Discovery of a potent, selective, and orally bioavailable c-Met inhibitor: 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458).
Deregulation of the receptor tyrosine kinase c-Met has been implicated in human cancers. Pyrazolones with N-1 bearing a pendent hydroxyalkyl side chain showed selective inhibition of c-Met over VEGFR2. However, studies revealed the generation of active, nonselective metabolites. Blocking this metabolic hot spot led to the discovery of 17 (AMG 458). When dosed orally, 17 significantly inhibited tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight.
Liu
Longbin
L
Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. lliu@amgen.com
Siegmund
Aaron
A
Xi
Ning
N
Kaplan-Lefko
Paula
P
Rex
Karen
K
Chen
April
A
Lin
Jasmine
J
Moriguchi
Jodi
J
Berry
Loren
L
Huang
Liyue
L
Teffera
Yohannes
Y
Yang
Yajing
Y
Zhang
Yihong
Y
Bellon
Steven F
SF
Lee
Matthew
M
Shimanovich
Roman
R
Bak
Annette
A
Dominguez
Celia
C
Norman
Mark H
MH
Harmange
Jean-Christophe
JC
Dussault
Isabelle
I
Kim
Tae-Seong
TS
D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
C530596:1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; D000631:Aminopyridines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D019859:Proto-Oncogene Proteins c-met