with an EC(50) of 26 nM.
Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. chenc@amgen.com
Ning
N
Chen
Roland W
RW
Bürli
Susana
S
Neira
Randall
R
Hungate
Dawei
D
Zhang
Violeta
V
Yu
Yen
Y
Nguyen
Yanyan
Y
Tudor
Matthew
M
Plant
Shaun
S
Flynn
Kristin L
KL
Meagher
Matthew R
MR
Lee
Xuxia
X
Zhang
Andrea
A
Itano
Michael
M
Schrag
Yang
Y
Xu
Gordon Y
GY
Ng
Essa
E
Hu
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006636:Histamine Release / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry*; D051381:Rats; D019089:Stem Cell Factor / Q000378:metabolism; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit